ORIGINAL ARTICLES Warfarin-induced skin necrosis in HIV-1 ...

African Journals Online (AJOL)

F Bhaijee, H Wainwright, G Meintjes, R J Wilkinson, G Todd, E de Vries, D J Pepper. Warfarin-induced skin necrosis (WISN) is a rare complication of warfarin ..... first few days of warfarin therapy.2,11 Warfarin is a vitamin K antagonist and ...

Use of warfarin in long-term care: a systematic review

Science.gov (United States)

2012-01-01

Background The use of warfarin in older patients requires special consideration because of concerns with comorbidities, interacting medications, and the risk of bleeding. Several studies have suggested that warfarin may be underused or inconsistently prescribed in long-term care (LTC); no published systematic review has evaluated warfarin use for stroke prevention in this setting. This review was conducted to summarize the body of published original research regarding the use of warfarin in the LTC population. Methods A systematic literature search of the PubMed, Cumulative Index to Nursing and Allied Health Literature, and Cochrane Library was conducted from January 1985 to August 2010 to identify studies that reported warfarin use in LTC. Studies were grouped by (1) rates of warfarin use and prescribing patterns, (2) association of resident and institutional characteristics with warfarin prescribing, (3) prescriber attitudes and concerns about warfarin use, (4) warfarin management and monitoring, and (5) warfarin-related adverse events. Summaries of study findings and quality assessments of each study were developed. Results Twenty-two studies met the inclusion criteria for this review. Atrial fibrillation (AF) was the most common indication for warfarin use in LTC and use of warfarin for stroke survivors was common. Rates of warfarin use in AF were low in 5 studies, ranging from 17% to 57%. These usage rates were low even among residents with high stroke risk and low bleeding risk. Scored bleeding risk had no apparent association with warfarin use in AF. In physician surveys, factors associated with not prescribing warfarin included risk of falls, dementia, short life expectancy, and history of bleeding. International normalized ratio was in the target range approximately half of the time. The combined overall rate of warfarin-related adverse events and potential events was 25.5 per 100 resident months on warfarin therapy. Conclusions Among residents with AF

Feasibility of implementing a comprehensive warfarin pharmacogenetics service.

Science.gov (United States)

Nutescu, Edith A; Drozda, Katarzyna; Bress, Adam P; Galanter, William L; Stevenson, James; Stamos, Thomas D; Desai, Ankit A; Duarte, Julio D; Gordeuk, Victor; Peace, David; Kadkol, Shrihari S; Dodge, Carol; Saraf, Santosh; Garofalo, John; Krishnan, Jerry A; Garcia, Joe G N; Cavallari, Larisa H

2013-11-01

To determine the procedural feasibility of a pharmacist-led interdisciplinary service for providing genotype-guided warfarin dosing for hospitalized patients newly starting warfarin. Prospective observational study. A 438-bed tertiary care hospital affiliated with a large academic institution. Eighty patients who started warfarin therapy and were managed by a newly implemented pharmacogenetics service. All patients received routine warfarin genotyping and clinical pharmacogenetics consultation. The primary outcomes were percentage of genotype-guided dose recommendations available prior to the second warfarin dose and adherence of the medical staff to doses recommended by the pharmacogenetics service. Of 436 genotype orders placed during the first 6 months of the service, 190 (44%) were deemed appropriate. For the 80 patients on the service who consented to data collection, 76% of the genotypes were available prior to the second warfarin dose. The median (range) time from genotype order to genotype result was 26 hours (7-80 hrs), and the time to genotype-guided dose recommendation was 30 hours (7-80 hrs). A total of 73% of warfarin doses ordered by the medical staff were within 0.5 mg of the daily dose recommended by the pharmacogenetics consult service. Providing routine genotype-guided warfarin dosing supported by a pharmacogenetics consult service is feasible from a procedural standpoint, with most genotypes available prior to the second warfarin dose and good adherence to genotype-guided dose recommendations by the medical staff. © 2013 Pharmacotherapy Publications, Inc.

Validation of Clinical Testing for Warfarin Sensitivity

Science.gov (United States)

Langley, Michael R.; Booker, Jessica K.; Evans, James P.; McLeod, Howard L.; Weck, Karen E.

2009-01-01

Responses to warfarin (Coumadin) anticoagulation therapy are affected by genetic variability in both the CYP2C9 and VKORC1 genes. Validation of pharmacogenetic testing for warfarin responses includes demonstration of analytical validity of testing platforms and of the clinical validity of testing. We compared four platforms for determining the relevant single nucleotide polymorphisms (SNPs) in both CYP2C9 and VKORC1 that are associated with warfarin sensitivity (Third Wave Invader Plus, ParagonDx/Cepheid Smart Cycler, Idaho Technology LightCycler, and AutoGenomics Infiniti). Each method was examined for accuracy, cost, and turnaround time. All genotyping methods demonstrated greater than 95% accuracy for identifying the relevant SNPs (CYP2C9 *2 and *3; VKORC1 −1639 or 1173). The ParagonDx and Idaho Technology assays had the shortest turnaround and hands-on times. The Third Wave assay was readily scalable to higher test volumes but had the longest hands-on time. The AutoGenomics assay interrogated the largest number of SNPs but had the longest turnaround time. Four published warfarin-dosing algorithms (Washington University, UCSF, Louisville, and Newcastle) were compared for accuracy for predicting warfarin dose in a retrospective analysis of a local patient population on long-term, stable warfarin therapy. The predicted doses from both the Washington University and UCSF algorithms demonstrated the best correlation with actual warfarin doses. PMID:19324988

Optimal initial dose adjustment of warfarin in orthopedic patients.

Science.gov (United States)

Lenzini, Petra A; Grice, Gloria R; Milligan, Paul E; Gatchel, Susan K; Deych, Elena; Eby, Charles S; Burnett, R Stephen J; Clohisy, John C; Barrack, Robert L; Gage, Brian F

2007-11-01

Warfarin sodium is commonly prescribed for the prophylaxis and treatment of venous thromboembolism. Dosing algorithms have not been widely adopted because they require a fixed initial warfarin dose (eg, 5 mg) and are not tailored to other factors that may affect the international normalized ratio (INR). To develop an algorithm that could predict a therapeutic warfarin dose based on drug interactions, INR response after the initial warfarin doses, and other clinical factors. We used stepwise regression to quantify the relationship between these factors in patients beginning prophylactic warfarin therapy immediately prior to joint replacement. In the derivation cohort (n = 271), we separately modeled the therapeutic dose after 2 and 3 initial doses. We prospectively validated these 2 models in an independent cohort (n = 105). About half of the therapeutic dose variability was predictable after 3 days of therapy: R2 was 53% in the derivation cohort and 42% in the validation cohort. INR response after 3 warfarin doses (INR3) inversely correlated with therapeutic dose (p < 0.001). Intraoperative blood loss transiently, but significantly, elevated the postoperative INR values. Other significant (p < 0.03) predictors were the first and second warfarin doses (+7% and +6%, respectively, per 1 mg), and statin use (-15.0%). The model derived after 2 warfarin doses explained 32% of the variability in therapeutic dose. We developed and validated algorithms that estimate therapeutic warfarin doses based on clinical factors and INR response available after 2-3 days of warfarin therapy. The algorithms are implemented online at www.WarfarinDosing.org.

[Enantioselective determinination of R-warfarin/S-warfarin in human plasma using liquid chromatography-tandem mass spectrometry and its application in a drug-drug interaction study].

Science.gov (United States)

Jin, Shu; Zhang, Yi-Fan; Chen, Xiao-Yan; Liu, Ke; Zhong, Da-Fang

2012-01-01

To study the drug-drug interaction of morinidazole and warfarin and its application, a sensitive and rapid liquid chromatography-tandem mass spectrometric (LC-MS/MS) method was developed for the determination of R-warfarin/S-warfarin in human plasma. In a random, two-period crossover study, 12 healthy volunteers received a single oral dose of 5 mg racemic warfarin in the absence and presence of morinidazole. Blood samples were collected according to a pre-designed time schedule. R-warfarin, S-warfarin and methyclothiazide were extracted with ethylether : methylenechloride (3 : 2), then separated on a Astec Chirobiotic V (150 mm x 4.6 mm ID, 5 microm) column using 5 mmol x L(-1) ammonium acetate (pH 4.0) - acetonitrile as mobile phase at a flow-rate of 1.5 mL x min(-1). The mobile phase was splitted and 0.5 mL x min(-1) was introduced into MS. A tandem mass spectrometer equipped with electrospray ionization source was used as detector and operated in the negative ion mode. Quantification was performed using multiple reaction monitoring (MRM). The resolution of warfarin enantiomers is 1.56. The linear calibration curves for R-warfarin and S-warfarin both were obtained in the concentration range of 5 - 1 000 ng x mL(-1). Intra- and inter-day relative standard deviation (RSD) for R-warfarin and S-warfarin over the entire concentration range across three validation runs was both less than 10%, and relative error (RE) ranged from -4.9% to 0.7%, separately. The method herein described is effective and convenient, and suitable for the study of metabolic interaction between morinidazole and warfarin. The results showed that coadministration of warfarin with morinidazole did not affect the pharmacokinetics of either R-warfarin or S-warfarin.

Warfarin use in hemodialysis patients: what is the risk?

LENUS (Irish Health Repository)

Phelan, P J

2011-03-01

Background: There is a paucity of data concerning the risks associated with warfarin in hemodialysis (HD) patients. We compared major bleeding episodes in this group with HD patients not receiving warfarin and with a cohort of non-HD patients receiving warfarin. Methods: A retrospective review of 141 HD patients on warfarin (HDW), 704 HD patients not on warfarin (HDNW) and 3,266 non-dialysis warfarin patients (NDW) was performed. Hospital admissions for hemorrhagic events and ischemic strokes were examined as was hospital length of stay and blood product use. INR variability was also assessed. Results: The incidence rates for major hemorrhage per 100 patient years was 10.8 in the HDW group as compared to 8.0 in the HDNW (p = 0.593) and 2.1 in the NDW (p < 0.001) groups. Mean units of red blood cell transfusions required was higher in patients on dialysis with no significant difference between HDW and HDNW groups. The risk of ischemic stroke per 100 patient years was 1.7 in the HDW group as compared to 0.7 in the HDNW groups (p = 0.636) and 0.4 in the NDW (p = 0.003). The HDW group had higher inter-measurement INR variability compared to the NDW group (p = 0.034). In patients with atrial fibrillation, HDW group had a higher incidence of ischemic stroke than the NDW group (2.2 versus 0.4 events per 100 patient years; p = 0.024). Conclusions: This study confirms the higher bleeding risk associated with HD\\/ESRD but suggests that warfarin use in these patients may not add significantly to this risk. We also demonstrated high rates of ischemic stroke in HD patients despite warfarin use. Summary: Our study compares the frequency of major hemorrhage and secondarily, ischemic stroke in HD patients receiving or not receiving warfarin, with non-HD patients receiving warfarin. The major finding was that frequency of hemorrhage was higher in HD patients receiving warfarin than in non-HD patients receiving warfarin, but not different in HD patients with or without warfarin. A

Warfarin use in hemodialysis patients: what is the risk?

LENUS (Irish Health Repository)

Phelan, P J

2012-02-01

BACKGROUND: There is a paucity of data concerning the risks associated with warfarin in hemodialysis (HD) patients. We compared major bleeding episodes in this group with HD patients not receiving warfarin and with a cohort of non-HD patients receiving warfarin. METHODS: A retrospective review of 141 HD patients on warfarin (HDW), 704 HD patients not on warfarin (HDNW) and 3,266 non-dialysis warfarin patients (NDW) was performed. Hospital admissions for hemorrhagic events and ischemic strokes were examined as was hospital length of stay and blood product use. INR variability was also assessed. RESULTS: The incidence rates for major hemorrhage per 100 patient years was 10.8 in the HDW group as compared to 8.0 in the HDNW (p = 0.593) and 2.1 in the NDW (p < 0.001) groups. Mean units of red blood cell transfusions required was higher in patients on dialysis with no significant difference between HDW and HDNW groups. The risk of ischemic stroke per 100 patient years was 1.7 in the HDW group as compared to 0.7 in the HDNW groups (p = 0.636) and 0.4 in the NDW (p = 0.003). The HDW group had higher inter-measurement INR variability compared to the NDW group (p = 0.034). In patients with atrial fibrillation, HDW group had a higher incidence of ischemic stroke than the NDW group (2.2 versus 0.4 events per 100 patient years; p = 0.024). CONCLUSIONS: This study confirms the higher bleeding risk associated with HD\\/ESRD but suggests that warfarin use in these patients may not add significantly to this risk. We also demonstrated high rates of ischemic stroke in HD patients despite warfarin use. SUMMARY: Our study compares the frequency of major hemorrhage and secondarily, ischemic stroke in HD patients receiving or not receiving warfarin, with non-HD patients receiving warfarin. The major finding was that frequency of hemorrhage was higher in HD patients receiving warfarin than in non-HD patients receiving warfarin, but not different in HD patients with or without warfarin. A

Interaktion mellem warfarin og oral miconazol-gel

DEFF Research Database (Denmark)

Ogard, C G; Vestergaard, Henrik

2000-01-01

We report a case of a 76 year-old woman who had been taking warfarin for seven years because of relapsing deep venous thrombosis. Her daily maintenance dose was 5 mg. Monthly measurements of international normalised ratio (INR) were stable between 2-3. She developed oral candidiasis and miconazole...... gel was prescribed. One week later she developed bleeding gums. Eight days later she was admitted to the hospital with haematuria. INR was > 10. Warfarin and the miconazole gel were withdrawn. She was treated with phytonadione. INR normalised after four days and she continued warfarin treatment....... Caution should be exercised whenever the combination of warfarin and miconazole gel are prescribed....

Topical Antimycotics for Oral Candidiasis in Warfarin Users.

Science.gov (United States)

Hellfritzsch, Maja; Pottegård, Anton; Pedersen, Andreas James Thestrup; Burghle, Alaa; Mouaanaki, Fatima; Hallas, Jesper; Grove, Erik Lerkevang; Damkier, Per

2017-04-01

Treatment for oral candidiasis in warfarin users may be complicated by drug-drug interactions (DDIs) between warfarin and topically applied antimycotics. However, current knowledge of these putative DDIs is merely based on case series. We therefore performed a cohort cross-over study with the objective to evaluate the potential DDIs between warfarin and miconazole oral gel or nystatin oral solution. The cohort consisted of individuals using warfarin in the period of 1998-2012 (n ≈ 7400). We collected data on cohort members' measurements of the international normalized ratio (INR) from a clinical database, and obtained information on their use of topically applied miconazole and nystatin from a regional prescription register. Potential DDIs were assessed by comparing INR values before and after initiation of an antimycotic drug. Among 17 warfarin users exposed to miconazole oral gel, the mean INR increased from 2.5 (95% CI: 2.1-2.8) to 3.8 (95% CI: 2.8-4.8) after exposure, corresponding to a mean INR increase of 1.4 (95% CI: 0.3-2.4). Among 30 warfarin users exposed to nystatin oral solution, the mean INR was 2.7 (95% CI: 2.3-3.1) before and 2.5 (95% CI: 2.2-2.9) after exposure. In conclusion, we found evidence supporting a clinically relevant drug-drug interaction between warfarin and miconazole oral gel. In contrast, we did not find any indication of an interaction between warfarin and nystatin oral solution. Nystatin rather than miconazole should be preferred when treating warfarin users for oral candidiasis. © 2016 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society).

Factors influencing warfarin control in Australia and Singapore.

Science.gov (United States)

Bernaitis, Nijole; Ching, Chi Keong; Teo, Siew Chong; Chen, Liping; Badrick, Tony; Davey, Andrew K; Crilly, Julia; Anoopkumar-Dukie, Shailendra

2017-09-01

Warfarin is widely used for patients with non-valvular atrial fibrillation (NVAF). Variations in warfarin control, as measured by time in therapeutic range (TTR), have been reported across different regions and ethnicities, particularly between Western and Asian countries. However, there is limited data on comparative factors influencing warfarin control in Caucasian and Asian patients. Therefore, the aim of this study was to determine warfarin control and potential factors influencing this in patients with NVAF in Australia and Singapore. Retrospective data was collected for patients receiving warfarin for January to June 2014 in Australia and Singapore. TTR was calculated for individuals with mean patient TTR used for analysis. Possible influential factors on TTR were analysed including age, gender, concurrent co-morbidities, and concurrent medication. The mean TTR was significantly higher in Australia (82%) than Singapore (58%). At both sites, chronic kidney disease significantly lowered this TTR. Further factors influencing control were anaemia and ageWarfarin control was significantly higher in Australia compared to Singapore, however chronic kidney disease reduced control at both sites. The different levels of control in these two countries, together with patient factors further reducing control may impact on anticoagulant choice in these countries with better outcomes from warfarin in Australia compared to Singapore. Copyright © 2017 Elsevier Ltd. All rights reserved.

New high-performance liquid chromatography method for the determination of (R)-warfarin and (S)-warfarin using chiral separation on a glycopeptide-based stationary phase.

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Malakova, Jana; Pavek, Petr; Svecova, Lucie; Jokesova, Iveta; Zivny, Pavel; Palicka, Vladimir

2009-10-01

Warfarin is a well-known anticoagulant agent that occurs in two enantiomers, (R)-(+)-warfarin and (S)-(-)-warfarin. A new liquid chromatography method for the determination of both enantiomers was developed, validated and applied in in vitro studies with the aim of evaluating the accumulation of (R)-warfarin and (S)-warfarin in the hepatoma HepG2 cell line. OptiMEM cell cultivation medium samples and cellular lysates were purified using Waters Oasis MAX extraction cartridges. The chiral separation of warfarin and the internal standard p-chlorowarfarin enantiomers was performed on an Astec Chirobiotic V2 column at a flow rate of 1.2mL/min. The mobile phase was composed of 31% acetonitrile, 5% of methanol and 64% of ammonium acetate buffer (10mmol/L, pH 4.1). The enantiomers were quantified using a fluorescence detector (lambda(excit)=320nm, lambda(emiss)=415nm). The limit of detection was found to be 0.121micromol/L of (S)-warfarin and 0.109micromol/L of (R)-warfarin. The range of applicability and linearity was estimated from 0.25 to 100micromol/L. The precision ranged from 1.3% to 12.2% of the relative standard deviation, and the accuracy reached acceptable values from 95.5% to 108.4%. The new bioanalytical method confirmed the same accumulation of (R)-warfarin and (S)-warfarin in the hepatoma HepG2 cell line.

The Active Metabolite of Warfarin (3'-Hydroxywarfarin) and Correlation with INR, Warfarin and Drug Weekly Dosage in Patients under Oral Anticoagulant Therapy: A Pharmacogenetics Study.

Science.gov (United States)

Gemmati, Donato; Burini, Francesco; Talarico, Anna; Fabbri, Matteo; Bertocco, Cesare; Vigliano, Marco; Moratelli, Stefano; Cuneo, Antonio; Serino, Maria Luisa; Avato, Francesco Maria; Tisato, Veronica; Gaudio, Rosa Maria

2016-01-01

Warfarin oral anticoagulant therapy (OAT) requires regular and frequent drug adjustment monitored by INR. Interindividual variability, drug and diet interferences, and genetics (VKORC1 and CYP2C9) make the maintenance/reaching of stable INR a not so easy task. HPLC assessment of warfarin/enantiomers was suggested as a valid monitoring-tool along with INR, but definite results are still lacking. We evaluated possible correlations between INR, warfarin/3'-hydroxywarfarin, and drug weekly dosage aimed at searching novel alternatives to OAT monitoring. VKORC1/CYP2C9 pharmacogenetics investigation was performed to account for the known influence on warfarin homeostasis. 133 OAT patients were recruited and assessed for warfarin/3'-hydroxywarfarin serum levels (HPLC), INR, and VKORC1 and CYP2C9 genotypes. A subgroup of 52 patients were monitored in detail (5 consecutive controls; c0-c4) till the target INR was reached. Correlation analyses were performed in both groups. In the whole OAT group both warfarin and 3'-hydroxywarfarin correlate with INR at comparable degree (r2 = 0.0388 and 0.0362 respectively). Conversely, warfarin weekly dosage better correlates with warfarin than with 3'-hydroxywarfarin (r2 = 0.0975 and r2 = 0.0381 respectively), but considering together warfarin plus 3'-hydroxywarfarin the correlation strongly increased (r2 = 0.1114; ppharmacogenetics studies confirmed that patients carrying the VKORC1 variant-allele required lower warfarin maintenance dosage and that the combination of VKORC1 and CYP2C9 yielded a warfarin responsive index (WRI) inversely related to the number variant alleles. Our results overall suggest that 3'-hydroxywarfarin monitoring could be of great advantage in INR monitoring respect to classical warfarin assessment showing significant contribution also in multivariate analysis. Therefore, additional active metabolites should be recognized and investigated as novel useful indicators.

Validation of clinical testing for warfarin sensitivity: comparison of CYP2C9-VKORC1 genotyping assays and warfarin-dosing algorithms.

Science.gov (United States)

Langley, Michael R; Booker, Jessica K; Evans, James P; McLeod, Howard L; Weck, Karen E

2009-05-01

Responses to warfarin (Coumadin) anticoagulation therapy are affected by genetic variability in both the CYP2C9 and VKORC1 genes. Validation of pharmacogenetic testing for warfarin responses includes demonstration of analytical validity of testing platforms and of the clinical validity of testing. We compared four platforms for determining the relevant single nucleotide polymorphisms (SNPs) in both CYP2C9 and VKORC1 that are associated with warfarin sensitivity (Third Wave Invader Plus, ParagonDx/Cepheid Smart Cycler, Idaho Technology LightCycler, and AutoGenomics Infiniti). Each method was examined for accuracy, cost, and turnaround time. All genotyping methods demonstrated greater than 95% accuracy for identifying the relevant SNPs (CYP2C9 *2 and *3; VKORC1 -1639 or 1173). The ParagonDx and Idaho Technology assays had the shortest turnaround and hands-on times. The Third Wave assay was readily scalable to higher test volumes but had the longest hands-on time. The AutoGenomics assay interrogated the largest number of SNPs but had the longest turnaround time. Four published warfarin-dosing algorithms (Washington University, UCSF, Louisville, and Newcastle) were compared for accuracy for predicting warfarin dose in a retrospective analysis of a local patient population on long-term, stable warfarin therapy. The predicted doses from both the Washington University and UCSF algorithms demonstrated the best correlation with actual warfarin doses.

Effect of age and sex on warfarin dosing

Directory of Open Access Journals (Sweden)

Khoury G

2014-07-01

Full Text Available Ghada Khoury,1 Marwan Sheikh-Taha2 1School of Pharmacy, 2Department of Pharmacy Practice, Lebanese American University, Byblos, Lebanon Objective: We examined the potential effect of sex and age on warfarin dosing in ambulatory adult patients. Methods: We conducted a retrospective chart review of patients attending an anticoagulation clinic. We included patients anticoagulated with warfarin for atrial fibrillation or venous thromboembolism who had a therapeutic international normalized ratio of 2–3 for 2 consecutive months. We excluded patients who had been on any drug that is known to have a major interaction with warfarin, smokers, and heavy alcohol consumers. Out of 340 screened medical records, 96 met the predetermined inclusion criteria. The primary outcome assessed was warfarin total weekly dose (TWD. Results: There was a statistically significant difference in the TWD among the ages (P<0.01; older patients required lower doses. However there was no statistically significant difference in the TWD between sexes (P=0.281. Conclusion: Age was found to have a significant effect on warfarin dosing. Even though women did require a lower TWD than men, this observation was not statistically significant. Keywords: warfarin, INR, anticoagulation, vitamin K antagonists, age

Warfarin: do we need genotype-based dose prediction?

Directory of Open Access Journals (Sweden)

Yenny Yenny

2016-02-01

Full Text Available For the treatment and prevention of thrombo-embolic disease, the most frequently used anticoagulant drug worldwide is warfarin, an oral coumarin derivative, with more than 30 million prescriptions written for this drug in the United States in 2004.(1 The drug has a narrow therapeutic index and its metabolism varies by as much as a factor of 10 among individual patients, making warfarin therapy difficult to manage. Hemorrhagic complication rates of warfarin are estimated to be 5-7.9% for major (life threatening hemorrhage and 14-36% for minor hemorrhage (e.g. nosebleeds, microscopic hematuria.(2 This condition makes it difficult to establish the appropriate dose of warfarin.

Topical Antimycotics for Oral Candidiasis in Warfarin Users

DEFF Research Database (Denmark)

Hellfritzsch, Maja; Pottegård, Anton; Pedersen, Andreas James Thestrup

2017-01-01

Treatment for oral candidiasis in warfarin users may be complicated by drug-drug interactions (DDIs) between warfarin and topically applied antimycotics. However, current knowledge of these putative DDIs is merely based on case series. We therefore performed a cohort cross-over study with the obj......Treatment for oral candidiasis in warfarin users may be complicated by drug-drug interactions (DDIs) between warfarin and topically applied antimycotics. However, current knowledge of these putative DDIs is merely based on case series. We therefore performed a cohort cross-over study...... increased from 2.5 (95% CI: 2.1-2.8) to 3.8 (95% CI: 2.8-4.8) after exposure, corresponding to a mean INR increase of 1.4 (95% CI: 0.3-2.4). Among 30 warfarin users exposed to nystatin oral solution, the mean INR was 2.7 (95% CI: 2.3-3.1) before and 2.5 (95% CI: 2.2-2.9) after exposure. In conclusion, we...

Warfarin dosage response related pharmacogenetics in Chinese population.

Directory of Open Access Journals (Sweden)

Siyue Li

Full Text Available As the most frequently prescribed anticoagulant, warfarin has large inter-individual variability in dosage. Genetic polymorphisms could largely explain the differences in dosage requirement. rs9923231 (VKORC1, rs7294 (VKORC1, rs1057910 (CYP2C9, rs2108622 (CYP4F2, and rs699664 (GGCX involved in the warfarin action mechanism and the circulatory vitamin K were selected to investigate their polymorphism characteristics and their effects on the pharmacodynamics and pharmacokinetics of warfarin in Chinese population.220 patients with cardiac valve replacement were recruited. International normalized ratio and plasma warfarin concentrations were determined. The five genetic polymorphisms were genotyping by pyro-sequencing. The relationships of maintenance dose, plasma warfarin concentration and INR were assessed among groups categorized by genotypes.rs9923231 and rs7294 in VKORC1 had the analogous genotype frequencies (D': 0.969. 158 of 220 recruited individuals had the target INR (1.5-2.5. Patients with AA of rs9923231 and CC of rs7294 required a significantly lower maintenance dose and plasma concentration than those with AG and TC, respectively. The mean weekly maintenance dose was also significantly lower in CYP2C9 rs1057910 mutated heterozygote than in patients with the wild homozygote. Eliminating the influence from environment factors (age, body weight and gender, rs9923231 and rs1057910 could explain about 32.0% of the variability in warfarin maintenance dose; rs7294 could explain 26.7% of the variability in plasma concentration. For patients with allele G of rs9923231 and allele T of rs7294, higher plasma concentration was needed to achieve the similar goal INR.A better understanding of the genetic variants in individuals can be the foundation of warfarin dosing algorithm and facilitate the reasonable and effective use of warfarin in Chinese.

ANTICOAGULANT TREATMENT OF AF: FOCUS ON THE WARFARIN DOSAGE

Directory of Open Access Journals (Sweden)

Y. Kovbasniuk

2015-10-01

  Summary Authors analyzed the results of some studies of AF and warfarin dosing. Than investigation of 75 patient with AF (permanent type was performed. According to demographic, anthropometric data and related conditions (diabetes mellitus type 2, myocardial infarction, acute cerebrovascular ischemia, pulmonary embolism, alcohol abuse - drinking more than one ounce of ≥3 weekly predictive model of warfarin dosing was developed: warfarin dose = 0.097 * BMI - 0.03 * AGE + 0.30 *ASS.Status+ 0.02 *WC+ 1, 88. After testing of final model authors concluded what derived formula was representative, to determine the optimal dose of warfarin given to patient based on demographic characteristics. Considering all of the abovementioned, this model can be recommended for use determining the treatment strategy in patients with AF. Keywords: anticoagulant treatment, warfarin, atrial fibrillation.

Evaluation of the effect of torsemide on warfarin dosage requirements.

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Lai, Sophia; Momper, Jeremiah D; Yam, Felix K

2017-08-01

Background According to drug interaction databases, torsemide may potentiate the effects of warfarin. Evidence for this drug-drug interaction, however, is conflicting and the clinical significance is unknown. Objective The aim of this study is to evaluate the impact of torsemide initiation on warfarin dosage requirements. Setting This study was conducted at the Veterans Affairs Healthcare System in San Diego, California. Method A retrospective cohort study was conducted using Veterans Affairs data from patients who were converted from bumetanide to torsemide between March 2014 and July 2014. Patients were also prescribed and taking warfarin during the observation period. Warfarin dosage requirements were evaluated to determine if any changes occurred within the first 3 months of starting torsemide. Main outcome measure The primary outcome was the average weekly warfarin dose before and after torsemide initiation. Results Eighteen patients met study inclusion criteria. The weekly warfarin dose before and after initiation of torsemide was not significantly different (34 ± 15 and 34 ± 13 mg, p > 0.05). Of those eighteen patients, only two experienced elevations in INR that required a decrease in warfarin dosage after torsemide initiation. Between those two patients, dosage reductions ranged from 5.3 to 18%. Conclusion These results indicated that most patients did not require any warfarin dosage adjustments after torsemide was initiated. The potential for interaction, however, still exists. While empiric warfarin dosage adjustments are not recommended when initiating torsemide, increased monitoring is warranted to minimize the risk of adverse effects.

The Active Metabolite of Warfarin (3'-Hydroxywarfarin) and Correlation with INR, Warfarin and Drug Weekly Dosage in Patients under Oral Anticoagulant Therapy: A Pharmacogenetics Study

Science.gov (United States)

Talarico, Anna; Fabbri, Matteo; Bertocco, Cesare; Vigliano, Marco; Moratelli, Stefano; Cuneo, Antonio; Serino, Maria Luisa; Avato, Francesco Maria

2016-01-01

Objectives Warfarin oral anticoagulant therapy (OAT) requires regular and frequent drug adjustment monitored by INR. Interindividual variability, drug and diet interferences, and genetics (VKORC1 and CYP2C9) make the maintenance/reaching of stable INR a not so easy task. HPLC assessment of warfarin/enantiomers was suggested as a valid monitoring-tool along with INR, but definite results are still lacking. We evaluated possible correlations between INR, warfarin/3’-hydroxywarfarin, and drug weekly dosage aimed at searching novel alternatives to OAT monitoring. VKORC1/CYP2C9 pharmacogenetics investigation was performed to account for the known influence on warfarin homeostasis. Methods 133 OAT patients were recruited and assessed for warfarin/3’-hydroxywarfarin serum levels (HPLC), INR, and VKORC1 and CYP2C9 genotypes. A subgroup of 52 patients were monitored in detail (5 consecutive controls; c0-c4) till the target INR was reached. Correlation analyses were performed in both groups Results In the whole OAT group both warfarin and 3’-hydroxywarfarin correlate with INR at comparable degree (r2 = 0.0388 and 0.0362 respectively). Conversely, warfarin weekly dosage better correlates with warfarin than with 3’-hydroxywarfarin (r2 = 0.0975 and r2 = 0.0381 respectively), but considering together warfarin plus 3’-hydroxywarfarin the correlation strongly increased (r2 = 0.1114; pwarfarin (r2 = 0.2157 and r2 = 0.0549; p = 0.0005 and p = 0.0944 respectively) seeming less affected by drug adjustments in the subgroup of 52 patients who started OAT. The multivariate analyses aimed at estimating the true contribution of 3’-hydroxywarfarin on INR value ascribed it the unique significant value (p = 0.0021) in spite of warfarin who lost association. The pharmacogenetics studies confirmed that patients carrying the VKORC1 variant-allele required lower warfarin maintenance dosage and that the combination of VKORC1 and CYP2C9 yielded a warfarin responsive index (WRI

Determination of total and unbound warfarin and warfarin alcohols in human plasma by high performance liquid chromatography with fluorescence detection.

Science.gov (United States)

Lomonaco, Tommaso; Ghimenti, Silvia; Piga, Isabella; Onor, Massimo; Melai, Bernardo; Fuoco, Roger; Di Francesco, Fabio

2013-11-01

Two analytical procedures are presented for the determination of the total content and unbound fraction of both warfarin and warfarin alcohols in human plasma. Chromatographic separation was carried out in isocratic conditions at 25°C on a C-18 reversed-phase column with a mobile phase consisting of a 70% buffer phosphate 25mM at pH=7, 25% methanol and 5% acetonitrile at a flow rate of 1.2mL/min. Fluorescence detection was performed at 390nm (excitation wavelength 310nm). Neither method showed any detectable interference or matrix effect. Inter-day recovery of the total warfarin and warfarin alcohols at a concentration level of 1000ng/mL was 89±3% and 73±3%, respectively, whereas for their unbound fraction (at a concentration level of 10ng/mL) was 66±8% and 90±7%, respectively. The intra- and inter-day precision (assessed as relative standard deviation) was alcohols, respectively. The methods were successfully applied to a pooled plasma sample obtained from 69 patients undergoing warfarin therapy. Copyright © 2013 Elsevier B.V. All rights reserved.

Warfarin resumption following anticoagulant-associated intracranial hemorrhage: A systematic review and meta-analysis.

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Chai-Adisaksopha, Chatree; Iorio, Alfonso; Hillis, Christopher; Siegal, Deborah; Witt, Daniel M; Schulman, Sam; Crowther, Mark

2017-12-01

This study aims to assess the effect of warfarin resumption in patients who experienced warfarin-associated intracranial hemorrhage (ICH). We conducted a systematic review and meta-analysis of studies evaluating the outcomes of adult patients who survived warfarin-associated ICH. We included studies that compared patients who resumed warfarin versus those who did not. Of 3145 studies screened, ten observational studies were included in the final analysis. Death occurred in 181 of 968 patients (18.7%) who resumed warfarin and 834 of 2579 (32.3%) who did not resume warfarin (RR 0.51, 95% CI 0.34 to 0.76, P=0.0009). Ischemic stroke occurred in 32 of 902 (3.5%) patients who resumed warfarin and 172 of 2467 (7.0%) patients who did not resume warfarin (RR 0.56, 95% CI 0.39 to 0.82, P=0.002). Venous thromboembolism occurred in 4 of 224 (1.8%) patients who resumed warfarin and of 33 of 681 (4.8%) patients who did not resume warfarin (RR 0.39, 95% CI, 0.15 to 1.03, P=0.06). Recurrent ICH occurred in 200 of 2994 (6.7%) patients who resumed warfarin and 358 of 4652 (7.7%) patients who did not resume warfarin (RR 0.89, 95% CI 0.65 to 1.23, P=0.49). The study suggests that warfarin resumption is associated with significant reduction in ischemic stroke and venous thromboembolism when compared to no warfarin resumption in patients who experience warfarin-associated ICH. Although these results are strongly supportive of restarting anticoagulation, prospective studies are required to confirm our results due to the high likelihood of bias in the included studies. Copyright © 2017 Elsevier Ltd. All rights reserved.

The potential drug-drug interaction between proton pump inhibitors and warfarin

DEFF Research Database (Denmark)

Henriksen, Daniel Pilsgaard; Stage, Tore Bjerregaard; Hansen, Morten Rix

2015-01-01

BACKGROUND: Proton pump inhibitors (PPIs) have been suggested to increase the effect of warfarin, and clinical guidelines recommend careful monitoring of international normalized ratio (INR) when initiating PPI among warfarin users. However, this drug-drug interaction is sparsely investigated...... in a clinical setting. The aim was to assess whether initiation of PPI treatment among users of warfarin leads to increased INR values. METHODS: The study was an observational self-controlled study from 1998 to 2012 leveraging data on INR measurements on patients treated with warfarin from primary care...... and outpatient clinics and their use of prescription drugs. Data were analyzed in 2015. We assessed INR, warfarin dose, and dose/INR ratio before and after initiating PPI treatment using the paired student's t-test. RESULTS: We identified 305 warfarin users initiating treatment with PPIs. The median age was 71...

Effects of etravirine on the pharmacokinetics and pharmacodynamics of warfarin in rats

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John, J; John, M; Wu, L; Hsiao, C; Abobo, CV; Liang, D

2013-01-01

Background and Purpose Warfarin is often used with etravirine (ETV) to prevent HIV-related thromboembolic events. As both warfarin and ETV bind to plasma proteins and are metabolized by hepatic cytochrome P450s, they are likely to interact. Hence, we evaluated the effect of ETV on the pharmacokinetics and blood clotting time of racemic warfarin in rats. Experimental Approach Two groups of male Sprague-Dawley rats, in which the jugular vein had been cannulated, were studied. The control group (n = 10) received 1 mg·kg−1 racemic warfarin i.v., and the test group (n = 13) 1 mg·kg−1 of racemic warfarin followed by 25 mg·kg−1 ETV i.v. Serial blood samples were collected for up to 144 h and the blood clotting time (calculated as international normalized ratio [INR]) measured in blood plasma at each sample point. Plasma concentrations of R-warfarin, S-warfarin, R-7-hydroxywarfarin and S-7-hydroxywarfarin were measured by a LC/MS/MS method using a chiral lux cellulose-1 column. Pharmacokinetic parameters were analysed using non-compartmental methods. Key Results ETV significantly increased, by threefold, the systemic clearance and volume of distribution of S-warfarin, but not those of R-warfarin. ETV decreased the total AUC of warfarin, but had no effect on its elimination half-life. ETV also increased the systemic clearance of both R-7-hydroxywarfarin and S-7-hydroxywarfarin but only increased the volume of distribution of R-7-hydroxywarfarin. Interestingly, the effect of warfarin on blood clotting time (INR) was significantly increased in the presence of etravirine. Conclusion and Implications Our data suggest that etravirine may potentiate the anticoagulant effect of warfarin and this could have clinical significance. PMID:23215758

Population Impact of Drug Interactions with Warfarin

DEFF Research Database (Denmark)

Martín-Pérez, Mar; Gaist, David; de Abajo, Francisco J

2018-01-01

OBJECTIVE:  To investigate the population impact of previously reported interactions between warfarin and other drugs on international normalized ratio (INR) levels. METHODS:  Using The Health Improvement Network (THIN), a United Kingdom primary care database, a cohort of warfarin users between.......55) and in the proportion of patients with INR levels out of therapeutic range (population...

Warfarin accelerated vascular calcification and worsened cardiac dysfunction in remnant kidney mice

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Ming-Tsun Tsai

2018-04-01

Full Text Available Background: Vascular calcification is highly prevalent in end-stage renal disease (ESRD and is a significant risk factor for future cardiovascular events and death. Warfarin use results in dysfunction of matrix Gla protein, an inhibitor of vascular calcification. However, the effect of warfarin on vascular calcification in patients with ESRD is still not well characterized. Thus we investigated whether arterial calcification can be accelerated by warfarin treatment both in vitro and in vivo using a mouse remnant kidney model. Methods: Human aortic smooth muscle cells (HASMC were cultured in medium supplemented with warfarin and phosphate to investigate the potential role of this drug in osteoblast transdifferentiation. For in vivo study, adult male C57BL/6 mice underwent 5/6 nephrectomy were treated with active vitamin D3 plus warfarin to determine the extent of vascular calcification and parameters of cardiovascular function. Results: We found that the expressions of Runx2 and osteocalcin in HASMC were markedly enhanced in the culture medium containing warfarin and high phosphate concentration. Warfarin induced calcification of cultured HASMC in the presence of high phosphate levels, and this effect is inhibited by vitamin K2. Severe aortic calcification and reduced left ventricular ejection fractions were also noted in 5/6 nephrectomy mice treated with warfarin and active vitamin D3. Conclusion: Warfarin treatment contributes to the accelerated vascular calcification in animal models of advanced chronic kidney disease. Clinicians should therefore be aware of the profound risk of warfarin use on vascular calcification and cardiac dysfunction in patients with ESRD and atrial fibrillation. Keywords: Left ventricular dysfunction, Uremia, Vascular calcification, Warfarin

Pharmacokinetics of warfarin in rats: role of serum protein binding and tissue distribution

International Nuclear Information System (INIS)

Cheung, W.K.

1985-01-01

The purpose of this study was to explore the role of serum protein binding and tissue distribution in the non-linear pharmacokinetics of warfarin in rats. The first phase of the research was an attempt to elucidate the causes of intersubject differences in serum protein binding of warfarin in rats. It was found that the distribution of S-warfarin between blood and liver, kidneys, muscle, or fatty tissue was non-linear. Based on the tissue distribution data obtained, a physiologically-based pharmacokinetic model was developed to describe the time course of S-warfarin concentrations in the serum and tissues of rats. The proposed model was able to display the dose-dependent pharmacokinetics of warfarin in rats. Namely a lower clearance and a smaller apparent volume of distribution with increasing dose, which appear to be due to the presence of capacity-limited, high-affinity binding sites for warfarin in various tissues. To determine if the binding of warfarin to the high-affinity binding sites in the liver of rats is reversible, concentrations of S-warfarin in the liver and serum of rats were monitored for a very long time after an intravenous injection of a 1 mg/kg dose. In another study in rats, non-radioactive warfarin was found to be able to displace tissue-bound C 14 -warfarin which was administered about 200 hours before the i.v. injection of the non-radioactive warfarin, showing that the binding of warfarin to the high-affinity binding sites in the body is persistent and reversible

A pharmacogenetics-based warfarin maintenance dosing algorithm from Northern Chinese patients.

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Jinxing Chen

Full Text Available Inconsistent associations with warfarin dose were observed in genetic variants except VKORC1 haplotype and CYP2C9*3 in Chinese people, and few studies on warfarin dose algorithm was performed in a large Chinese Han population lived in Northern China. Of 787 consenting patients with heart-valve replacements who were receiving long-term warfarin maintenance therapy, 20 related Single nucleotide polymorphisms were genotyped. Only VKORC1 and CYP2C9 SNPs were observed to be significantly associated with warfarin dose. In the derivation cohort (n = 551, warfarin dose variability was influenced, in decreasing order, by VKORC1 rs7294 (27.3%, CYP2C9*3(7.0%, body surface area(4.2%, age(2.7%, target INR(1.4%, CYP4F2 rs2108622 (0.7%, amiodarone use(0.6%, diabetes mellitus(0.6%, and digoxin use(0.5%, which account for 45.1% of the warfarin dose variability. In the validation cohort (n = 236, the actual maintenance dose was significantly correlated with predicted dose (r = 0.609, P<0.001. Our algorithm could improve the personalized management of warfarin use in Northern Chinese patients.

Clinical and Genetic Determinants of Warfarin Pharmacokinetics and Pharmacodynamics during Treatment Initiation

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Gong, Inna Y.; Schwarz, Ute I.; Crown, Natalie; Dresser, George K.; Lazo-Langner, Alejandro; Zou, GuangYong; Roden, Dan M.; Stein, C. Michael; Rodger, Marc; Wells, Philip S.; Kim, Richard B.; Tirona, Rommel G.

2011-01-01

Variable warfarin response during treatment initiation poses a significant challenge to providing optimal anticoagulation therapy. We investigated the determinants of initial warfarin response in a cohort of 167 patients. During the first nine days of treatment with pharmacogenetics-guided dosing, S-warfarin plasma levels and international normalized ratio were obtained to serve as inputs to a pharmacokinetic-pharmacodynamic (PK-PD) model. Individual PK (S-warfarin clearance) and PD (Imax) parameter values were estimated. Regression analysis demonstrated that CYP2C9 genotype, kidney function, and gender were independent determinants of S-warfarin clearance. The values for Imax were dependent on VKORC1 and CYP4F2 genotypes, vitamin K status (as measured by plasma concentrations of proteins induced by vitamin K absence, PIVKA-II) and weight. Importantly, indication for warfarin was a major independent determinant of Imax during initiation, where PD sensitivity was greater in atrial fibrillation than venous thromboembolism. To demonstrate the utility of the global PK-PD model, we compared the predicted initial anticoagulation responses with previously established warfarin dosing algorithms. These insights and modeling approaches have application to personalized warfarin therapy. PMID:22114699

Healthcare utilization and costs for patients initiating Dabigatran or Warfarin.

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Reynolds, Shannon L; Ghate, Sameer R; Sheer, Richard; Gandhi, Pranav K; Moretz, Chad; Wang, Cheng; Sander, Stephen; Costantino, Mary E; Annavarapu, Srinivas; Andrews, George

2017-06-21

Novel oral anticoagulants (NOAC) such as dabigatran, when compared to warfarin, have been shown to potentially reduce the risk of stroke in patients with non-valvular atrial fibrillation (NVAF) together with lower healthcare resource utilization (HCRU) and similar total costs. This study expands on previous work by comparing HCRU and costs for patients newly diagnosed with NVAF and newly initiated on dabigatran or warfarin, and is the first study specifically in a Medicare population. A retrospective matched-cohort study was conducted using data from administrative health care claims during the study period 01/01/2010-12/31/2012. Cox regression analyses were used to compare all-cause risk of first hospitalizations and emergency room (ER) visits. Medical, pharmacy, and total costs per-patient-per-month (PPPM) were compared between dabigatran and warfarin users. A total of 1110 patients initiated on dabigatran were propensity score-matched with corresponding patients initiated on warfarin. The mean number of hospitalizations (0.92 vs. 1.13, P = 0.012), ER visits (1.32 vs. 1.56, P warfarin users. Patients initiated on dabigatran had significantly lower risk of first all-cause ER visits [hazard ratio (HR): 0.84, 95% confidence interval (CI): 0.73-0.98] compared to those initiated on warfarin. Adjusted mean pharmacy costs PPPM were significantly greater for dabigatran users ($510 vs. $250, P warfarin users. Dabigatran users had significantly lower HCRU compared to warfarin users. In addition, dabigatran users had lower risk of all-cause ER visits. Despite higher pharmacy costs, the two cohorts did not differ significantly in medical or total all-cause costs.

Synthesis of 13C warfarin labelled at the hemiketal carbon, and its resolution

International Nuclear Information System (INIS)

Savell, V.H. Jr.; Valente, E.J.; Eggleston, D.S.

1989-01-01

Warfarin (cyclic hemiketal form: 2-hydroxy-2-methyl-4-phenyl-3,4-dihydro-2H,5H-pyrano[3,2-c][1]benz opyran-5-one) is labeled with 98+% 13 C at the anomeric carbon (C2) and resolved into its enantiomers. Acetone-2- 13 C(98.6%) condenses with benzaldehyde in aqueous base to produce 4-phenyl-3-buten-2-one-2- 13 C(98+%). Michael-type addition of this to 4-hydroxycoumarin in methanol produces the labeled diastereomeric warfarin methyl ketals which on deprotection form racemic warfarin-2- 13 C(98+%). Classical resolution of labeled warfarin with quinidine produces partly resolved (S)-(-)-warfarin-2- 13 C(98+%). Labeled warfarin is a suitable probe for warfarin configuration for which three distinct isomeric forms are known. (Author)

Warfarin binding to plasma of workers exposed to toluene diisocyanate

Energy Technology Data Exchange (ETDEWEB)

Bachmann, K.; Shapiro, R.; Forney, R.B. Jr.

1982-02-01

The extent of (14)C-warfarin binding to plasma proteins was evaluated in a group of normal, healthy volunteers and in two groups of individuals occupationally exposed to toluene diisocyanate (TDI). Plasma binding was assessed by ultrafiltration after the addition of racemic (14)C-warfarin to a final concentration of 0.8 microgram/ml. Chronic occupational exposure to TDI did not affect the extent of warfarin binding since warfarin free fractions (normalized to an albumin concentration of 4.5 g/dl) were 1.09 +/- 0.23 (mean +/- SD), 0.98 +/- 0.19, and 0.97 +/- 0.15 for controls and the two groups of TDI-exposed individuals, respectively.

Warfarin and fibrinolysis - a challenging combination: an observational cohort study

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Luurila Harri

2011-04-01

Full Text Available Abstract Background Patients presenting with ST-segment elevation myocardial infarction (STEMI frequently use warfarin. Fibrinolytic agents and warfarin both increase bleeding risk, but only a few studies have been published concerning the bleeding risk of warfarin-prescribed patients receiving fibrinolysis. The objective of this study was to define the prevalence for intracranial haemorrhage (ICH or major bleeding in patients on warfarin treatment receiving pre-hospital fibrinolysis. Methods This was an observational cohort study. Data for this retrospective case series were collected in Helsinki Emergency Medical Service catchment area from 1.1.1997 to 30.6.2010. All warfarin patients with suspected ST-segment elevation myocardial infarction (STEMI, who received pre-hospital fibrinolysis, were included. Bleeding complications were detected from Medical Records and classified as ICH, major or minor bleeding. Results Thirty-six warfarin patients received fibrinolysis during the study period. Fourteen patients had bleeding complications. One (3%, 95% CI 0-15% patient had ICH, six (17%, 95% CI 7-32% had major and seven (19%, 95% CI 9-35% had minor bleeding. The only fatal bleeding occurred in a patient with ICH. Patients' age, fibrinolytic agent used or aspirin use did not predispose to bleeding complications. High International Normalized Ratio (INR seemed to predispose to bleedings with values over 3, but no statistically significant difference was found. Conclusions Bleedings occur frequently in warfarin patients treated with fibrinolysis in the real world setting, but they are rarely fatal.

Safety and Efficacy of Warfarin Therapy in Kawasaki Disease.

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Baker, Annette L; Vanderpluym, Christina; Gauvreau, Kimberly A; Fulton, David R; de Ferranti, Sarah D; Friedman, Kevin G; Murray, Jenna M; Brown, Loren D; Almond, Christopher S; Evans-Langhorst, Margaret; Newburger, Jane W

2017-10-01

To describe the safety and efficacy of warfarin for patients with Kawasaki disease and giant coronary artery aneurysms (CAAs, ≥8 mm). Giant aneurysms are managed with combined anticoagulation and antiplatelet therapies, heightening risk of bleeding complications. We reviewed the time in therapeutic range; percentage of international normalization ratios (INRs) in range (%); bleeding events, clotting events; INRs ≥6; INRs ≥5 and warfarin therapy was 7.2 years (2.3-13.3 years). Goal INR was 2.0-3.0 (n = 6) or 2.5-3.5 (n = 3), based on CAA size and history of CAA thrombosis. All patients were treated with aspirin; 1 was on dual antiplatelet therapy and warfarin. The median time in therapeutic range was 59% (37%-85%), and median percentage of INRs in range was 68% (52%-87%). INR >6 occurred in 3 patients (4 events); INRs ≥5 warfarin and aspirin, with INRs in range only two-thirds of the time. Future studies should evaluate the use of direct oral anticoagulants in children as an alternative to warfarin. Copyright © 2017 Elsevier Inc. All rights reserved.

Selective macrophage inhibition abolishes warfarin-induced reduction of metastasis

NARCIS (Netherlands)

Maat, B.

1980-01-01

Warfarin administered to tumor-bearing mice reduces the number of spontaneous lung metastases. Both macrophage inhibitors silica and carrageenan abolish the warfarin-induced decrease in tumour metastasis, which strongly supports the concept that the antitumour effect of coumarin derivatives is

Interaction between gemfibrozil and warfarin: case report and review of the literature.

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Dixon, Dave L; Williams, Virginia G

2009-06-01

Possible procoagulant effects can occur when lipid-lowering fibric acid derivatives, such as gemfibrozil and fenofibrate, are taken concomitantly with warfarin. Although there are several detailed reports of fenofibrate potentiating the anticoagulant effects of warfarin, few case reports have been published regarding an interaction between gemfibrozil and warfarin. We describe a 62-year-old man who was taking warfarin for paroxysmal atrial fibrillation and came to the anticoagulation clinic for a routine follow-up. For 9 months, the patient's international normalized ratio (INR) had been stable (target range 2.0-3.0) with warfarin 45 mg/week. At this clinic visit, however, his INR was supratherapeutic at 5.8; the only identified change in his drug therapy was the addition of gemfibrozil 600 mg twice/day, started 3 weeks earlier. The patient denied any changes in his dietary intake of vitamin K, alcohol use, or addition of nonprescription or herbal agents. Recent laboratory tests revealed no signs of thyroid abnormalities and only an insignificant elevation in his alanine aminotransferase level. His warfarin dose was decreased to 35-37.5 mg/week (a 22% reduction), and a therapeutic INR was maintained until gemfibrozil was later discontinued because of myalgia. After consecutive subtherapeutic INRs, his warfarin dose was increased to 45 mg/week and a therapeutic INR was maintained. Use of the Drug Interaction Probability Scale indicated that the likelihood of the gemfibrozil-warfarin interaction was probable. The exact mechanism of the proposed interactions between fibric acid derivatives and warfarin remains unknown but may be multifactorial through inhibition of cytochrome P450 isoenzymes, displacement from protein binding sites, or changes in coagulation factor synthesis. Regardless of the fibric acid derivative chosen, an empiric dosage reduction of 20% and close INR monitoring are warranted in patients receiving warfarin.

Edoxaban versus Warfarin in Patients with Atrial Fibrillation

DEFF Research Database (Denmark)

Giugliano, Robert P; Ruff, Christian T; Braunwald, Eugene

2013-01-01

. The principal safety end point was major bleeding. RESULTS: The annualized rate of the primary end point during treatment was 1.50% with warfarin (median time in the therapeutic range, 68.4%), as compared with 1.18% with high-dose edoxaban (hazard ratio, 0.79; 97.5% confidence interval [CI], 0.63 to 0.99; P....001 for noninferiority) and 1.61% with low-dose edoxaban (hazard ratio, 1.07; 97.5% CI, 0.87 to 1.31; P=0.005 for noninferiority). In the intention-to-treat analysis, there was a trend favoring high-dose edoxaban versus warfarin (hazard ratio, 0.87; 97.5% CI, 0.73 to 1.04; P=0.08) and an unfavorable trend with low......-dose edoxaban versus warfarin (hazard ratio, 1.13; 97.5% CI, 0.96 to 1.34; P=0.10). The annualized rate of major bleeding was 3.43% with warfarin versus 2.75% with high-dose edoxaban (hazard ratio, 0.80; 95% CI, 0.71 to 0.91; PP...

Warfarin: pharmacological profile and drug interactions with antidepressants

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Juliana Souto Teles

2012-03-01

Full Text Available Oral anticoagulants are among the drugs with the greatest numberof drug interactions. The concomitant use of several medications isa common practice in patients with cardiovascular problems, whooften also present with depression; therefore, the probability of aninteraction occurring between warfarin and the antidepressants ishigh, and may result in increased or decreased anticoagulant activity.Since the possible interactions between these two classes of drugshave been poorly explored in literature, with a risk to the patients who use them, we reviewed the pharmacology of warfarin and its possible interactions with antidepressants. Of the antidepressants analyzed, those that showed relevant effects on the interaction with warfarin were, in decreasing order: paroxetine, venlafaxine, fluoxetine, and duloxetine.

Synthesis of [sup 13]C warfarin labelled at the hemiketal carbon, and its resolution

Energy Technology Data Exchange (ETDEWEB)

Savell, V.H. Jr.; Valente, E.J. (Mississippi College, Clinton. MS (United States). Dept. of Chemistry); Eggleston, D.S. (Smith, Kline and French Labs., King of Prussia, PA (United States). Physical and Structural Chemistry)

1989-06-01

Warfarin (cyclic hemiketal form: 2-hydroxy-2-methyl-4-phenyl-3,4-dihydro-2H,5H-pyrano[3,2-c][1]benz opyran-5-one) is labeled with 98+% [sup 13]C at the anomeric carbon (C2) and resolved into its enantiomers. Acetone-2-[sup 13]C(98.6%) condenses with benzaldehyde in aqueous base to produce 4-phenyl-3-buten-2-one-2-[sup 13]C(98+%). Michael-type addition of this to 4-hydroxycoumarin in methanol produces the labeled diastereomeric warfarin methyl ketals which on deprotection form racemic warfarin-2-[sup 13]C(98+%). Classical resolution of labeled warfarin with quinidine produces partly resolved (S)-(-)-warfarin-2-[sup 13]C(98+%). Labeled warfarin is a suitable probe for warfarin configuration for which three distinct isomeric forms are known. (Author).

Vascular access site complication in transfemoral coronary angiography between uninterrupted warfarin and heparin bridging.

Science.gov (United States)

Wongcharoen, Wanwarang; Pinyosamosorn, Kittipong; Gunaparn, Siriluck; Boonnayhun, Suchada; Thonghong, Tasalak; Suwannasom, Pannipa; Phrommintikul, Arintaya

2017-08-01

Warfarin discontinuation with heparin bridging is a common practice in patients receiving warfarin prior to elective coronary angiography (CAG). The uninterrupted warfarin strategy has been suggested to be alternative option for patients with high thromboembolic risk. Therefore, we aimed to assess the safety of elective transfemoral CAG during uninterrupted warfarin therapy compared to heparin bridging. This study was a randomized open-label design with blinded event evaluation. The 110 consecutive patients (age ≥ 18 years) receiving warfarin before the planned transfemoral CAG were randomly assigned to either heparin bridging or uninterrupted warfarin with targeted INR (2.0-3.0). The primary outcome was the incidence of major vascular access site complications. The baseline characteristics were comparable between two groups (mean age was 60.1 ± 7.8 years, 49 males). The mean INR on the day of CAG of heparin bridging and uninterrupted warfarin groups was 1.2 ± 0.3 and 2.2 ± 0.5 (P warfarin patients (P = 0.243). The total vascular access site complications occurred in 6 (10.9%) heparin-bridging and one (1.8%) uninterrupted warfarin patients (P = 0.113). No patient developed either other bleeding or thromboembolic events during 7 days after CAG. We demonstrated that an uninterrupted warfarin strategy did not increase vascular access site complications in patients undergoing transfemoral CAG compared to heparin bridging therapy. Due to the safety and the ease of uninterrupted warfarin strategy, this approach should be encouraged in patients receiving long-term warfarin who undergo elective transfemoral CAG. © 2017, Wiley Periodicals, Inc.

Oral warfarin intake affects skin inflammatory cytokine responses in rats.

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Aleksandrov, Aleksandra Popov; Mirkov, Ivana; Zolotarevski, Lidija; Ninkov, Marina; Mileusnic, Dina; Kataranovski, Dragan; Kataranovski, Milena

2017-09-01

Warfarin is an anticoagulant used in prevention/prophylaxis of thromboembolism. Besides the effects on coagulation, non-hemorrhagic reactions have also been documented. Although cutaneous reactions were reported in some patients, the impact on skin immunity was not explored. In the present paper, the effect of 30-day oral warfarin intake on skin cytokine responses in rats was analyzed. Increased release of inflammatory cytokines (TNF, IL-1β and IL-10) was noted by skin explants from rats which received warfarin, but without effect on IL-6. No impact on epidermal cell cytokine secretion was seen, except a tendency of an increase of IL-6 response to stimulation with microbial product lipopolysaccharide (LPS). Topical application of contact allergen dinitrochlorobenzene (DNCB) resulted in slight (numerical solely) increase of TNF release by skin explants of warfarin-treated animals, while epidermal cells responded by increased secretion of all four cytokines examined. The data presented provide new information on the potential of oral warfarin to modulate skin innate immune activity. Copyright © 2017 Elsevier B.V. All rights reserved.

Important Information to Know When You Are Taking: Warfarin (Coumadin) and Vitamin K

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... Important information to know when you are taking: Warfarin (Coumadin) and Vitamin K The food you eat ... provides you with information about the interaction between warfarin (Coumadin) and vitamin K. Why was warfarin (Coumadin) ...

Rationale, design, and preliminary results of the Quebec Warfarin Cohort Study.

Science.gov (United States)

Perreault, Sylvie; Shahabi, Payman; Côté, Robert; Dumas, Stéphanie; Rouleau-Mailloux, Étienne; Feroz Zada, Yassamin; Provost, Sylvie; Mongrain, Ian; Dorais, Marc; Huynh, Thao; Kouz, Simon; Diaz, Ariel; Blostein, Mark; de Denus, Simon; Turgeon, Jacques; Ginsberg, Jeffrey; Lelorier, Jacques; Lalonde, Lyne; Busque, Lambert; Kassis, Jeannine; Talajic, Mario; Tardif, Jean-Claude; Dubé, Marie-Pierre

2018-05-01

Over- and undercoagulation with warfarin are associated with hemorrhagic and thromboembolic events, respectively. Genetic and clinical factors affect warfarin response, and the causes of this variability remain unclear. We present descriptive statistics and test for predictors of poor anticoagulation control. The Quebec Warfarin Cohort (QWC) comprises 1059 new warfarin users, with prospective follow-up using telephone questionnaires every 3 months for 1 year, and using healthcare administrative databases (RAMQ and Med-Echo) for 5 years prior to cohort entry and up to 10 years following active patient participation. Genetic material was collected, and genotyping of CYP2C9 and VKORC1 genes was conducted. Measured outcomes included the percentage of time patients spent within therapeutic range, anticoagulation control, warfarin dose, bleeding, and thromboembolic events. We report baseline characteristics and outcomes after 1 year of follow-up. Poor anticoagulation control was defined as time in therapeutic range <60% in the 3- to 12-month interval. Participants had a mean age of 71 years, and 62% were men. The most common indication for warfarin was atrial fibrillation (87%). Mean time in therapeutic range was 56% (±25%) in the 3 months following warfarin initiation, and 70% (±21%) in the 3- to 12-month interval. During follow-up, the rate of stroke or systemic embolism was 1.8 events per 100 person-years; for major bleeding events, 3.3 events per 100 person-years. Independent predictors of poor anticoagulation control were chronic kidney disease, heart failure, dyslipidemia, and age. The QWC represents a good research cohort to investigate clinical and genetic factors in a warfarin-anticoagulated population. © 2018 Wiley Periodicals, Inc.

A Pharmacogenetics-Based Warfarin Maintenance Dosing Algorithm from Northern Chinese Patients

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Luo, Fang; Wang, Jin'e; Shi, Yi; Tan, Yu; Chen, Qianlong; Zhang, Yu; Hui, Rutai; Wang, Yibo

2014-01-01

Inconsistent associations with warfarin dose were observed in genetic variants except VKORC1 haplotype and CYP2C9*3 in Chinese people, and few studies on warfarin dose algorithm was performed in a large Chinese Han population lived in Northern China. Of 787 consenting patients with heart-valve replacements who were receiving long-term warfarin maintenance therapy, 20 related Single nucleotide polymorphisms were genotyped. Only VKORC1 and CYP2C9 SNPs were observed to be significantly associated with warfarin dose. In the derivation cohort (n = 551), warfarin dose variability was influenced, in decreasing order, by VKORC1 rs7294 (27.3%), CYP2C9*3(7.0%), body surface area(4.2%), age(2.7%), target INR(1.4%), CYP4F2 rs2108622 (0.7%), amiodarone use(0.6%), diabetes mellitus(0.6%), and digoxin use(0.5%), which account for 45.1% of the warfarin dose variability. In the validation cohort (n = 236), the actual maintenance dose was significantly correlated with predicted dose (r = 0.609, Pwarfarin use in Northern Chinese patients. PMID:25126975

The impact of peritransplant warfarin use on renal transplant outcome.

LENUS (Irish Health Repository)

Connaughton, Dervla M

2011-03-31

The unplanned nature of kidney transplantation necessitates that patients undergo surgery without prior cessation of warfarin. Our study analyses the impact of warfarin treatment in the peritransplant period on graft outcome and perioperative transfusion requirements.

Warfarin traps human vitamin K epoxide reductase in an intermediate state during electron transfer

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Shen, Guomin; Cui, Weidong; Zhang, Hao; Zhou, Fengbo; Huang, Wei; Liu, Qian; Yang, Yihu; Li, Shuang; Bowman, Gregory R.; Sadler, J. Evan; Gross, Michael L.; Li, Weikai

2017-01-01

Although warfarin is the most widely used anticoagulant worldwide, the mechanism by which warfarin inhibits its target, human vitamin K epoxide reductase (hVKOR), remains unclear. Here we show that warfarin blocks a dynamic electron-transfer process in hVKOR. A major fraction of cellular hVKOR is at an intermediate redox state of this process containing a Cys51-Cys132 disulfide, a characteristic accommodated by a four-transmembrane-helix structure of hVKOR. Warfarin selectively inhibits this major cellular form of hVKOR, whereas disruption of the Cys51-Cys132 disulfide impairs warfarin binding and causes warfarin resistance. Relying on binding interactions identified by cysteine alkylation footprinting and mass spectrometry coupled with mutagenesis analysis, we are able to conduct structure simulations to reveal a closed warfarin-binding pocket stabilized by the Cys51-Cys132 linkage. Understanding the selective warfarin inhibition of a specific redox state of hVKOR should enable the rational design of drugs that exploit the redox chemistry and associated conformational changes in hVKOR. PMID:27918545

Cytochrome P450-mediated warfarin metabolic ability is not a critical determinant of warfarin sensitivity in avian species: In vitro assays in several birds and in vivo assays in chicken.

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Watanabe, Kensuke P; Kawata, Minami; Ikenaka, Yoshinori; Nakayama, Shouta M M; Ishii, Chihiro; Darwish, Wageh Sobhi; Saengtienchai, Aksorn; Mizukawa, Hazuki; Ishizuka, Mayumi

2015-10-01

Coumarin-derivative anticoagulant rodenticides used for rodent control are posing a serious risk to wild bird populations. For warfarin, a classic coumarin derivative, chickens have a high median lethal dose (LD50), whereas mammalian species generally have much lower LD50. Large interspecies differences in sensitivity to warfarin are to be expected. The authors previously reported substantial differences in warfarin metabolism among avian species; however, the actual in vivo pharmacokinetics have yet to be elucidated, even in the chicken. In the present study, the authors sought to provide an in-depth characterization of warfarin metabolism in birds using in vivo and in vitro approaches. A kinetic analysis of warfarin metabolism was performed using liver microsomes of 4 avian species, and the metabolic abilities of the chicken and crow were much higher in comparison with those of the mallard and ostrich. Analysis of in vivo metabolites from chickens showed that excretions predominantly consisted of 4'-hydroxywarfarin, which was consistent with the in vitro results. Pharmacokinetic analysis suggested that chickens have an unexpectedly long half-life despite showing high metabolic ability in vitro. The results suggest that the half-life of warfarin in other bird species could be longer than that in the chicken and that warfarin metabolism may not be a critical determinant of species differences with respect to warfarin sensitivity. © 2015 SETAC.

Effect of gemfibrozil on the pharmacokinetics and pharmacodynamics of racemic warfarin in healthy subjects

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Lilja, Jari J; Backman, Janne T; Neuvonen, Pertti J

2005-01-01

Aims Case reports suggest that gemfobrozil can increase the anticoagulant effect of warfarin. Because gemfibrozil inhibits CYP2C9 in vitro, we studied its effects on the pharmacokinetics and pharmacodynamics of racemic warfarin. Methods In a randomized cross-over study, 10 healthy subjects ingested 600 mg gemfibrozil or placebo twice daily for 8 days. On day 3, they were administered a single dose of 10 mg racemic R-S-warfarin orally. The concentrations of R- and S-warfarin in plasma and thromboplastin time were monitored up to 168 h. Results Gemfibrozil decreased the mean (±SD) area under the plasma concentration-time curve [AUC(0–∞)] of S-warfarin by 11%, from 19.9 ± 5.2 mg l−1 h to 17.6 ± 4.7 mg l−1 h (95% CI on the difference −3.7, −0.78; P gemfibrozil phase to 29.5 ± 6.9 mg l−1 h during the placebo phase (95% CI −3.3, −0.33; P Gemfibrozil did not alter the anticoagulant effect of warfarin. Conclusion Unexpectedly, gemfibrozil slightly decreased the plasma concentrations of R- and S-warfarin. Displacement of warfarin from plasma albumin by gemfibrozil or its interference with the absorption of warfarin could explain the present findings. Usual therapeutic doses of gemfibrozil seem to have limited effects on the pharmacokinetics and pharmacodynamics of single dose warfarin in healthy subjects. PMID:15801938

Sol-gel Derived Warfarin - Silica Composites for Controlled Drug Release.

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Dolinina, Ekaterina S; Parfenyuk, Elena V

2017-01-01

Warfarin, commonly used anticoagulant in clinic, has serious shortcomings due to its unsatisfactory pharmacodynamics. One of the efficient ways for the improvement of pharmacological and consumer properties of drugs is the development of optimal drug delivery systems. The aim of this work is to synthesize novel warfarin - silica composites and to study in vitro the drug release kinetics to obtain the composites with controlled release. The composites of warfarin with unmodified (UMS) and mercaptopropyl modified silica (MPMS) were synthesized by sol-gel method. The composite formation was confirmed by FTIR spectra. The concentrations of warfarin released to media with pH 1.6, 6.8 and 7.4 were measured using UV spectroscopy. The drug release profiles from the solid composites were described by a series of kinetic models which includes zero order kinetics, first order kinetics, the modified Korsmeyer-Peppas model and Hixson-Crowell model. The synthesized sol-gel composites have different kinetic behavior in the studied media. In contrast to the warfarin composite with unmodified silica, the drug release from the composite with mercaptopropyl modified silica follows zero order kinetics for 24 h irrespective to the release medium pH due to mixed mechanism (duffusion + degradation and/or disintegration of silica matrix). The obtained results showed that warfarin - silica sol-gel composites have a potential application for the development of novel oral formulation of the drug with controlled delivery. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Suboptimal Anticoagulant Management in Japanese Patients with Nonvalvular Atrial Fibrillation Receiving Warfarin for Stroke Prevention.

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Hirano, Teruyuki; Kaneko, Hirokazu; Mishina, Sari; Wang, Feng; Morita, Satoshi

2017-10-01

Atrial fibrillation (AF) is the most common cardiac arrhythmia, with increasing prevalence in Japan. Although prothrombin time-international normalized ratio (PT-INR) targets for monitoring warfarin therapy in patients with nonvalvular AF (NVAF) are well defined, real-world patient characteristics and PT-INR levels remain unknown among Japanese patients with NVAF who initiate and continue warfarin (warfarin maintainers) versus those who switch from warfarin to direct oral anticoagulants (DOACs; warfarin switchers). Patients with NVAF receiving oral anticoagulants between February 2013 and June 2015 were identified using a nationwide electronic medical record (EMR) database from 69 hospitals in Japan. Demographics and characteristics of patients, PT-INR, time in therapeutic range (TTR), and frequency in range (FIR) of PT-INR between warfarin maintainers and warfarin switchers were assessed. A total of 1705 patients met inclusion criteria and were examined (1501 warfarin maintainers versus 204 warfarin switchers). CHADS 2 , CHA 2 DS 2 -VASc, and HAS-BLED scores were comparable between groups. However, these scores were significantly higher among warfarin switchers at the time of switching than at the time of warfarin initiation. Furthermore, TTR and FIR of PT-INR were lower in warfarin switchers than in maintainers. Nevertheless, TTR and FIR were below 50% (PT-INR, 1.6-2.6) in both patient groups. In this EMR-based clinical study, patients who switched to DOACs had both poor or inadequate PT-INR control and higher risk factors of stroke. Many patients receiving warfarin did not achieve sufficient PT-INR therapeutic range. DOACs could be recommended in Japanese patients with NVAF with inadequate PT-INR control and increased risk of stroke. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

Attempted Suicide by Massive Warfarin Ingestion Conservatively Managed Using Phytonadione

Directory of Open Access Journals (Sweden)

Katherine L. March

2016-01-01

Full Text Available Treatment strategies for acute toxicity following massive ingestion of warfarin are not well described in the literature. Warfarin is the primary oral anticoagulation agent used in the treatment of thromboembolic disease, and patients with acute toxicity are at risk for life-threatening hemorrhages. Treatment options include phytonadione (vitamin K1, fresh frozen plasma (FFP, and prothrombin complex concentrates (PCCs used alone or in combination. FFP and PCC can be associated with volume complications, undesirable thromboembolic events, and increased costs. We describe the case of a 63-year-old female with acute warfarin toxicity following a massive ingestion of warfarin (420 mg–450 mg in an attempt to commit suicide. Upon arrival to the emergency department, serial INR checks were initiated to help guide dosing strategy and later adjusted based on INR response to treatment using only phytonadione.

Retrobulbar Hematoma from Warfarin Toxicity and the Limitations of Bedside Ocular Sonography

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2010-05-01

worldwide. Peer Reviewed Title: Retrobulbar Hematoma from Warfarin Toxicity and the Limitations of Bedside Ocular Sonography Journal Issue: Western...Preferred Citation: Thompson D, Stanescu C, Pryor P, Laselle B. Retrobulbar Hematoma from Warfarin Toxicity and the Limitations of Bedside Ocular...nontrauamtic retrobulbar hematoma associated with warfarin toxicity. The application and limitations of focused bedside ocular sonography for this

Algorithms for monitoring warfarin use: Results from Delphi Method.

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Kano, Eunice Kazue; Borges, Jessica Bassani; Scomparini, Erika Burim; Curi, Ana Paula; Ribeiro, Eliane

2017-10-01

Warfarin stands as the most prescribed oral anticoagulant. New oral anticoagulants have been approved recently; however, their use is limited and the reversibility techniques of the anticoagulation effect are little known. Thus, our study's purpose was to develop algorithms for therapeutic monitoring of patients taking warfarin based on the opinion of physicians who prescribe this medicine in their clinical practice. The development of the algorithm was performed in two stages, namely: (i) literature review and (ii) algorithm evaluation by physicians using a Delphi Method. Based on the articles analyzed, two algorithms were developed: "Recommendations for the use of warfarin in anticoagulation therapy" and "Recommendations for the use of warfarin in anticoagulation therapy: dose adjustment and bleeding control." Later, these algorithms were analyzed by 19 medical doctors that responded to the invitation and agreed to participate in the study. Of these, 16 responded to the first round, 11 to the second and eight to the third round. A 70% consensus or higher was reached for most issues and at least 50% for six questions. We were able to develop algorithms to monitor the use of warfarin by physicians using a Delphi Method. The proposed method is inexpensive and involves the participation of specialists, and it has proved adequate for the intended purpose. Further studies are needed to validate these algorithms, enabling them to be used in clinical practice.

Hemorrhagic Transformation After Large Cerebral Infarction in Rats Pretreated With Dabigatran or Warfarin.

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Kwon, Il; An, Sunho; Kim, Jayoung; Yang, Seung-Hee; Yoo, Joonsang; Baek, Jang-Hyun; Nam, Hyo Suk; Kim, Young Dae; Lee, Hye Sun; Choi, Hyun-Jung; Heo, Ji Hoe

2017-10-01

It is uncertain whether hemorrhagic transformation (HT) after large cerebral infarction is less frequent in dabigatran users than warfarin users. We compared the occurrence of HT after large cerebral infarction among rats pretreated with dabigatran, warfarin, or placebo. This was a triple-blind, randomized, and placebo-controlled experiment. After treatment with warfarin (0.2 mg/kg), dabigatran (20 mg/kg), or saline for 7 days, Wistar rats were subjected to transient middle cerebral artery occlusion. As the primary outcome, HT was determined by gradient-recalled echo imaging. For the secondary outcome, intracranial hemorrhage was assessed via gradient-recalled echo imaging in surviving rats and via autopsy for dead rats. Of 62 rats, there were 33 deaths (53.2%, 17 technical reasons). Of the intention-to-treat population, 33 rats underwent brain imaging. HT was less frequent in the dabigatran group than the warfarin group (placebo 2/14 [14%], dabigatran 0/10 [0%], and warfarin 9/9 [100%]; dabigatran versus warfarin; P warfarin group (19/29 [65.5%]; P =0.003), but not in the dabigatran group (6/19 [31.6%]; P =0.420). Mortality was significantly higher in the warfarin group than the dabigatran group (79.3% versus 47.4%; P =0.022), but not related to the hemorrhage frequency. The risk of HT after a large cerebral infarction was significantly increased in rats pretreated with warfarin than those with dabigatran. However, the results here may not have an exact clinical translation. © 2017 American Heart Association, Inc.

Lack of a meaningful effect of anacetrapib on the pharmacokinetics and pharmacodynamics of warfarin in healthy subjects

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Krishna, Rajesh; Stypinski, Daria; Ali, Melissa; Garg, Amit; Cote, Josee; Maes, Andrea; DeGroot, Bruce; Liu, Yang; Li, Susie; Connolly, Sandra M; Wagner, John A; Stoch, S Aubrey

2012-01-01

AIM Anacetrapib is currently being developed for the treatment of dyslipidaemia. Since warfarin, an anticoagulant with a narrow therapeutic index, is expected to be commonly prescribed in this population, a drug interaction study was conducted. METHODS In a randomized, open-label, two-period fixed-sequence design, 12 healthy male subjects received two different treatments (treatment A followed by treatment B). In treatment A, a single oral dose of 30 mg warfarin (3 × 10 mg CoumadinTM) was administered on day 1. After a washout interval, subjects began treatment B, where they were given daily 100 mg doses of anacetrapib (1 × 100 mg) beginning on day −14 and continuing through day 7, with concomitant administration of 30 mg warfarin (3 × 10 mg) on day 1. All anacetrapib and warfarin doses were administered with a standard low fat breakfast. After warfarin concentrations and prothrombin time were measured, standard pharmacokinetic, pharmacodynamic and statistical (linear mixed effects model) analyses were applied. RESULTS Anacetrapib was generally well tolerated when co-administered with warfarin in the healthy males in this study. The geometric mean ratios (GMRs) for warfarin + anacetrapib : warfarin alone and 90% confidence interval (CIs) for warfarin AUC(0–∞) were 0.94 (0.90, 0.97) for the R(+) warfarin enantiomer and 0.93 (0.87, 0.98) for the S(−) warfarin enantiomer, both being contained in the interval (0.80, 1.25), supporting the primary hypothesis of the study. The GMRs warfarin + anacetrapib : warfarin alone and 90% CIs for the statistical comparison of warfarin Cmax were 1.01 (0.97, 1.05) for both the R(+) warfarin and the S(−) warfarin enantiomers, and were also contained in the interval (0.80, 1.25). The GMR (warfarin + anacetrapib : warfarin alone) and 90% CI for the statistical comparison of INR AUC(0–168 h) was 0.93 (0.89, 0.96). CONCLUSION The single dose pharmacokinetics and pharmacodynamics of orally administered warfarin were not

Edoxaban versus Warfarin for the Treatment of Symptomatic Venous Thromboembolism

DEFF Research Database (Denmark)

Büller, Harry R; Décousus, Hervé; Grosso, Michael A

2013-01-01

Whether the oral factor Xa inhibitor edoxaban can be an alternative to warfarin in patients with venous thromboembolism is unclear.......Whether the oral factor Xa inhibitor edoxaban can be an alternative to warfarin in patients with venous thromboembolism is unclear....

Risk of Gastrointestinal Bleeding with Rivaroxaban: A Comparative Study with Warfarin

Directory of Open Access Journals (Sweden)

Muhammed Sherid

2016-01-01

Full Text Available Introduction. The risk of gastrointestinal (GI bleeding with rivaroxaban has not been studied extensively. The aim of our study was to assess this risk in comparison to warfarin. Methods. We examined the medical records for patients who were started on rivaroxaban or warfarin from April 2011 to April 2013. Results. We identified 300 patients (147 on rivaroxaban versus 153 on warfarin. GI bleeding occurred in 4.8% patients with rivaroxaban when compared to 9.8% patients in warfarin group (p=0.094. GI bleeding occurred in 8% with therapeutic doses of rivaroxaban (>10 mg/d compared to 9.8% with warfarin (p=0.65. Multivariate analysis showed that patients who were on rivaroxaban for ≤40 days had a higher incidence of GI bleeding than those who were on it for >40 days (OR = 2.8, p=0.023. Concomitant use of dual antiplatelet agents was associated with increased risk of GI bleeding in the rivaroxaban group (OR = 7.4, p=0.0378. Prior GI bleeding was also a risk factor for GI bleeding in rivaroxaban group (OR = 15.5. Conclusion. The incidence of GI bleeding was similar between rivaroxaban and warfarin. The risk factors for GI bleeding with rivaroxaban were the first 40 days of taking the drug, concomitant dual antiplatelet agents, and prior GI bleeding.

Oral warfarin affects peripheral blood leukocyte IL-6 and TNFα production in rats.

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Popov, Aleksandra; Belij, Sandra; Subota, Vesna; Zolotarevski, Lidija; Mirkov, Ivana; Kataranovski, Dragan; Kataranovski, Milena

2013-01-01

Warfarin is a Vitamin K (VK) antagonist that affects Vitamin K-dependent (VKD) processes, including blood coagulation, as well as processes unrelated to hemostasis such as bone growth, calcification, and growth of some cell types. In addition, warfarin exerts influence on some non-VKD-related activities, including anti-tumor and immunomodulating activity. With respect to the latter, both immune stimulating and suppressive effects have been noted in different experimental systems. To explore the in vivo immunomodulatory potential of warfarin on one type of activity (i.e., cytokine production) in two different immune cell populations (i.e., mononuclear or polymorphonuclear cells), effects of subchronic oral warfarin intake in rats on pro-inflammatory cytokine (i.e., TNFα, IL-6) production by peripheral blood mononuclear and polymorphonuclear cells (granulocytes) was examined. Differential effects of warfarin intake on TNFα and IL-6 were noted, depending on the type of peripheral blood leukocytes and on the cytokine examined. Specifically, a lack of effect on TNFα and a priming of IL-6 production by mononuclear cells along with a decrease in TNFα and a lack of effect on IL-6 in polymorphonuclear cells were seen in warfarin-exposed hosts. The cell- and cytokine-dependent effects from subchronic oral warfarin intake on peripheral blood leukocytes demonstrated in this study could, possibly, differentially affect reactions mediated by these cells. Ultimately, the observed effects in rats might have implications for those humans who are on long-term/prolonged warfarin therapy.

The future of warfarin pharmacogenetics in under-represented minority groups

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Cavallari, Larisa H; Perera, Minoli A

2012-01-01

Genotype-based dosing recommendations are provided in the US FDA-approved warfarin labeling. However, data that informed these recommendations were from predominately Caucasian populations. Studies show that variants contributing to warfarin dose requirements in Caucasians provide similar contributions to dose requirements in US Hispanics, but significantly lesser contributions in African–Americans. Further data demonstrate that variants occurring commonly in individuals of African ancestry, but rarely in other racial groups, significantly influence dose requirements in African–Americans. These data suggest that it is important to consider variants specific for African–Americans when implementing genotype-guided warfarin dosing in this population. PMID:22871196

Aspirin versus warfarin in atrial fibrillation: decision analysis may help patients' choice.

LENUS (Irish Health Repository)

Romero-Ortuno, Roman

2012-03-01

the primary prevention of ischaemic stroke in chronic non-valvular atrial fibrillation (AF) typically involves consideration of aspirin or warfarin. CHA(2)DS(2)-VASc estimates annual stroke rates for untreated AF patients, which are reduced by 60% with warfarin and by 20% with aspirin. HAS-BLED estimates annual rates of major bleeding on warfarin. The latter risk with aspirin is 0.5-1.2% per year.

Patterns of international normalized ratio values among new warfarin patients with nonvalvular atrial fibrillation.

Science.gov (United States)

Nelson, Winnie W; Milentijevic, Dejan; Wang, Li; Baser, Onur; Damaraju, C V; Schein, Jeffrey R

2016-12-01

Limited information exists regarding the relationship between international normalized ratio (INR) control/stability and the discontinuation of warfarin therapy among patients with nonvalvular atrial fibrillation (NVAF). This study evaluated the association between INR stabilization and warfarin discontinuation and assessed INR patterns before and after INR stabilization among patients (≥18 years) with NVAF who newly initiated warfarin (Veterans Health Administration datasets; October 1, 2007 through September 30, 2012). Achievement of INR stabilization (≥3 consecutive in-range therapeutic INR measurements ≥7 days apart) was examined from warfarin initiation through the end of warfarin exposure. Proportion of time in therapeutic range during warfarin exposure was calculated (Rosendaal method) and categorized as at least 60% or less than 60%. Among 34 346 patients, 49.4% achieved INR stabilization (mean time to stabilization, 98 days). Approximately 40% of INR values were out-of-range, even after achieving stabilization. During 30 days following an INR 4.0 or higher, patients had more INR testing than the overall mean (2.51 vs. 1.67 tests). Warfarin discontinuation was 4.2 times more likely among patients without INR stabilization versus those with INR stabilization (P < 0.00001). Patients with poor INR control (time in therapeutic range <60%) were 1.76 times more likely to discontinue warfarin within 1 year (P < 0.0001). INR stabilization is a better predictor of warfarin discontinuation than poor INR control. Improved approaches are necessary to maintain appropriate anticoagulation levels among patients with NVAF.

Acquired absolute vitamin K deficiency in a patient undergoing warfarin therapy.

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Takada, Hiroaki; Toru, Hifumi; Bunya, Naofumi; Kiriu, Nobuaki; Kato, Hiroshi; Koido, Yuichi; Yasuhiro, Kuroda

2014-06-01

We report a case of absolute vitamin K deficiency (VKD) diagnosed by measuring serum VK levels in an elderly woman undergoing warfarin therapy. A 78-year-old woman was admitted to our hospital because of dyspnea and sore throat diagnosed as pharyngitis 1 week before admission. On admission, the sore throat had exacerbated and dyspnea developed. She had history of atrial fibrillation, for which warfarin 1.5 mg/d was started approximately 10 years prior and her international normalized ratio (INR) had been maintained at an acceptable therapeutic level. Blood results revealed unmeasurable INR and abnormally prolonged activated partial thromboplastin time (APTT). She was diagnosed with adenoiditis and warfarin-related coagulopathy and administered intravenous VK (20 mg) and fresh frozen plasma (FFP; 4 U), which improved INR and APTT. Since the coagulopathy responded to intravenous VK administration, the patient was clinically diagnosed with warfarin-related relative VKD. Approximately 1 month later, she returned with complaints of sore throat. Blood results indicated abnormal INR (7.22) and APTT (N80.0 s). She was diagnosed with recurrent adenoiditis and VK deficient coagulopathy. The patient’s serum VK levels were low (VK1 level, 0.13 ng/mL; VK2 levels, 0.85 ng/mL). Initial treatment of VK (20 mg) and FFP followed by intravenous VK (20 mg/d) for 6 days, her symptoms dissipated. Warfarin was suspected to have caused absolute VKD. Severe coagulopathy in patients undergoing warfarin therapy is primarily caused by, relative VKD. However, the possibility of warfarin-related absolute VKD should be suspected when INRis not sufficiently improved by intravenous VK administration.

Use of an iPad to Provide Warfarin Video Education to Hospitalized Patients.

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Kim, Jenny Jane; Mohammad, Rima A; Coley, Kim C; Donihi, Amy C

2015-09-01

To evaluate the effectiveness of a warfarin educational video in the hospital setting and to determine patients' satisfaction with using an iPad to view a warfarin educational video. This prospective quality improvement project included adult (≥18 years of age) patients on warfarin in the hospital. All patients completed pre-video and post-video knowledge tests on the iPad before and after viewing the educational video on warfarin therapy. Patients also completed a patient satisfaction survey. Forty hospitalized patients were educated using the warfarin video and included for analysis. The majority of patients were new to warfarin therapy (65%). Forty-three percent of patients passed the pre-video knowledge test, and 90% passed the post-video knowledge test (P iPad and found it easy to use. Patients who were younger (iPad more than older patients (P = 0.01) and male subjects (P = 0.02), respectively. Also, younger patients found the iPad easier to use compared with patients who were older (P = 0.01). Educating hospitalized patients about warfarin by using a video on an iPad was effective. Video education on an iPad may be an alternative to traditional education in the hospital setting.

Cardioversion and Risk of Adverse Events with Dabigatran versus Warfarin

DEFF Research Database (Denmark)

Pallisgaard, J. L.; Lindhardt, T. B.; Hansen, M. L.

2015-01-01

AIM: Cardioversion can rapidly and effectively restore sinus rhythm in patients with persistent atrial fibrillation. Since 2011 dabigatran has been available as an alternative to warfarin to prevent thromboembolic events in patients with non-valvular atrial fibrillation undergoing cardioversion. We......-valvular atrial fibrillation and first time cardioversion from 2011 to 2012; 37% in the dabigatran group (n = 456), and 63% in the warfarin group (n = 774). Median time to cardioversion was 4.0 (interquartile range [IQR] 2.9 to 6.5) and 6.9 (IQR 3.9 to 12.1) weeks in the dabigatran and warfarin groups...... respectively, and the adjusted odds ratio of cardioversion within the first 4 weeks was 2.3 (95% confidence interval [CI] 1.7 to 3.1) in favor of dabigatran. The cumulative incidence of composite endpoint of stroke, bleeding or death were 2.0% and 1.0% at 30 weeks in the warfarin and dabigatran groups...

Switching from rivaroxaban to warfarin: an open label pharmacodynamic study in healthy subjects

Science.gov (United States)

Moore, Kenneth Todd; Byra, William; Vaidyanathan, Seema; Natarajan, Jaya; Ariyawansa, Jay; Salih, Hiba; Turner, Kenneth C

2015-01-01

Aims The primary objective was to explore the pharmacodynamic changes during transition from rivaroxaban to warfarin in healthy subjects. Safety, tolerability and pharmacokinetics were assessed as secondary objectives. Methods An open label, non-randomized, sequential two period study. In treatment period 1 (TP1), subjects received rivaroxaban 20 mg once daily (5 days), followed by co-administration with a warfarin loading dose regimen of 5 or 10 mg (for the 10 mg regimen, the dose could be uptitrated to attain target international normalized ratio [INR] ≥2.0) once daily (2–4 days). When trough INR values ≥2.0 were attained, rivaroxaban was discontinued and warfarin treatment continued as monotherapy (INR 2.0–3.0). During treatment period 2, subjects received the same warfarin regimen as in TP1, but without rivaroxaban. Results During co-administration, maximum INR and prothrombin time (PT) values were higher than with rivaroxaban or warfarin monotherapy. The mean maximum effect (Emax) for INR after co-administration was 2.79–4.15 (mean PT Emax 41.0–62.7 s), compared with 1.41–1.74 (mean PT Emax 20.1–25.2 s) for warfarin alone. However, rivaroxaban had the smallest effect on INR at trough rivaroxaban concentrations. Neither rivaroxaban nor warfarin significantly affected maximum plasma concentrations of the other drug. Conclusions The combined pharmacodynamic effects during co-administration of rivaroxaban and warfarin were greater than additive, but the pharmacokinetics of both drugs were unaffected. Co-administration was well tolerated. When transitioning from rivaroxaban to warfarin, INR monitoring during co-administration should be performed at the trough rivaroxaban concentration to minimize the effect of rivaroxaban on INR. PMID:25475601

[Clinical applications of dosing algorithm in the predication of warfarin maintenance dose].

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Huang, Sheng-wen; Xiang, Dao-kang; An, Bang-quan; Li, Gui-fang; Huang, Ling; Wu, Hai-li

2011-12-27

To evaluate the feasibility of clinical application for genetic based dosing algorithm in the predication of warfarin maintenance dose in Chinese population. The clinical data were collected and blood samples harvested from a total of 126 patients undergoing heart valve replacement. The genotypes of VKORC1 and CYP2C9 were determined by melting curve analysis after PCR. They were divided randomly into the study and control groups. In the study group, the first three doses of warfarin were prescribed according to the predicted warfarin maintenance dose while warfarin was initiated at 2.5 mg/d in the control group. The warfarin doses were adjusted according to the measured international normalized ratio (INR) values. And all subjects were followed for 50 days after an initiation of warfarin therapy. At the end of a 50-day follow-up period, the proportions of the patients on a stable dose were 82.4% (42/51) and 62.5% (30/48) for the study and control groups respectively. The mean durations of reaching a stable dose of warfarin were (27.5 ± 1.8) and (34.7 ± 1.8) days and the median durations were (24.0 ± 1.7) and (33.0 ± 4.5) days in the study and control groups respectively. Significant differences existed in the durations of reaching a stable dose between the two groups (P = 0.012). Compared with the control group, the hazard ratio (HR) for the duration of reaching a stable dose was 1.786 in the study group (95%CI 1.088 - 2.875, P = 0.026). The predicted dosing algorithm incorporating genetic and non-genetic factors may shorten the duration of achieving efficiently a stable dose of warfarin. And the present study validates the feasibility of its clinical application.

Quality of warfarin control in atrial fibrillation patients in South East Queensland, Australia.

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Bernaitis, N; Badrick, T; Davey, A K; Anoopkumar-Dukie, S

2016-08-01

Warfarin is widely prescribed to decrease the risk of stroke in atrial fibrillation (AF) patients. Due to patient variability in response, regular monitoring is required, and time in therapeutic range (TTR) used to indicate quality of warfarin control with a TTR>60% is recommended. Recently, an Australian Government review of anticoagulants identified the need to establish current warfarin control and determine the potential place of the newer oral anticoagulants. To determine warfarin control by a pathology practice in Queensland, Australia and identify factors influencing TTR. Retrospective data were collected from Sullivan Nicolaides Pathology, a major pathology practice offering a warfarin care programme in Australia. Patients enrolled in their programme as of September 2014 were included in the study. TTR was calculated using INR test results, and test dates using the Rosendaal method with mean patient TTR were used for analysis and comparison. Exclusions were target therapeutic range outside 2.0-3.0, less than two INR tests and programme treatment time of less than 30 days. The eligible 3692 AF patients had 73.6% of INR tests within the therapeutic range. The mean TTR was 81%, with 97% of patients above a TTR of 60%. TTR was not significantly influenced by age, gender or socioeconomic factors. The observed mean TTR of over 80% is superior to the minimum recommended threshold of 60%. The TTR achieved by the Queensland pathology practice demonstrates that dedicated warfarin programmes can produce high-quality warfarin care, ensuring the full benefit of warfarin for Australian patients. © 2016 Royal Australasian College of Physicians.

Molecular displacement of warfarin from human serum albumin by flavonoid aglycones

International Nuclear Information System (INIS)

Poór, Miklós; Li, Yin; Kunsági-Máté, Sándor; Petrik, József; Vladimir-Knežević, Sanda; Kőszegi, Tamás

2013-01-01

The well-known 4-hydroxycoumarin derivative warfarin is a widespread anticoagulant drug. Besides its strong albumin binding property warfarin has a narrow therapeutic window. Therefore, a few percent of displacement from albumin can result in serious biological consequences. The flavonoid molecular group also shows very strong plasma albumin binding characteristics occupying the same binding site. It is plausible to hypothesize that flavonoid aglycones may be able to displace warfarin from human serum albumin (HSA). In our study the competing activities of different flavone (acacetin, apigenin, chrysin, luteolin), flavonol (galangin, quercetin) and flavanone (hesperetin, naringenin) aglycones were investigated using fluorescence spectroscopy. Our results represent that flavonoids are able to displace warfarin from the surface of HSA. On the other hand, when comparing flavone or flavonol groups to flavanones the latter group seems to be much weaker competitor. These observations were also supported by calculation of stability constants. Our investigations strongly suggest that we should reckon with the described molecular displacement. However, further in vivo studies are needed to support the findings of our model system. -- Highlights: • Various flavonoids are able to displace warfarin from human serum albumin. • Flavones and flavonols are much more effective competitors than flavanones. • Even 300 nM aglycone concentrations show the interaction with 3 μM warfarin. • Flavonoid pairs show quasi-additive desorbing property. • Flavones and flavonols are much stronger competitors than the examined drugs

Molecular displacement of warfarin from human serum albumin by flavonoid aglycones

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Poór, Miklós [Institute of Laboratory Medicine, University of Pécs, Pécs H-7624 (Hungary); Li, Yin; Kunsági-Máté, Sándor [Department of General and Physical Chemistry, University of Pécs, Pécs H-7624 (Hungary); János Szentágothai Research Center, H-7624 Pécs (Hungary); Petrik, József [Department of Medical Biochemistry and Hematology, Faculty of Pharmacy and Biochemistry, University of Zagreb, HR-10000 Zagreb (Croatia); Vladimir-Knežević, Sanda [Department of Pharmacognosy, Faculty of Pharmacy and Biochemistry, University of Zagreb, HR-10000 Zagreb (Croatia); Kőszegi, Tamás, E-mail: koszegit@freemail.hu [Institute of Laboratory Medicine, University of Pécs, Pécs H-7624 (Hungary)

2013-10-15

The well-known 4-hydroxycoumarin derivative warfarin is a widespread anticoagulant drug. Besides its strong albumin binding property warfarin has a narrow therapeutic window. Therefore, a few percent of displacement from albumin can result in serious biological consequences. The flavonoid molecular group also shows very strong plasma albumin binding characteristics occupying the same binding site. It is plausible to hypothesize that flavonoid aglycones may be able to displace warfarin from human serum albumin (HSA). In our study the competing activities of different flavone (acacetin, apigenin, chrysin, luteolin), flavonol (galangin, quercetin) and flavanone (hesperetin, naringenin) aglycones were investigated using fluorescence spectroscopy. Our results represent that flavonoids are able to displace warfarin from the surface of HSA. On the other hand, when comparing flavone or flavonol groups to flavanones the latter group seems to be much weaker competitor. These observations were also supported by calculation of stability constants. Our investigations strongly suggest that we should reckon with the described molecular displacement. However, further in vivo studies are needed to support the findings of our model system. -- Highlights: • Various flavonoids are able to displace warfarin from human serum albumin. • Flavones and flavonols are much more effective competitors than flavanones. • Even 300 nM aglycone concentrations show the interaction with 3 μM warfarin. • Flavonoid pairs show quasi-additive desorbing property. • Flavones and flavonols are much stronger competitors than the examined drugs.

Impact of warfarin discharge education program on hospital readmission and treatment costs.

Science.gov (United States)

Brunetti, Luigi; Lee, Seung-Mi; Doherty, Nancy; Suh, David; Kim, Jeong-Eun; Lee, Sun-Hong; Choi, Yong Chan; Suh, Dong-Churl

2018-03-31

Background Although warfarin is highly effective, management of patients prescribed warfarin is complex due to its narrow therapeutic window. Objective To evaluate the impact of a formal warfarin discharge education program (WDEP) on hospital readmission and treatment costs in patients who received warfarin therapy. Setting Robert Wood Johnson University Hospital Somerset in Somerville, New Jersey, USA. Method In this interventional cohort study, patients were assigned to either the WDEP group or the usual care group. The effects of the WDEP on readmission within 90 days after discharge were analyzed using Cox proportional hazards models. Factors influencing treatment cost were identified using generalized linear model with log-link function and gamma distribution. Main outcome measure Hospital readmission within 90 days and treatment costs associated with hospital readmission. Results Among 692 eligible patients, 203 in each group were matched using propensity scores and there were no statistically significant differences in the patient baseline characteristics between two groups. The risk of all-cause readmission within 90 days was significantly lower in the WDEP group compared to the usual care group (relative risk = 0.46, 95% CI 0.28-0.76). The treatment costs associated with hospital readmission in the WDEP group were 19% lower than those in the usual care group after adjusting for the study variables. Conclusion A formal, individualized WDEP provided by pharmacists resulted in significant reduction of readmission and treatment costs. The economic burden of treatment costs associated with warfarin can be controlled if well-organized warfarin education is provided to patients who received warfarin therapy.

Chondrodysplasia punctata after warfarin. Case report with 18-month follow-up

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Tamburrini, O.; Bartolomeo-De Iuri, A.; Di Guglielmo, G.L.

1987-05-01

Administration of warfarin during pregnancy may cause a rare syndrome characterized by nasal hypoplasia, usually associated with stippled epiphyseal and extraepiphyseal calcifications ressembling chondrodysplasia punctata. A case of chondrodysplasia punctata after warfarin with 18 months follow-up is reported.

Major Interaction between Warfarin and Na Valproate: A Case Report

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Bizhan Kouchaki

2015-10-01

Full Text Available  Abstract: Warfarin is the most commonly used oral anticoagulant drug in clinical practice with extreme inter and intra-individual variation in pharmacokinetic properties. Na Valproate, a broad spectrum anticonvulsant agent, is best known for its enzyme inhibition properties and also displacement of protein binding sites. Interaction between Warfarin and psychotropic drugs including Valproate are important and perhaps under recognized. In this report, we present a 48 year old female patient with chief complaints of abdominal pain, tea-color urine, blurred vision and headache. She had been suffering from "migraine headache" for 15 years that was relatively well controlled with Na Valproate 200mg twice daily. She was experienced a deep vein thrombosis (DVT following oral contraceptive. For management of DVT, she was received Warfarin 5mg/day which was increased to 7.5 mg /day after 2 weeks. Three days after this increment of dose, her Prothrombin Time (PT rose to 35.3 seconds (three times of normal value and evidences of bleeding including hematuria and hematemesis were observed. Based on  the history and laboratory findings, "Warfarin toxicity" was the first impression and she was treated with fresh frozen plasma and vitamin K with a well recovery. This experience emphasizes the clinical significant interaction between Warfarin and Na Valproate, which may take place even with the usual doses of each agent.  

Comparing intracerebral hemorrhages associated with direct oral anticoagulants or warfarin

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Kurogi, Ryota; Nishimura, Kunihiro; Nakai, Michikazu; Kada, Akiko; Kamitani, Satoru; Nakagawara, Jyoji; Toyoda, Kazunori; Ogasawara, Kuniaki; Ono, Junichi; Shiokawa, Yoshiaki; Aruga, Toru; Miyachi, Shigeru; Nagata, Izumi; Matsuda, Shinya; Yoshimura, Shinichi; Okuchi, Kazuo; Suzuki, Akifumi; Nakamura, Fumiaki; Onozuka, Daisuke; Ido, Keisuke; Kurogi, Ai; Mukae, Nobutaka; Nishimura, Ataru; Arimura, Koichi; Kitazono, Takanari; Hagihara, Akihito

2018-01-01

Objectives This cross-sectional survey explored the characteristics and outcomes of direct oral anticoagulant (DOAC)–associated nontraumatic intracerebral hemorrhages (ICHs) by analyzing a large nationwide Japanese discharge database. Methods We analyzed data from 2,245 patients who experienced ICHs while taking anticoagulants (DOAC: 227; warfarin: 2,018) and were urgently hospitalized at 621 institutions in Japan between April 2010 and March 2015. We compared the DOAC- and warfarin-treated patients based on their backgrounds, ICH severities, antiplatelet therapies at admission, hematoma removal surgeries, reversal agents, mortality rates, and modified Rankin Scale scores at discharge. Results DOAC-associated ICHs were less likely to cause moderately or severely impaired consciousness (DOAC-associated ICHs: 31.3%; warfarin-associated ICHs: 39.4%; p = 0.002) or require surgical removal (DOAC-associated ICHs: 5.3%; warfarin-associated ICHs: 9.9%; p = 0.024) in the univariate analysis. Propensity score analysis revealed that patients with DOAC-associated ICHs also exhibited lower mortality rates within 1 day (odds ratio [OR] 4.96, p = 0.005), within 7 days (OR 2.29, p = 0.037), and during hospitalization (OR 1.96, p = 0.039). Conclusions This nationwide study revealed that DOAC-treated patients had less severe ICHs and lower mortality rates than did warfarin-treated patients, probably due to milder hemorrhages at admission and lower hematoma expansion frequencies. PMID:29490916

Warfarin skin necrosis mimicking calciphylaxis in a patient with secondary hyperparathyroidism undergoing peritoneal dialysis

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Jee Eun Park

2016-03-01

Full Text Available Warfarin skin necrosis (WSN is an infrequent complication of warfarin treatment and is characterized by painful ulcerative skin lesions that appear a few days after the start of warfarin treatment. Calciphylaxis also appears as painful skin lesions caused by tissue injury resulting from localized ischemia caused by calcification of small- to medium-sized vessels in patients with end-stage renal disease. We report on a patient who presented with painful skin ulcers on the lower extremities after the administration of warfarin after a valve operation. Calciphylaxis was considered first because of the host factors; eventually, the skin lesions were diagnosed as WSN by biopsy. The skin lesions improved after warfarin discontinuation and short-term steroid therapy. Most patients with end-stage renal disease have some form of cardiovascular disease and some require temporary or continual warfarin treatment. It is important to differentiate between WSN and calciphylaxis in patients with painful skin lesions.

Long-Term Statin Administration Does Not Affect Warfarin Time in Therapeutic Range in Australia or Singapore

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Nijole Bernaitis

2018-05-01

Full Text Available Background: Warfarin requires ongoing monitoring of the International Normalised Ratio (INR. This is because numerous factors influence the response, including drug interactions with commonly-prescribed medications, such as statins. The administration of statins with warfarin may change INR; however, there is limited information regarding the effects on warfarin control as measured by time in therapeutic range (TTR. Statins may also alter bleeds with warfarin, but there are conflicting reports demonstrating both increased and decreased bleeds, and limited data on diverse ethnic populations. Therefore, the aim of this study was to determine the effect of statin administration on warfarin control and bleeds in patients in Australia and Singapore. Methods: Retrospective data were collected for patients on warfarin between January and June 2014 in Australia and Singapore. Patient data were used to calculate TTR and bleed events. Concurrent statin therapy was assessed and comparisons of TTR and bleed incidence were made across patient subgroups. Results: Warfarin control in Australia and Singapore was not significantly affected by statins, as measured by TTR (83% and 58%, respectively, frequency of testing, and warfarin doses. In Australia, statin use did not significantly affect bleeds, whilst in Singapore the bleed incidence was significantly lower for patients on statins. Conclusions: Chronic concurrent administration of statins with warfarin does not adversely affect warfarin TTR in Australia or Singapore. In Singapore, patients on statins, compared to no statins, had a lower bleed incidence and this requires further investigation, especially given the potential genetic influences of ethnicity on both statin and warfarin metabolism.

Comparison of Warfarin Requirements in Post-cardiac Surgery Patients: Valve Replacement Versus Non-valve Replacement.

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Olson, Logan M; Nei, Andrea M; Joyce, David L; Ou, Narith N; Dierkhising, Ross A; Nei, Scott D

2018-01-11

Anticoagulation with warfarin affects approximately 140,000 post-cardiac surgery patients every year, yet there remains limited published data in this patient population. Dosing remains highly variable due to intrinsic risk factors that plague cardiac surgery candidates and a lack of diverse literature that can be applied to those who have undergone a cardiac surgery alternative to heart valve replacement (HVR). In the present study, our aim was to compare the warfarin requirements between HVR and non-HVR patients. This was a single-center, retrospective study of post-cardiac surgery patients initiated on warfarin at Mayo Clinic Hospital, Rochester, from January 1st, 2013 to October 31st, 2016. The primary outcome was the maintenance warfarin dose at the earliest of discharge or warfarin day 10 between patients with HVR and non-HVR cardiac surgeries. A total of 683 patients were assessed during the study period: 408 in the HVR group and 275 in the non-HVR group. The mean warfarin maintenance doses in the HVR and non-HVR groups were 2.55 mg [standard deviation (SD) 1.52] and 2.43 mg (SD 1.21), respectively (adjusted p = 0.65). A multivariable analysis was performed to adjust for gender, age, body mass index and drug interactions. This was the largest study to evaluate warfarin dose requirements in post-cardiac surgery patients and is the first to compare warfarin requirements between HVR and non-HVR patients during the immediate post-operative period. Both groups had similar warfarin requirements, which supports expanding the initial warfarin dosing recommendations of the 9th edition Chest guideline to include non-HVR patients as well as HVR patients.

Bleeding due to a probable interaction between warfarin and Gouqizi (Lycium Barbarum L.

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Jinhua Zhang

2015-01-01

Full Text Available Unlike what is widely anticipated by the public, herbal medicines are not always safe despite being natural. We describe a 65-year-old Chinese man taking a prolonged maintenance dose of warfarin who experienced an elevated international normalized ratio (INR with associated bleeding after drinking Gouqizi (goji berry wine. This report illustrates that large doses (more than 6–12 g of Gouqizi can significantly enhance the anticoagulant action of warfarin and may cause similar adverse effects in keeping with three previous reports. Therefore, the use of herbal medicines must adhere to pharmacopoeia-recommended guidelines, including dosage regimes. Doctors should advise patients regarding possible interactions between herbs and warfarin when prescribing and should increase the frequency of INR monitoring for those patients concurrently receiving warfarin and medicinal herbs. Further study is needed to do for the mechanism of interaction between Gouqizi and warfarin.

Acute Abdomen Due to Uncontrolled Use of Warfarin: Spontaneous Intra-abdominal

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Fatih Dal

2017-12-01

Full Text Available Warfarin is an oral anticoagulant, which is commonly used in the treatment and prophylaxis of thromboembolic conditions. Bleeding is the primary adverse effect associated with warfarin. The majority of warfarin-related bleedings are spontaneous minor hemorrhages occurring in the subcutaneous or intramuscular tissues and can be treated by decreasing the dose of oral anticoagulants. However, although rare, it is possible to encounter spontaneous major bleedings with increased risk of mortality. Conservative approach is the preferred initial therapy for hemodynamically stable patients with major intra-abdominal hemorrhages that we define as the intermediate group patients. Nevertheless, surgery is required for hemodynamically unstable patients with acute abdominal pain in cases of ongoing active hemorrhage, generalized peritonitis, obstruction, acute abdomen, intestinal ischemia, and perforation. In this article, we present a rare case of acute abdomen and spontaneous intra-abdominal hemorrhage resulting from uncontrolled use of warfarin and a new classification requirement.

Warfarinized Patients with Proximal Femoral Fractures: Survey of UK Clinical Practice.

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Starks, Ian; Cooke, Stephen; Docker, Charles; Raine, Andrew

2009-06-01

In an aging population, anticoagulation in patients with musculoskeletal injuries is increasingly prevalent. The North American literature indicates an absence of consensus concerning the most appropriate management for this group. We aim to test the hypothesis that there is a lack of consensus in the UK regarding the perioperative management of patients with hip fractures on long-term warfarin therapy. A representative group of 400 consultant orthopedic surgeons was surveyed by postal questionnaire regarding their policy on the reversal of anticoagulation in warfarinized patients with hip fractures. The consultants contacted were selected to represent a geographical spread throughout the UK. There were 159 respondents (40% response rate), of which 79% (126) had a trauma commitment. 95 (75%) of these had a protocol for the reversal of anticoagulation prior to surgery. The commonest method used was to simply withhold warfarin and wait (70%). Other methods included FFP (16%), and low-dose (23%) and high-dose (14%) vitamin K. Some respondents used more than onemethod. Although nearly all respondents preferred an INR < 2.0 prior to surgery, 55% preferred an INR < 1.5. Hip fracture in the presence of long-term warfarin use is associated with significantly increased morbidity. This problem is likely to increase. Our results demonstrate variation in approach throughout the UK with regard to warfarin reversal and the acceptable INR at which to operate in this group of patients. We propose that low-dose vitamin K is considered more widely as a safe and effective method of warfarin reversal in this group.

Elevated International Normalized Ratio in a Patient Taking Warfarin and Mauby: A Case Report.

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Sorbera, Maria; Joseph, Tina; DiGregorio, Robert V

2017-10-01

We describe a 70-year-old Haitian man who had been taking warfarin for 5 years for atrial fibrillation and pulmonary hypertension. This patient had his international normalized ratio (INR) checked in the pharmacist-run anticoagulation clinic and was followed monthly. Prior to the interaction, his INR was therapeutic for 5 months while taking warfarin 10.5 mg/d. The patient presented with an INR > 8.0. Patient held 4 days of warfarin and restarted on warfarin 8.5 mg/d. Two weeks later, his INR was 2.5. After continuing dose, patient presented 2 weeks later and INR was 4.8. Upon further questioning, the patient stated he recently began ingesting mauby. Mauby is a bitter dark liquid extracted from the bark of the mauby tree that is commonly used in the Caribbean population as a folk remedy with many health benefits. This case report illustrates that mauby may have a probable drug-herb interaction (Naranjo Algorithm Score of 6) when given with warfarin. There is a lack of published literature and unclear information on the Internet describing the interaction of mauby and warfarin. Health professionals should be cautious regarding interactions between warfarin and mauby until the interaction is fully elucidated.

Dichotomal effect of the coumadin derivative warfarin on inflammatory signal transduction

NARCIS (Netherlands)

Kater, Arnon P.; Peppelenbosch, Maikel P.; Brandjes, Dees P. M.; Lumbantobing, Mika

2002-01-01

Warfarin, a widely prescribed drug for preventing thrombosis, is thought to act solely through inhibition of vitamin K-dependent coagulation factors. Low concentrations of warfarin inhibit interleukin-6 production and phosphorylation Of I-kappaB but not activation of p38 mitogen-activated protein

[Advantages and disadvantages of warfarin and pradaxa therapy for venous thromboembolism].

Science.gov (United States)

Sukovatykh, B S; Belikov, L N; Savchuk, O F; Sukovatykh, M B

2014-01-01

An analysis of complex examination of 110 patients with venous thromboembolism was made. The patients were separated into 2 groups. The first group included 60 patients, who had the start heparin therapy during 7 days with the following 6-month warfarin therapy. Warfarin was substituted by pradaxa (dabigatran) for 50 patients of the second group. The efficacy of pradaxa could be compared with warfarin. However, pradaxa had a number of advantages such as the predictable anticoagulant effect, standard dosages. This medicine is more predictable and doesn't require a control of homeostasis and an adjustment of drug dosage.

Comparing intracerebral hemorrhages associated with direct oral anticoagulants or warfarin.

Science.gov (United States)

Kurogi, Ryota; Nishimura, Kunihiro; Nakai, Michikazu; Kada, Akiko; Kamitani, Satoru; Nakagawara, Jyoji; Toyoda, Kazunori; Ogasawara, Kuniaki; Ono, Junichi; Shiokawa, Yoshiaki; Aruga, Toru; Miyachi, Shigeru; Nagata, Izumi; Matsuda, Shinya; Yoshimura, Shinichi; Okuchi, Kazuo; Suzuki, Akifumi; Nakamura, Fumiaki; Onozuka, Daisuke; Ido, Keisuke; Kurogi, Ai; Mukae, Nobutaka; Nishimura, Ataru; Arimura, Koichi; Kitazono, Takanari; Hagihara, Akihito; Iihara, Koji

2018-03-27

This cross-sectional survey explored the characteristics and outcomes of direct oral anticoagulant (DOAC)-associated nontraumatic intracerebral hemorrhages (ICHs) by analyzing a large nationwide Japanese discharge database. We analyzed data from 2,245 patients who experienced ICHs while taking anticoagulants (DOAC: 227; warfarin: 2,018) and were urgently hospitalized at 621 institutions in Japan between April 2010 and March 2015. We compared the DOAC- and warfarin-treated patients based on their backgrounds, ICH severities, antiplatelet therapies at admission, hematoma removal surgeries, reversal agents, mortality rates, and modified Rankin Scale scores at discharge. DOAC-associated ICHs were less likely to cause moderately or severely impaired consciousness (DOAC-associated ICHs: 31.3%; warfarin-associated ICHs: 39.4%; p = 0.002) or require surgical removal (DOAC-associated ICHs: 5.3%; warfarin-associated ICHs: 9.9%; p = 0.024) in the univariate analysis. Propensity score analysis revealed that patients with DOAC-associated ICHs also exhibited lower mortality rates within 1 day (odds ratio [OR] 4.96, p = 0.005), within 7 days (OR 2.29, p = 0.037), and during hospitalization (OR 1.96, p = 0.039). This nationwide study revealed that DOAC-treated patients had less severe ICHs and lower mortality rates than did warfarin-treated patients, probably due to milder hemorrhages at admission and lower hematoma expansion frequencies. Copyright © 2018 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.

Cost-effectiveness of pharmacogenetics-guided warfarin therapy vs. alternative anticoagulation in atrial fibrillation.

Science.gov (United States)

Pink, J; Pirmohamed, M; Lane, S; Hughes, D A

2014-02-01

Pharmacogenetics-guided warfarin dosing is an alternative to standard clinical algorithms and new oral anticoagulants for patients with nonvalvular atrial fibrillation. However, clinical evidence for pharmacogenetics-guided warfarin dosing is limited to intermediary outcomes, and consequently, there is a lack of information on the cost-effectiveness of anticoagulation treatment options. A clinical trial simulation of S-warfarin was used to predict times within therapeutic range for different dosing algorithms. Relative risks of clinical events, obtained from a meta-analysis of trials linking times within therapeutic range with outcomes, served as inputs to an economic analysis. Neither dabigatran nor rivaroxaban were cost-effective options. Along the cost-effectiveness frontier, in relation to clinically dosed warfarin, pharmacogenetics-guided warfarin and apixaban had incremental cost-effectiveness ratios of £13,226 and £20,671 per quality-adjusted life year gained, respectively. On the basis of our simulations, apixaban appears to be the most cost-effective treatment.

Apixaban versus warfarin in patients with atrial fibrillation.

Science.gov (United States)

Granger, Christopher B; Alexander, John H; McMurray, John J V; Lopes, Renato D; Hylek, Elaine M; Hanna, Michael; Al-Khalidi, Hussein R; Ansell, Jack; Atar, Dan; Avezum, Alvaro; Bahit, M Cecilia; Diaz, Rafael; Easton, J Donald; Ezekowitz, Justin A; Flaker, Greg; Garcia, David; Geraldes, Margarida; Gersh, Bernard J; Golitsyn, Sergey; Goto, Shinya; Hermosillo, Antonio G; Hohnloser, Stefan H; Horowitz, John; Mohan, Puneet; Jansky, Petr; Lewis, Basil S; Lopez-Sendon, Jose Luis; Pais, Prem; Parkhomenko, Alexander; Verheugt, Freek W A; Zhu, Jun; Wallentin, Lars

2011-09-15

Vitamin K antagonists are highly effective in preventing stroke in patients with atrial fibrillation but have several limitations. Apixaban is a novel oral direct factor Xa inhibitor that has been shown to reduce the risk of stroke in a similar population in comparison with aspirin. In this randomized, double-blind trial, we compared apixaban (at a dose of 5 mg twice daily) with warfarin (target international normalized ratio, 2.0 to 3.0) in 18,201 patients with atrial fibrillation and at least one additional risk factor for stroke. The primary outcome was ischemic or hemorrhagic stroke or systemic embolism. The trial was designed to test for noninferiority, with key secondary objectives of testing for superiority with respect to the primary outcome and to the rates of major bleeding and death from any cause. The median duration of follow-up was 1.8 years. The rate of the primary outcome was 1.27% per year in the apixaban group, as compared with 1.60% per year in the warfarin group (hazard ratio with apixaban, 0.79; 95% confidence interval [CI], 0.66 to 0.95; P<0.001 for noninferiority; P=0.01 for superiority). The rate of major bleeding was 2.13% per year in the apixaban group, as compared with 3.09% per year in the warfarin group (hazard ratio, 0.69; 95% CI, 0.60 to 0.80; P<0.001), and the rates of death from any cause were 3.52% and 3.94%, respectively (hazard ratio, 0.89; 95% CI, 0.80 to 0.99; P=0.047). The rate of hemorrhagic stroke was 0.24% per year in the apixaban group, as compared with 0.47% per year in the warfarin group (hazard ratio, 0.51; 95% CI, 0.35 to 0.75; P<0.001), and the rate of ischemic or uncertain type of stroke was 0.97% per year in the apixaban group and 1.05% per year in the warfarin group (hazard ratio, 0.92; 95% CI, 0.74 to 1.13; P=0.42). In patients with atrial fibrillation, apixaban was superior to warfarin in preventing stroke or systemic embolism, caused less bleeding, and resulted in lower mortality. (Funded by Bristol-Myers Squibb

Verification of Pharmacogenetics-Based Warfarin Dosing Algorithms in Han-Chinese Patients Undertaking Mechanic Heart Valve Replacement

Science.gov (United States)

Zhao, Li; Chen, Chunxia; Li, Bei; Dong, Li; Guo, Yingqiang; Xiao, Xijun; Zhang, Eryong; Qin, Li

2014-01-01

Objective To study the performance of pharmacogenetics-based warfarin dosing algorithms in the initial and the stable warfarin treatment phases in a cohort of Han-Chinese patients undertaking mechanic heart valve replacement. Methods We searched PubMed, Chinese National Knowledge Infrastructure and Wanfang databases for selecting pharmacogenetics-based warfarin dosing models. Patients with mechanic heart valve replacement were consecutively recruited between March 2012 and July 2012. The predicted warfarin dose of each patient was calculated and compared with the observed initial and stable warfarin doses. The percentage of patients whose predicted dose fell within 20% of their actual therapeutic dose (percentage within 20%), and the mean absolute error (MAE) were utilized to evaluate the predictive accuracy of all the selected algorithms. Results A total of 8 algorithms including Du, Huang, Miao, Wei, Zhang, Lou, Gage, and International Warfarin Pharmacogenetics Consortium (IWPC) model, were tested in 181 patients. The MAE of the Gage, IWPC and 6 Han-Chinese pharmacogenetics-based warfarin dosing algorithms was less than 0.6 mg/day in accuracy and the percentage within 20% exceeded 45% in all of the selected models in both the initial and the stable treatment stages. When patients were stratified according to the warfarin dose range, all of the equations demonstrated better performance in the ideal-dose range (1.88–4.38 mg/day) than the low-dose range (warfarin dose prediction and in the low-dose and the ideal-dose ranges. Conclusions All of the selected pharmacogenetics-based warfarin dosing regimens performed similarly in our cohort. However, the algorithms of Wei, Huang, and Miao showed a better potential for warfarin prediction in the initial and the stable treatment phases in Han-Chinese patients undertaking mechanic heart valve replacement. PMID:24728385

Pulmonary Embolism Inpatients Treated With Rivaroxaban Had Shorter Hospital Stays and Lower Costs Compared With Warfarin.

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Margolis, Jay M; Deitelzweig, Steven; Kline, Jeffrey; Tran, Oth; Smith, David M; Crivera, Concetta; Bookhart, Brahim; Schein, Jeff

2016-11-01

Using real-world data, this study compares inpatient length of stay (LOS) and costs for patients with a primary diagnosis of pulmonary embolism (PE) initiating treatment with oral anticoagulation with rivaroxaban versus warfarin. Hospitalizations from MarketScan's Hospital Drug Database were selected from November 1, 2012, through December 31, 2013, for adults with a primary diagnosis of PE initiating treatment with rivaroxaban or warfarin. Warfarin patients were matched 1:1 to rivaroxaban patients using exact and propensity score matching. Hospital LOS, treatment patterns, and hospitalization costs were evaluated. Matched cohorts included 751 rivaroxaban-treated patients and 751 warfarin-treated patients. Adjusted mean LOS was 3.77 days for rivaroxaban patients (95% CI, 3.66-3.87 days) and 5.48 days for warfarin patients (95% CI, 5.33-5.63 days; P < .001). Mean (SD) LOS was shorter for patients taking rivaroxaban whether admission was for provoked PE (rivaroxaban: 5.2 [5.1] days; warfarin: 7.0 [6.5] days; P < .001) or unprovoked PE (rivaroxaban: 3.4 [2.3] days; warfarin: 5.1 [2.7] days; P < .001). Mean (SD) days from first dose to discharge were 2.5 (1.7) (rivaroxaban) and 4.0 (2.9) (warfarin) when initiated with parenteral anticoagulants (P < .001) and 2.7 (1.7) (rivaroxaban) and 4.0 (2.2) (warfarin) without parenteral anticoagulants (P < .001). The rivaroxaban cohort incurred significantly lower unadjusted mean (SD) hospitalization costs (rivaroxaban: $8473 [$9105]; warfarin: $10,291 [$9185]; P < .001), confirmed by covariate adjustment with generalized linear modeling estimating predicted mean hospitalization costs of $8266 for rivaroxaban patients (95% CI, $7851-$8681) and $10,511 for warfarin patients (95% CI, $10,031-$10,992; P < .001). patients with PE treated with rivaroxaban incurred significantly lower hospitalization costs by $2245 per admission compared with patients treated with warfarin, which was attributable to cost offsets from 1.71 fewer days of

Warfarin-induced calciphylaxis successfully treated with sodium thiosulphate.

Science.gov (United States)

Hafiji, Juber; Deegan, Patrick; Brais, Rebecca; Norris, Paul

2013-05-01

Calciphylaxis is a rare life-threatening form of skin necrosis. Although traditionally observed in patients with end-stage renal disease and/or hyperparathyroidism, calciphylaxis has also been reported to occur in 'non-traditional' patients with normal renal and parathyroid function. We report a case of warfarin-induced calciphylaxis treated successfully with sodium thiosulphate and discuss the role of Vitamin K2 as a potential therapeutic option in the management of warfarin-induced calciphylaxis. © 2012 The Authors. Australasian Journal of Dermatology © 2012 The Australasian College of Dermatologists.

SPECIAL CONSIDERATIONS REGARDING WARFARIN DOSE TITRATION IN PATIENTS WITH ATRIAL FIBRILLATION DEPENDING ON CLINICAL FACTORS

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E. L. Artanova

2011-01-01

Full Text Available Aim. To study the relations of clinical characteristics and individual warfarin dose titration in patients with atrial fibrillation. Material and methods. Period of warfarin dose titration was analyzed in 68 patients with atrial fibrillation due to ischemic heart disease. Adjusted warfarin dose in milligram, duration of dose titration in days and maximal international normalized ratio (INR were taken into account. Sex, age, history of myocardial infarction and stroke, concomitant diseases, amiodarone therapy were considered among clinical characteristics. Results. Adjusted warfarin dose was significantly higher in obesity , and it was lower in case of experienced myocardial infarction. The INR highest levels and maximal amplitudes of its fluctuations were observed in patients with thyroid gland nodes and smokers. Period of warfarin dose titration was longer in patients treated with amiodarone. Conclusion. Warfarin dose titration in patients with atrial fibrillation depends on the presence of myocardial infarction, obesity , thyroid nodular changes, smoking and amiodarone treatment.

Initiation and persistence with warfarin therapy in atrial fibrillation according to ethnicity

DEFF Research Database (Denmark)

Hansen, Carolina Malta; Olesen, Jonas Bjerring; Hansen, Morten Lock

2012-01-01

The aim of this study was to investigate initiation of and persistence with warfarin treatment in patients with atrial fibrillation (AF) according to ethnicity. Patients hospitalized with first-time AF from 1997 to 2009, prescription claims of warfarin and country of birth were identified...... by individual-level linkage of nationwide administrative agencies. Cox proportional hazards models were used to estimate the relationship between covariates affecting initiation and non-persistence with warfarin treatment. A total of 151,537 patients were included in the study and 5,061(3.3%) were of non......-Danish origin. CHADS2 score distribution varied substantially according to ethnicity, the proportion of patients with CHADS2 score ≥1 being 79.2, 78.1, 65.9, and 46.0% for patients of Danish, Western, Eastern, and African origin, respectively. 79,239(52.4%) of all patients initiated treatment with warfarin...

Monkey liver cytochrome P450 2C19 is involved in R- and S-warfarin 7-hydroxylation.

Science.gov (United States)

Hosoi, Yoshio; Uno, Yasuhiro; Murayama, Norie; Fujino, Hideki; Shukuya, Mitsunori; Iwasaki, Kazuhide; Shimizu, Makiko; Utoh, Masahiro; Yamazaki, Hiroshi

2012-12-15

Cynomolgus monkeys are widely used as primate models in preclinical studies. However, some differences are occasionally seen between monkeys and humans in the activities of cytochrome P450 enzymes. R- and S-warfarin are model substrates for stereoselective oxidation in humans. In this current research, the activities of monkey liver microsomes and 14 recombinantly expressed monkey cytochrome P450 enzymes were analyzed with respect to R- and S-warfarin 6- and 7-hydroxylation. Monkey liver microsomes efficiently mediated both R- and S-warfarin 7-hydroxylation, in contrast to human liver microsomes, which preferentially catalyzed S-warfarin 7-hydroxylation. R-Warfarin 7-hydroxylation activities in monkey liver microsomes were not inhibited by α-naphthoflavone or ketoconazole, and were roughly correlated with P450 2C19 levels and flurbiprofen 4-hydroxylation activities in microsomes from 20 monkey livers. In contrast, S-warfarin 7-hydroxylation activities were not correlated with the four marker drug oxidation activities used. Among the 14 recombinantly expressed monkey P450 enzymes tested, P450 2C19 had the highest activities for R- and S-warfarin 7-hydroxylations. Monkey P450 3A4 and 3A5 slowly mediated R- and S-warfarin 6-hydroxylations. Kinetic analysis revealed that monkey P450 2C19 had high V(max) and low K(m) values for R-warfarin 7-hydroxylation, comparable to those for monkey liver microsomes. Monkey P450 2C19 also mediated S-warfarin 7-hydroxylation with V(max) and V(max)/K(m) values comparable to those for recombinant human P450 2C9. R-warfarin could dock favorably into monkey P450 2C19 modeled. These results collectively suggest high activities for monkey liver P450 2C19 toward R- and S-warfarin 6- and 7-hydroxylation in contrast to the saturation kinetics of human P450 2C9-mediated S-warfarin 7-hydroxylation. Copyright © 2012 Elsevier Inc. All rights reserved.

Effect of Ankaferd Blood Stopper on Skin Superoxide Dismutase and Catalase Activities in Warfarin-Treated Rats.

Science.gov (United States)

Aktop, Sertaç; Emekli-Alturfan, Ebru; Gönül, Onur; Göçmen, Gökhan; Garip, Hasan; Yarat, Ayşen; Göker, Kamil

2017-03-01

Ankaferd Blood Stopper (ABS) is a new promising local hemostatic agent, and its mechanism on hemostasis has been shown by many studies. However, the effects of ABS on skin superoxide dismutase (SOD) and catalase (CAT) activities have not been investigated before. The aim of this study was to evaluate the effects of this new generation local hemostatic agent on warfarin-treated rats focusing on its the antioxidant potential in short-term soft tissue healing. Twelve systemically warfarin treated (warfarin group) and 12 none treated Wistar Albino rats (control group) were selected for the trial. Rats in the warfarin group were treated intraperitonally with 0.1 mg/kg warfarin, and rats in the control group were given 1 mL/kg saline 3 days earlier to surgical procedure and continued until killing. All rats had incisions on dorsal dermal tissue, which was applied ABS or no hemostatic agent before suturing. Six of each group were killed on day 4, and the other 6 were killed on day 8. Blood and skin samples were taken. Prothrombin time (PT) in blood samples, CAT, and SOD activities in skin samples were determined. Warfarin treatment dose was found to be convenient and warfarin treatment increased the PT levels as expected. Warfarin treatment decreased CAT activity significantly compared to the control group. The ABS treatment significantly increased SOD activities in the warfarin group at the end of the eighth day. Ankaferd Blood Stopper acted positively in short-term tissue healing by increasing SOD activity in warfarin-treated rats. Therefore, ABS may be suggeted as a promoting factor in tissue healing.

Verification of pharmacogenetics-based warfarin dosing algorithms in Han-Chinese patients undertaking mechanic heart valve replacement.

Science.gov (United States)

Zhao, Li; Chen, Chunxia; Li, Bei; Dong, Li; Guo, Yingqiang; Xiao, Xijun; Zhang, Eryong; Qin, Li

2014-01-01

To study the performance of pharmacogenetics-based warfarin dosing algorithms in the initial and the stable warfarin treatment phases in a cohort of Han-Chinese patients undertaking mechanic heart valve replacement. We searched PubMed, Chinese National Knowledge Infrastructure and Wanfang databases for selecting pharmacogenetics-based warfarin dosing models. Patients with mechanic heart valve replacement were consecutively recruited between March 2012 and July 2012. The predicted warfarin dose of each patient was calculated and compared with the observed initial and stable warfarin doses. The percentage of patients whose predicted dose fell within 20% of their actual therapeutic dose (percentage within 20%), and the mean absolute error (MAE) were utilized to evaluate the predictive accuracy of all the selected algorithms. A total of 8 algorithms including Du, Huang, Miao, Wei, Zhang, Lou, Gage, and International Warfarin Pharmacogenetics Consortium (IWPC) model, were tested in 181 patients. The MAE of the Gage, IWPC and 6 Han-Chinese pharmacogenetics-based warfarin dosing algorithms was less than 0.6 mg/day in accuracy and the percentage within 20% exceeded 45% in all of the selected models in both the initial and the stable treatment stages. When patients were stratified according to the warfarin dose range, all of the equations demonstrated better performance in the ideal-dose range (1.88-4.38 mg/day) than the low-dose range (pharmacogenetics-based warfarin dosing regimens performed similarly in our cohort. However, the algorithms of Wei, Huang, and Miao showed a better potential for warfarin prediction in the initial and the stable treatment phases in Han-Chinese patients undertaking mechanic heart valve replacement.

Fluconazole-Warfarin Interaction: A case report with deadly consequences

Directory of Open Access Journals (Sweden)

Elliot V Hersh

2017-06-01

Full Text Available Adverse drug-drug interactions are more common in the elderly because of the commonality of polypharmacy. When one of the interacting drugs has a low therapeutic index, the consequences can be life-threatening or fatal. This case describes a fatal cerebral haemorrhage in an 80-year old male on stable doses of warfarin prescribed by his cardiologist, who was prescribed fluconazole 200mg, once daily, for 14 days by an oral and maxillofacial surgeon to treat an intraoral fungal infection. The oral surgeon was aware that the patient was on warfarin and his INR two days prior to the appointment was 2.4. While a drug interaction alert was sent to the patient’s primary care family physician regarding fluconazole and the simvastatin she had been prescribing, the interaction was not reviewed by her for another 9- days. She then informed the patient that “it was fine” to finish the fluconazole. However, this phone conversation prompted the patient to discontinue the fluconazole after 8 doses. Two days later, the patient was confused and driving his car erratically. His son rushed him to the hospital where a CAT scan revealed a large frontal intraparenchymal haemorrhage. His INR was a 9.6. This event illustrates that this well-documented adverse drug interaction needs to be better highlighted in dental and medical training. Warfarin’s primary metabolic pathway involves the cytochrome P-450 2C9 isoform and fluconazole is a strong inhibitor of this enzyme, with the potential outcome being excessive warfarin blood levels. Frequent INR monitoring with potential warfarin dosage adjustments downward if fluconazole is prescribed, or the complete avoidance of fluconazole is recommended in patients taking warfarin. The importance of communication and coordinated care between different health care providers cannot be overstated.

Impact on survival of warfarin in patients with pulmonary arterial hypertension receiving subcutaneous treprostinil.

Science.gov (United States)

Ascha, Mona; Zhou, Xuan; Rao, Youlan; Minai, Omar A; Tonelli, Adriano R

2017-10-01

Anticoagulation is a common treatment modality in patients with pulmonary arterial hypertension (PAH). Further studies are needed to appropriately assess the risk/benefit ratio of anticoagulation, particularly in PAH patients receiving PAH-specific therapies. We use observational long-term data on PAH patients treated with subcutaneous (SQ) treprostinil from a large open-label study. Patients were followed for up to 4 years. The use of warfarin and bleeding events were recorded. At total of 860 patients (age [mean±SD] 46±15 years, 76% female, 83% Caucasian, 49% idiopathic PAH, and 76% New York Heart Association [NYHA] functional class III) were included. All patients received SQ treprostinil (15% also other pulmonary hypertension [PH]-therapies) and 590 (69%) received warfarin during the study. The proportions of women, African American, and idiopathic pulmonary hypertension (IPAH) patients were higher in the group receiving warfarin. A higher proportion of patients with congenital heart disease and portopulmonary hypertension did not receive warfarin. There were no differences in unadjusted long-term survival between PAH patients receiving warfarin or not (log-rank test, P value=.69), even when only considering idiopathic PAH (P=.32). In addition, no difference was found in adjusted long-term survival both in PAH (P=.84) and idiopathic PAH patients (P=.44) based on the use of warfarin. Furthermore, no survival difference based on the use of warfarin were noted between propensity score-matched PAH patients (P=.37). Long-term anticoagulation with warfarin was not associated with any significant effect on survival in PAH or idiopathic PAH patients treated with SQ treprostinil. © 2017 John Wiley & Sons Ltd.

Efficacy of protocol-based pharmacotherapy management on anticoagulation with warfarin for patients with cardiovascular surgery.

Science.gov (United States)

Katada, Y; Nakagawa, S; Minakata, K; Odaka, M; Taue, H; Sato, Y; Yonezawa, A; Kayano, Y; Yano, I; Nakatsu, T; Sakamoto, K; Uehara, K; Sakaguchi, H; Yamazaki, K; Minatoya, K; Sakata, R; Matsubara, K

2017-10-01

Anticoagulation therapy with warfarin requires periodic monitoring of prothrombin time-international normalized ratio (PT-INR) and adequate dose adjustments based on the data to minimize the risk of bleeding and thromboembolic events. In our hospital, we have developed protocol-based pharmaceutical care, which we called protocol-based pharmacotherapy management (PBPM), for warfarin therapy. The protocol requires pharmacists to manage timing of blood sampling for measuring PT-INR and warfarin dosage determination based on an algorithm. This study evaluated the efficacy of PBPM in warfarin therapy by comparing to conventional pharmaceutical care. From October 2013 to June 2015, a total of 134 hospitalized patients who underwent cardiovascular surgeries received post-operative warfarin therapy. The early series of patients received warfarin therapy as the conventional care (control group, n=77), whereas the latter received warfarin therapy based on the PBPM (PBPM group, n=68). These patients formed the cohort of the present study and were retrospectively analysed. The indications for warfarin included aortic valve replacement (n=56), mitral valve replacement (n=4), mitral valve plasty (n=22) and atrial fibrillation (n=29). There were no differences in patients' characteristics between both groups. The percentage time in therapeutic range in the first 10 days was significantly higher in the PBPM group (47.1%) than that in the control group (34.4%, PWarfarin therapy based on our novel PBPM was clinically safe and resulted in significantly better anticoagulation control compared to conventional care. © 2017 John Wiley & Sons Ltd.

Warfarin resistance associated with genetic polymorphism of VKORC1: linking clinical response to molecular mechanism using computational modeling.

Science.gov (United States)

Lewis, Benjamin C; Nair, Pramod C; Heran, Subash S; Somogyi, Andrew A; Bowden, Jeffrey J; Doogue, Matthew P; Miners, John O

2016-01-01

The variable response to warfarin treatment often has a genetic basis. A protein homology model of human vitamin K epoxide reductase, subunit 1 (VKORC1), was generated to elucidate the mechanism of warfarin resistance observed in a patient with the Val66Met mutation. The VKORC1 homology model comprises four transmembrane (TM) helical domains and a half helical lid domain. Cys132 and Cys135, located in the N-terminal end of TM-4, are linked through a disulfide bond. Two distinct binding sites for warfarin were identified. Site-1, which binds vitamin K epoxide (KO) in a catalytically favorable orientation, shows higher affinity for S-warfarin compared with R-warfarin. Site-2, positioned in the domain occupied by the hydrophobic tail of KO, binds both warfarin enantiomers with similar affinity. Displacement of Arg37 occurs in the Val66Met mutant, blocking access of warfarin (but not KO) to Site-1, consistent with clinical observation of warfarin resistance.

Thromboembolic and Major Bleeding Events With Rivaroxaban Versus Warfarin Use in a Real-World Setting.

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Russo-Alvarez, Giavanna; Martinez, Kathryn A; Valente, Megan; Bena, James; Hu, Bo; Luxenburg, Jennifer; Chaitoff, Alexander; Ituarte, Catherine; Brateanu, Andrei; Rothberg, Michael B

2018-01-01

Although randomized trials demonstrate the noninferiority of rivaroxaban compared with warfarin in the context of nonvalvular atrial fibrillation (AF), little is known about how these drugs compare in practice. To assess the relative effectiveness and safety of rivaroxaban versus warfarin in a large health system and to evaluate this association by time in therapeutic range (TTR). We conducted a retrospective cohort study with propensity matching in the Cleveland Clinic Health System. The study included patients initiated on warfarin or rivaroxaban for thromboembolic prevention in nonvalvular AF between January 2012 and July 2016. The main outcomes were thromboembolic events and major bleeds. Analyses were stratified by warfarin patients' TTR. The cohort consisted of 472 propensity-matched pairs. The mean age was 73.6 years (SD = 11.7), and the mean CHADS 2 score was 1.8. The median TTR for warfarin patients was 64%. In the propensity-matched analysis, there was no significant difference in thromboembolic or major bleeding events between groups. Among warfarin patients with a TTR warfarin and rivaroxaban were associated with similar safety and effectiveness, even among those with suboptimal therapeutic control. Individualized decision making, taking into account the nontherapeutic tradeoffs associated with these medications (eg, monitoring, half-life, cost) is warranted.

Preemptive warfarin dose reduction after initiation of sulfamethoxazole-trimethoprim or metronidazole.

Science.gov (United States)

Powers, Anna; Loesch, Erin B; Weiland, Anthony; Fioravanti, Nicole; Lucius, David

2017-07-01

To evaluate the utility of a preemptive warfarin dose reduction at the time of initiation of either sulfamethoxazole-trimethoprim or metronidazole, a retrospective chart review of patients who received an outpatient prescription for warfarin and either sulfamethoxazole-trimethoprim and/or metronidazole from July 1, 2011 to July 1, 2015 was conducted. Clinical outcomes compared Veterans who had a warfarin dose reduction and those who did not within 120 h (5 days) of antibiotic initiation. The primary outcome compared the pre-and post-antibiotic International Normalized Ratio (INR) of patients in the intervention group (warfarin dose reduction) with those in the control group (no intervention). Secondary outcomes assessed incidence of thromboembolic and major bleeding events within 30 days of antibiotic completion. Fifty patients were assessed. Forty-nine patients had at least one follow-up appointment; 126 follow-up visits were evaluated. There was a statistically significant difference for the change in therapeutic INR at the first follow-up appointment (p = 0.029) for those patients in the control group. On average, the patients in the intervention group required fewer follow-up visits (p = 0.019). There were no statistically significant differences for the overall rate of therapeutic INR values between groups, as well as no instances of a thromboembolic or major bleeding events during the follow-up period. Clinically significant differences were observed for patients who received a preemptive warfarin dose reduction upon initiation of sulfamethoxazole-trimethoprim or metronidazole. Patients in the intervention group required fewer follow-up appointments and were more likely maintain a therapeutic INR within the 30 days following the antibiotic course. Results of this study will be presented the at Pharmacy and Therapeutics committee in an effort to seek approval for policy development to initiate a local preemptive warfarin dose adjustment as a standard

Survey of the use of warfarin and the newer anticoagulant dabigatran in patients with atrial fibrillation

Directory of Open Access Journals (Sweden)

Choi JC

2014-02-01

Full Text Available Jiyoon C Choi,1 Marco d DiBonaventura,2 Lewis Kopenhafer,2 Winnie W Nelson31LifeScan, Inc, West Chester, PA, 2Health Sciences Practice, Kantar Health, New York, NY, 3Janssen Scientific Affairs LLC, Raritan, NJ, USABackground: Oral dabigatran was recently approved as an alternative to warfarin for prevention of stroke and systemic embolism in patients with nonvalvular atrial fibrillation. Unlike warfarin, dabigatran has a fixed dosage and few drug interactions, and does not require anticoagulation monitoring or dietary restrictions.Methods: This study aimed to describe and compare characteristics of patients with atrial fibrillation who used dabigatran or only warfarin. Patients with a self-reported diagnosis of atrial fibrillation aged ≥18 years who were receiving (or had received warfarin or dabigatran completed an online survey. Differences in characteristics of dabigatran and warfarin users were tested using chi-squared tests and analysis of variance for categorical and continuous variables, respectively.Results: Overall, 364 patients were surveyed (204 warfarin users, 160 dabigatran users. The mean age was 65.1 years, and 68.7% were male. Dabigatran users were more likely than warfarin users to be female (36.9% versus 27.0% and to have experienced adverse events, including gastrointestinal bleeding, in the 3 months before the survey (21.9% versus 6.9%; P<0.05. Both groups reported high medication adherence (dabigatran users 0.65 versus warfarin users 0.63 missed doses/month. Dabigatran users were more likely than warfarin users to discuss treatment options with their physician before beginning therapy (36.9% versus 24.5%; P<0.05 and less likely to switch anticoagulant medication (10.7% versus 31.9%; P<0.05. Although dabigatran users were more likely to experience adverse events, they reported greater satisfaction with anticoagulation treatment than warfarin users.Conclusion: The efficacy and convenience reported by dabigatran users

Warfarin Initiation, Atrial Fibrillation, and Kidney Function: Comparative Effectiveness and Safety of Warfarin in Older Adults With Newly Diagnosed Atrial Fibrillation.

Science.gov (United States)

Jun, Min; James, Matthew T; Ma, Zhihai; Zhang, Jianguo; Tonelli, Marcello; McAlister, Finlay A; Manns, Braden J; Ravani, Pietro; Quinn, Robert R; Wiebe, Natasha; Perkovic, Vlado; Wilton, Stephen B; Winkelmayer, Wolfgang C; Hemmelgarn, Brenda R

2017-06-01

The effectiveness and safety of warfarin use among patients with atrial fibrillation (AF) and reduced kidney function are uncertain. Community-based retrospective cohort study (May 1, 2003, to March 31, 2012) using province-wide laboratory and administrative data in Alberta, Canada. 14,892 adults 66 years or older with new AF and a measurement of kidney function. Long-term dialysis patients or kidney transplant recipients were excluded. Propensity scores were used to construct a matched-pairs cohort of patients with AF who did and did not have a warfarin prescription within a 60-day period surrounding their AF diagnosis. Within 1 year of initiating warfarin therapy (or the matched date for nonusers): (1) the composite of all-cause death, ischemic stroke, or transient ischemic attack (also assessed as separate end points) and (2) first hospitalization or emergency department visit for a major bleeding episode defined as an intracranial, upper or lower gastrointestinal, or other bleeding. Baseline glomerular filtration rate (GFR) was estimated using the CKD-EPI creatinine equation. Patients were matched within estimated GFR (eGFR) categories: ≥90, 60 to 89, 45 to 59, 30 to 44, and warfarin therapy initiation was associated with lower risk for the composite outcome compared to nonuse (adjusted HRs [95% CI] for eGFR categories ≥ 90, 60-89, 45-59, 30-44, and warfarin therapy was not associated with higher risk for major bleeding except for those with eGFRs of 60 to 89mL/min/1.73m 2 (HR, 1.36; 95% CI, 1.13-1.64). Selection bias. Among older adults with AF, warfarin therapy initiation was associated with a significantly lower 1-year risk for the composite outcome across all strata of kidney function. The risk for major bleeding associated with warfarin use was increased only among those with eGFRs of 60 to 89mL/min/1.73m 2 . Copyright © 2016 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.

Comparison of 3-Factor Prothrombin Complex Concentrate and Low-Dose Recombinant Factor VIIa for Warfarin Reversal

OpenAIRE

Chapman, Scott A; Irwin, Eric D; Abou-Karam, Nada M; Rupnow, Nichole M; Hutson, Katherine E; Vespa, Jeffrey; Roach, Robert M

2014-01-01

Introduction Prothrombin complex concentrate (PCC) and recombinant Factor VIIa (rFVIIa) have been used for emergent reversal of warfarin anticoagulation. Few clinical studies have compared these agents in warfarin reversal. We compared warfarin reversal in patients who received either 3 factor PCC (PCC3) or low-dose rFVIIa (LDrFVIIa) for reversal of warfarin anticoagulation. Methods Data were collected from medical charts of patients who received at least one dose of PCC3 (20 units/kg) or LDr...

Outcomes With Edoxaban Versus Warfarin in Patients With Previous Cerebrovascular Events

DEFF Research Database (Denmark)

Rost, Natalia S; Giugliano, Robert P; Ruff, Christian T

2016-01-01

BACKGROUND AND PURPOSE: Patients with atrial fibrillation and previous ischemic stroke (IS)/transient ischemic attack (TIA) are at high risk of recurrent cerebrovascular events despite anticoagulation. In this prespecified subgroup analysis, we compared warfarin with edoxaban in patients with ver......BACKGROUND AND PURPOSE: Patients with atrial fibrillation and previous ischemic stroke (IS)/transient ischemic attack (TIA) are at high risk of recurrent cerebrovascular events despite anticoagulation. In this prespecified subgroup analysis, we compared warfarin with edoxaban in patients...... with versus without previous IS/TIA. METHODS: ENGAGE AF-TIMI 48 (Effective Anticoagulation With Factor Xa Next Generation in Atrial Fibrillation-Thrombolysis in Myocardial Infarction 48) was a double-blind trial of 21 105 patients with atrial fibrillation randomized to warfarin (international normalized ratio......). Because only HDER is approved, we focused on the comparison of HDER versus warfarin. RESULTS: Of 5973 (28.3%) patients with previous IS/TIA, 67% had CHADS2 (congestive heart failure, hypertension, age, diabetes, prior stroke/transient ischemic attack) >3 and 36% were ≥75 years. Compared with 15 132...

Warfarin and vitamin K intake in the era of pharmacogenetics

OpenAIRE

Lurie, Yael; Loebstein, Ronen; Kurnik, Daniel; Almog, Shlomo; Halkin, Hillel

2010-01-01

The considerable variability in the warfarin dose–response relationship between individuals, is explained mainly by genetic variation in its major metabolic (CYP2C9) and target (VKORC1) enzymes. Despite the predominance of pharmacogenetics, environmental factors also affect the pharmacokinetics and pharmacodynamics of warfarin, and are often overlooked. Among these factors, dietary and supplemental vitamin K consumption is a controllable contributor to within-, and between-patient variability...

Hepatic uptake and storage of warfarin. The relation with the target enzyme vitamin K 2,3-epoxide reductase

International Nuclear Information System (INIS)

Thijssen, H.H.; Baars, L.G.

1987-01-01

The mechanisms of the reported dose-dependent warfarin pharmacokinetics were investigated using [ 14 C]warfarin. When administered in microdoses (9 micrograms i.v.) to rats (male Wistars, 270-300 g), a steep distribution phase (T1/2 = 0.25 hr) was followed by a relatively slow beta-phase (T1/2 = 40 hr). The observed volume of distribution was 390 ml. This pharmacokinetic behavior contrasted highly with the one seen for higher (greater than 0.2 mg/kg) doses (unlabeled) warfarin; volume of distribution = 45 ml, T1/2 = 12.5 hr. If a macrodose (0.2 mg/kg) preceded (16 hr) the microdose, normal pharmacokinetics were observed for the latter, suggesting a saturable deep compartment. The administration of 4-hydroxycoumarins (i.e., acenocoumarol, phenprocoumon and warfarin) after the microdose of [ 14 C]warfarin was in its beta-phase caused a rapid rise of plasma [ 14 C]warfarin indicating [ 14 C]warfarin to be displaced from the deep compartment. The rate of appearance of [ 14 C]warfarin was 0.3 hr-1 irrespective the 4-hydroxycoumarin used. The hepatic distribution of [ 14 C]warfarin was investigated and the effect of a displacer thereupon. Fifty-three hours after the [ 14 C]warfarin administration, the liver contained about 40% of the dose; 45% of it was bound to microsomes. The administration of acenocoumarol (0.2 mg/kg) at 48 hr, halved the liver content. [ 14 C]warfarin was redistributed from microsomes (-65%) and from the 10,000 X g pellet (-65%) into the cytosol (+260%) and the plasma (+320%). Microsomal bound [ 14 C]warfarin in vitro could not be washed out or be displaced unless dithiothreitol (50 mM) was included in the washing buffers

Warfarin and Rivaroxaban Duplication: A Case Report and Medication Error Analysis.

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Fusco, Julie A; Paulus, Eric J; Shubat, Alexandra R; Miah, Sharminara

2015-12-01

A 62-year-old African American man received unintentional duplicate anticoagulation therapy with warfarin 5 mg and rivaroxaban 20 mg daily for the treatment of recurrent pulmonary embolism. The patient presented to the anticoagulation clinic 6 days after hospital discharge with an International Normalized Ratio (INR) of 2.3 and he was instructed to continue warfarin 5 mg daily. Seven days later, he returned to the clinic with an INR >8.0 using a point-of-care device. He denied any signs or symptoms of bleeding. During the interview, he reported starting a new medication for neuropathy 5 days earlier. The clinical pharmacist contacted the dispensing pharmacy and determined rivaroxaban 20 mg was the new medication. The patient denied receiving new prescription counseling at the dispensing pharmacy. Because rivaroxaban can falsely elevate INR results, the actual INR value was unknown. To minimize the risk for recurrent venous thromboembolism, vitamin K was not administered and no warfarin doses were held. Rather, the patient was instructed to stop rivaroxaban and reduce the warfarin dose. Five days later, the patient returned with an INR of 4.3. He still had not experienced any signs or symptoms of bleeding. The patient was quickly stabilized on a warfarin maintenance dose of 22.5 mg weekly. The anticoagulation clinic pharmacist notified management at the clinic and at the dispensing pharmacy in an effort to identify process errors and prevent additional incidents.

VKORC1 polymorphisms and warfarin maintenance dose in population of Sakha (Yakuts).

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Chertovskikh, Y V; Malova, E U; Maksimova, N R; Popova, N V; Sychev, D A

2015-01-01

Vitamin K antagonists are effective in the prevention and treatment of thromboembolic disorders. Warfarin is one of the most widely prescribed vitamin K antagonists in the world [1, 2]. It has a narrow therapeutic range and a given dose may result in a large inter-individual variation of response. Insufficient dose may fail to prevent thromboembolism, while an overdose increases the risk of bleeding. Patient-specific factors (e.g., age, body size, race, concurrent diseases, and medications) explain some of the variability in warfarin dosage, but genetic factors influencing warfarin response explain a significantly higher proportion of this variability [3]. Molecular analysis of the gene that encodes the target enzyme vitamin K epoxide reductase complex 1 (VKORC1) strongly suggests that its genetic variations greatly affect the individual response to oral anticoagulants [4-7]. To evaluate effects of VKORC1 polymorphisms on warfarin dose excess anticoagulation (INR >4.0) in the population of Sakha (S) patients. 53 patients (29-women, 24-men) with atrial fibrillation (68%), congestive heart failure (60%), hypertension (49%) and cardiac valve replacement (26%) were recruited. The age range was 26-80 years, with a mean age of 62.87 ± 12.57 years.International normalized ratio and plasma warfarin concentrations were determined. Genotyping was carried out by RT-PCR (real-time PCR). The three genetic polymorphisms of the gene VKORC1 G3673A (rs9923231) were studied: normal (GG), heterozygous (GA) and homozygous (AA). Fisher exact probability test and chi-square test (with Yates correction) were applied to compare data among the AA and GG + GA groups; also Mann-Whitney test was used. The median maintenance daily dose of warfarin among AA carriers was 3.0 mg/day [1.25-7.5 mg], while in GG and GA patients it was 3.13 mg/day [1.88-7.92 mg]. The mean daily warfarin dosage was higher in GG and GA genotype carriers 4.05 mg/day (SD ± 1.7) than in patients with AA genotype 3

Measurement of warfarin in the oral fluid of patients undergoing anticoagulant oral therapy.

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Silvia Ghimenti

Full Text Available BACKGROUND: Patients on warfarin therapy undergo invasive and expensive checks for the coagulability of their blood. No information on coagulation levels is currently available between two controls. METHODOLOGY: A method was developed to determine warfarin in oral fluid by HPLC and fluorimetric detection. The chromatographic separation was performed at room temperature on a C-18 reversed-phase column, 65% PBS and 35% methanol mobile phase, flow rate 0.7 mL/min, injection volume 25 µL, excitation wavelength 310 nm, emission wavelength 400 nm. FINDINGS: The method was free from interference and matrix effect, linear in the range 0.2-100 ng/mL, with a detection limit of 0.2 ng/mL. Its coefficient of variation was <3% for intra-day measurements and <5% for inter-day measurements. The average concentration of warfarin in the oral fluid of 50 patients was 2.5±1.6 ng/mL (range 0.8-7.6 ng/mL. Dosage was not correlated to INR (r = -0.03, p = 0.85 but positively correlated to warfarin concentration in the oral fluid (r = 0.39, p = 0.006. The correlation between warfarin concentration and pH in the oral fluid (r = 0.37, p = 0.009 confirmed the importance of pH in regulating the drug transfer from blood. A correlation between warfarin concentration in the oral fluid and INR was only found in samples with pH values ≥7.2 (r = 0.84, p = 0.004. CONCLUSIONS: Warfarin diffuses from blood to oral fluid. The method allows to measure its concentration in this matrix and to analyze correlations with INR and other parameters.

Safety Outcomes of Apixaban Compared With Warfarin in Patients With End-Stage Renal Disease.

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Sarratt, Stefanie C; Nesbit, Ross; Moye, Robert

2017-06-01

Current guidelines make no specific recommendations on the selection of direct oral anticoagulants for the prevention and treatment of venous thromboembolism in patients with end-stage renal disease (ESRD) receiving hemodialysis. Based on these guidelines, warfarin remains the anticoagulant of choice in these patients. To compare bleeding rates in patients receiving apixaban or warfarin with ESRD undergoing chronic hemodialysis. This was a single-center, retrospective, institutional review board-approved cohort analysis. Patients with ESRD undergoing chronic hemodialysis and receiving anticoagulation therapy with either apixaban or warfarin were included in this study. All data were collected from paper charts and electronic medical records and included documentation of bleeding events and related interventions. The primary outcome of this study was clinically relevant major bleeding events. Secondary outcomes included clinically relevant nonmajor bleeding events and minor bleeding events. A total of 160 patients were included in this study (warfarin group, n = 120; apixaban group, n = 40). There were 7 major bleeding events in the warfarin group compared with zero in the apixaban group ( P = 0.34). There were similar rates of clinically relevant nonmajor bleeding events (12.5% vs 5.8%, P = 0.17) and minor bleeding (2.5% vs 2.5%, P = 0.74) events in patients receiving apixaban and warfarin. There were no observed differences in bleeding rates in patients receiving apixaban compared with those receiving warfarin. Apixaban may be a cautious consideration in hemodialysis patients until there is further insight into the effect of subsequent, multiple doses on drug accumulation and clinical outcomes.

Warfarin monitoring in nursing homes assessed by case histories. Do recommendations and electronic alerts affect judgements?

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Teruel, Reyes Serrano; Thue, Geir; Fylkesnes, Svein Ivar; Sandberg, Sverre; Kristoffersen, Ann Helen

2017-09-01

Older adults treated with warfarin are prone to complications, and high-quality monitoring is essential. The aim of this case history based study was to assess the quality of warfarin monitoring in a routine situation, and in a situation with an antibiotic-warfarin interaction, before and after receiving an electronic alert. In April 2014, a national web-based survey with two case histories was distributed among Norwegian nursing home physicians and general practitioners working part-time in nursing homes. Case A represented a patient on stable warfarin treatment, but with a substantial INR increase within the therapeutic interval. Case B represented a more challenging patient with trimethoprim sulfamethoxazole (TMS) treatment due to pyelonephritis. In both cases, the physicians were asked to state the next warfarin dose and the INR recall interval. In case B, the physicians could change their suggestions after receiving an electronic alert on the TMS-warfarin interaction. Three hundred and ninety eight physicians in 292 nursing homes responded. Suggested INR recall intervals and warfarin doses varied substantially in both cases. In case A, 61% gave acceptable answers according to published recommendations, while only 9% did so for case B. Regarding the TMS-warfarin interaction in case history B, the electronic alert increased the percentage of respondents correctly suggesting a dose reduction from 29% to 53%. Having an INR instrument in the nursing home was associated with shortened INR recall times. Practical advice on handling of warfarin treatment and drug interactions is needed. Electronic alerts as presented in electronic medical records seem insufficient to change practice. Availability of INR instruments may be important regarding recall time.

Treatments for Reversing Warfarin Anticoagulation in Patients with Acute Intracranial Hemorrhage: A Structured Literature Review

Science.gov (United States)

2011-07-08

available soon. Treatments for reversing warfarin anticoagulation in patients with acute intracranial hemorrhage: a structured literature review...DATE 08 JUL 2011 2. REPORT TYPE 3. DATES COVERED 00-00-2011 to 00-00-2011 4. TITLE AND SUBTITLE Treatments For Reversing Warfarin ...distribution unlimited 13. SUPPLEMENTARY NOTES International Journal of Emergency Medicine 2011 14. ABSTRACT The acute management of patients on warfarin

Vitamin K2 for the reversal of warfarin-related coagulopathy.

Science.gov (United States)

Hifumi, Toru; Takada, Hiroaki; Ogawa, Daisuke; Suzuki, Kenta; Hamaya, Hideyuki; Shinohara, Natsuyo; Abe, Yuko; Takano, Koshiro; Kawakita, Kenya; Hagiike, Masanobu; Koido, Yuichi; Kuroda, Yasuhiro

2015-08-01

The American Heart Association/American College of Cardiology Foundation recommends vitamin K1 for warfarin-related coagulopathy. In Japan, vitamin K2 is used more commonly for such purpose. The difference between vitamins K1 and K2 in reversing warfarin-related coagulopathy has not been discussed. Herein, we report a case that was reversed with vitamin K2; alterations in vitamins K1 and K2 levels and coagulation markers are also presented.

Vitamin K for improved anticoagulation control in patients receiving warfarin.

Science.gov (United States)

Mahtani, Kamal R; Heneghan, Carl J; Nunan, David; Roberts, Nia W

2014-05-15

Effective use of warfarin involves keeping the international normalised ratio (INR) within a relatively narrow therapeutic range. However, patients respond widely to their dose of warfarin. Overcoagulation can lead to an increased risk of excessive bleeding, while undercoagulation can lead to increased clot formation. There is some evidence that patients with a variable response to warfarin may benefit from a concomitant low dose of vitamin K. To assess the effects of concomitant supplementation of low-dose oral vitamin K for anticoagulation control in patients being initiated on or taking a maintenance dose of warfarin. To identify previous reviews, we searched the Database of Abstracts of Reviews of Effects (DARE via The Cochrane Library, Wiley) (Issue 2, 2011). To identify primary studies, we searched the Cochrane Central Register of Controlled Trials (CENTRAL via The Cochrane Library, Wiley) (Issue 2, 2014), Ovid MEDLINE (R) In-Process & Other Non-Indexed Citations database and Ovid MEDLINE (R) (OvidSP) (1946 to 25 February 2014), Embase (OvidSP) (1974 to week 8 of 2014), Science Citation Index Expanded™ & Conference Proceedings Citation Index - Science (Web of Science™) (1945 to 27 February 2014), and the NHS Economics Evaluations Database (NHS EED) (via The Cochrane Library, Wiley) (Issue 2, 2014). We did not apply any language or date restrictions. We used additional methods to identify grey literature and ongoing studies. Randomised controlled trials comparing the addition of vitamin K versus placebo in patients initiating warfarin or already taking warfarin. Two review authors independently selected and extracted data from included studies. When disagreement arose, a third author helped reached a consensus. We also assessed risk of bias. We identified two studies with a total of 100 participants for inclusion in the review. We found the overall risk of bias to be unclear in a number of domains. Neither study reported the time taken to the first INR in

Educating patients about warfarin therapy using information technology: A survey on healthcare professionals’ perspectives

Directory of Open Access Journals (Sweden)

Mullan J

2012-06-01

Full Text Available Objective: To explore healthcare professionals’ views about the benefits and challenges of using information technology (IT resources for educating patients about their warfarin therapy.Methods: A cross-sectional survey of both community and hospital-based healthcare professionals (e.g., doctors, pharmacists and nurses involved using a purpose-designed questionnaire. The questionnaires were distributed using a multi-modal approach to maximise response rates.Results: Of the total 300 questionnaires distributed, 109 completed surveys were received (43.3% response rate. Over half (53.2% of the healthcare participants were aged between 40-59 years, the majority (59.5% of whom were female. Fifty nine (54.1% participants reported having had no access to warfarin-specific IT-based patient education resources, and a further 19 (38.0% of the participants who had IT-access reported that they never used such resources. According to the healthcare participants, the main challenges associated with educating their patients about warfarin therapy included: patient-related factors, such as older age, language barriers, cognitive impairments and/or ethnic backgrounds or healthcare professional factors, such as time constraints. The healthcare professionals reported that there were several aspects about warfarin therapy which they found difficult to educate their patients about which is why they identified computers and interactive touch screen kiosks as preferred IT devices to deliver warfarin education resources in general practices, hospital-based clinics and community pharmacies. At the same time, the healthcare professionals also identified a number of facilitators (e.g., to reinforce warfarin education, to offer reliable and easily comprehensible information and barriers (e.g., time and costs of using IT resources, difficulty in operating the resources that could impact on the effective implementation of these devices in educating patients about their

Predictors of warfarin use in atrial fibrillation in the United States: a systematic review and meta-analysis

Science.gov (United States)

2012-01-01

Background Despite warfarin's marked efficacy, not all eligible patients receive it for stroke prevention in AF. The aim of this meta-analysis was to evaluate the association between prescriber and/or patient characteristics and subsequent prescription of warfarin for stroke prevention in patients with atrial fibrillation (AF). Methods Observational studies conducted in the US using multivariate analysis to determine the relationship between characteristics and the odds of receiving warfarin for stroke prevention were identified in MEDLINE, EMBASE and a manual review of references. Effect estimates of prescriber and/or patient characteristics from individual studies were pooled to calculate odds ratios (ORs) with 95% confidence intervals. Results Twenty-eight studies reporting results of 33 unique multivariate analyses were identified. Warfarin use across studies ranged from 9.1%-79.8% (median = 49.1%). There was a moderately-strong correlation between warfarin use and year of study (r = 0.60, p = 0.002). Upon meta-analysis, characteristics associated with a statistically significant increase in the odds of warfarin use included history of cerebrovascular accident (OR = 1.59), heart failure (OR = 1.36), and male gender (OR = 1.12). Those associated with a significant reduction in the odds of warfarin use included alcohol/drug abuse (OR = 0.62), perceived barriers to compliance (OR = 0.87), contraindication(s) to warfarin (OR = 0.81), dementia (OR = 0.32), falls (OR = 0.60), gastrointestinal hemorrhage (OR = 0.47), intracranial hemorrhage (OR = 0.39), hepatic (OR = 0.59), and renal impairment (OR = 0.69). While age per 10-year increase (OR = 0.78) and advancing age as a dichotomized variable (cut-off varied by study) (OR = 0.57) were associated with significant reductions in warfarin use; qualitative review of results of studies evaluating age as a categorical variable did not confirm this relationship. Conclusions Warfarin use has increased somewhat over time. The

[Comparison of quality and hemorragic risk of oral anticoagulant therapy using acenocoumarol versus warfarin].

Science.gov (United States)

Oliva Berini, Elvira; Galán Alvarez, Pilar; Pacheco Onrubia, Ana María

2008-06-21

Long half life oral anticoagulants have shown a higher anticoagulation stability and a lower hemorragic risk than those of a short half life. We have compared therapeutic stability and hemorragic risk of acenocoumarol versus warfarin in 2 groups of patients on preventive anticoagulation because of atrial fibrilation (international normalised ratio [INR]: 2-3). Data on 120 patients treated with acenocoumarol and 120 on warfarin treatment who had started and continued treatment in our hospital for a minimum of a year was collected. The percentage of visits within the intended range of INR (2 to 3) was 65.5% with warfarin and 63.4% with acenocoumarol. Thirty percent of patients on warfarin had 75% or more of their controls within range, while for those treated with acenocoumarol this percentage was 22.5%. In the acenocoumarol group, 0.3 visits/patient/year presented an INR > or = 6 versus 0.07 in the warfarin group (p = 0.003). Patients treated with acenocoumarol show a higher risk of presenting with an INR > or = 6, but no statistically significant differences are observed in therapeutic stability.

Association of Proton Pump Inhibitors with Reduced Risk of Warfarin-related Serious Upper Gastrointestinal Bleeding

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Ray, Wayne A.; Chung, Cecilia P.; Murray, Katherine T.; Smalley, Walter E.; Daugherty, James R.; Dupont, William D.; Stein, C. Michael

2016-01-01

Background & Aims Proton-pump inhibitors (PPIs) might reduce the risk of serious warfarin-related upper gastrointestinal bleeding, but the evidence of their efficacy for this indication is limited. A gastroprotective effect of PPIs would be particularly important for patients who take warfarin with antiplatelet drugs or nonselective non-steroidal anti-inflammatory drugs (NSAIDs), which further increase the risk of gastrointestinal bleeding. Methods This retrospective cohort study of patients beginning warfarin treatment in Tennessee Medicaid and the 5% National Medicare Sample identified 97,430 new episodes of warfarin treatment with 75,720 person-years of follow up. The study endpoints were hospitalizations for upper gastrointestinal bleeding potentially preventable by PPIs and for bleeding at other sites. Results Patients who took warfarin without PPI co-therapy had 119 hospitalizations for upper gastrointestinal bleeding per 10,000 person-years of treatment. The risk decreased by 24% among patients who received PPI co-therapy (adjusted hazard ratio [HR], 0.76; 95% CI, 0.63–0.91). There was no significant reduction in the risk of other gastrointestinal bleeding hospitalizations (HR, 1.07; 95% CI, 0.94–1.22) or non-gastrointestinal bleeding hospitalizations (HR, 0.98; 95% CI, 0.84–1.15) in this group. Among patients concurrently using antiplatelet drugs or NSAIDs, those without PPI co-therapy had 284 upper gastrointestinal bleeding hospitalizations per 10,000 person-years of warfarin treatment. The risk decreased by 45% (HR, 0.55; 95% CI, 0.39–0.77) with PPI co-therapy. PPI co-therapy had no significant protective effect for warfarin patients not using antiplatelet drugs or NSAIDs (HR, 0.86; 95% CI, 0.70-1.06). Findings were similar in both study populations. Conclusions In an analysis of patients beginning warfarin treatment in Tennessee Medicaid and the 5% National Medicare Sample, PPI co-therapy was associated with reduced risk of warfarin-related upper

Cardioversion and Risk of Adverse Events with Dabigatran versus Warfarin-A Nationwide Cohort Study.

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Jannik Langtved Pallisgaard

Full Text Available Cardioversion can rapidly and effectively restore sinus rhythm in patients with persistent atrial fibrillation. Since 2011 dabigatran has been available as an alternative to warfarin to prevent thromboembolic events in patients with non-valvular atrial fibrillation undergoing cardioversion. We studied time to cardioversion, risk of adverse events, and risk of readmission with atrial fibrillation after cardioversion according to anticoagulation therapy.Through the nationwide Danish registries we included 1,230 oral anticoagulation naïve patients with first time non-valvular atrial fibrillation and first time cardioversion from 2011 to 2012; 37% in the dabigatran group (n = 456, and 63% in the warfarin group (n = 774. Median time to cardioversion was 4.0 (interquartile range [IQR] 2.9 to 6.5 and 6.9 (IQR 3.9 to 12.1 weeks in the dabigatran and warfarin groups respectively, and the adjusted odds ratio of cardioversion within the first 4 weeks was 2.3 (95% confidence interval [CI] 1.7 to 3.1 in favor of dabigatran. The cumulative incidence of composite endpoint of stroke, bleeding or death were 2.0% and 1.0% at 30 weeks in the warfarin and dabigatran groups respectively, with an adjusted hazard ratio of 1.33 (95% CI 0.33 to 5.42. Cumulative incidence of readmission with atrial fibrillation after 30 weeks were 9% and 11% in the warfarin and dabigatran groups, respectively, and an adjusted hazard ratio of 0.66 (95% CI 0.41 to 1.08.Anticoagulation treatment with dabigatran allows shorter time to cardioversion for atrial fibrillation than warfarin, and appears to be an effective and safe alternative treatment strategy to warfarin.

International normalized ratio stability in warfarin-experienced patients with nonvalvular atrial fibrillation.

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Nelson, Winnie W; Desai, Sunita; Damaraju, Chandrasekharrao V; Lu, Lang; Fields, Larry E; Wildgoose, Peter; Schein, Jeffery R

2015-06-01

Maintaining stable levels of anticoagulation using warfarin therapy is challenging. Few studies have examined the stability of the international normalized ratio (INR) in patients with nonvalvular atrial fibrillation (NVAF) who have had ≥6 months' exposure to warfarin anticoagulation for stroke prevention. Our objective was to describe INR control in NVAF patients who had been receiving warfarin for at least 6 months. Using retrospective patient data from the CoagClinic™ database, we analyzed data from NVAF patients treated with warfarin to assess the quality of INR control and possible predictors of poor INR control. Time within, above, and below the recommended INR range (2.0-3.0) was calculated for patients who had received warfarin for ≥6 months and had three or more INR values. The analysis also assessed INR patterns and resource utilization of patients with an INR >4.0. Logistic regression models were used to determine factors associated with poor INR control. Patients (n = 9433) had an average of 1.6 measurements per 30 days. Mean follow-up time was 544 days. Approximately 39% of INR values were out of range, with 23% of INR values being 3.0. Mean percent time with INR in therapeutic range was 67%; INR 3.0 was 14%. Patients with more than one reading of INR >4.0 (~39%) required an average of one more visit and took 3 weeks to return to an in-range INR. Male sex and age >75 years were predictive of better INR control, whereas a history of heart failure or diabetes were predictive of out-of-range INR values. However, patient characteristics did not predict the likelihood of INR >4.0. Out-of-range INR values remain frequent in patients with NVAF treated with warfarin. Exposure to high INR values was common, resulting in increased resource utilization.

SPECIAL CONSIDERATIONS REGARDING WARFARIN DOSE TITRATION IN PATIENTS WITH ATRIAL FIBRILLATION DEPENDING ON CLINICAL FACTORS

OpenAIRE

E. L. Artanova; E. V. Saleeva; I. M. Sokolov; Y. G. Shvarts

2011-01-01

Aim. To study the relations of clinical characteristics and individual warfarin dose titration in patients with atrial fibrillation. Material and methods. Period of warfarin dose titration was analyzed in 68 patients with atrial fibrillation due to ischemic heart disease. Adjusted warfarin dose in milligram, duration of dose titration in days and maximal international normalized ratio (INR) were taken into account. Sex, age, history of myocardial infarction and stroke, concomitant diseases, a...

Locations and Mucosal Lesions Responsible for Major Gastrointestinal Bleeding in Patients on Warfarin or Dabigatran.

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Kolb, Jennifer M; Flack, Kathryn Friedman; Chatterjee-Murphy, Prapti; Desai, Jay; Wallentin, Lars C; Ezekowitz, Michael; Connolly, Stuart; Reilly, Paul; Brueckmann, Martina; Ilgenfritz, John; Aisenberg, James

2018-03-27

Different oral anticoagulants may be associated with gastrointestinal bleeding (GIB) from different locations or mucosal lesions. We aimed to test this hypothesis. Two blinded gastroenterologists independently analyzed source documents from the randomized evaluation of long-term anticoagulant therapy (RE-LY) trial of dabigatran 150 mg BID (D150), dabigatran 110 mg BID (D110) versus warfarin in non-valvular atrial fibrillation (NVAF). Major GIB events (total n = 546) and life-threatening GIB events (n = 258) were more common with D150 versus warfarin (RR 1.57 [1.28-1.92] and RR 1.62 [1.20-2.18], respectively) and similar for D110 compared to warfarin (RR 1.11 [0.89-1.38] and RR 1.16 [0.84-1.61], respectively). Fatal bleeding was similarly rare across treatment groups. Lower GI major bleeding and life-threatening bleeding were more common with D150 compared to warfarin (RR 2.23 [1.47, 3.38] and RR 2.64 [1.36, 5.13], respectively) and with D110 compared to warfarin (RR 1.78 [1.16, 2.75] and RR 2.00 [1.00, 4.00], respectively). MGIB from colonic angiodysplasia was increased with dabigatran versus warfarin (P < 0.01 for both dose comparisons). Subacute and chronic MGIB events were more common with D150 than with warfarin (RR 1.72 [1.06, 2.78] and RR 1.66 [1.12, 2.45], respectively), as were hematochezia or melena (RR 1.67 [1.18, 2.36] and RR 1.72 [1.20, 2.47], respectively). In a chronic NVAF population, D150 but not D110 is associated with increased major and life-threatening GI bleeding in comparison with warfarin. At both dabigatran doses, increased bleeding from the colorectum, in particular from angiodysplasia, is seen.

Medication persistence and discontinuation of rivaroxaban versus warfarin among patients with non-valvular atrial fibrillation.

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Nelson, Winnie W; Song, Xue; Coleman, Craig I; Thomson, Erin; Smith, David M; Damaraju, C V; Schein, Jeffrey R

2014-12-01

To compare real-world persistence and discontinuation among non-valvular atrial fibrillation (NVAF) patients on rivaroxaban and warfarin in the US. A large nationally representative US claims database was used to conduct a retrospective cohort analysis of patients with NVAF treated with rivaroxaban or warfarin from 1 July 2010 through 31 March 2013. Index date was the date of the first prescription of rivaroxaban or warfarin. All patients were followed until the earliest of inpatient death, end of continuous enrollment, or end of study period. Rivaroxaban patients were matched 1:1 by propensity scores. Medication persistence was defined as absence of refill gap of ≥ 60 days. Discontinuation was defined as no additional refill for at least 90 days and until the end of follow-up. Cox proportional hazards models were estimated to examine the adjusted hazard ratios (aHRs) of rivaroxaban vs. warfarin on non-persistence and discontinuation. A total of 32,886 NVAF patients on rivaroxaban or warfarin met the study inclusion criteria. Each of the 7259 rivaroxaban patients identified were matched 1:1 to warfarin patients. Patients on rivaroxaban had a significantly better rate of persistence (aHR: 0.63, 95% CI 0.59-0.68) and lower rate of discontinuation (aHR: 0.54, 95% CI 0.49-0.58) compared to warfarin recipients. Claims data may have contained inaccuracies and miscoding. Confounding may remain even after propensity score matching and additional adjustments in model. Refill data may not fully reflect actual medication use. Longer follow-up may produce more precise estimates of persistence and discontinuation. This matched cohort analysis indicated that rivaroxaban was associated with significantly higher medication persistence and lower discontinuation rates compared to warfarin.

In-hospital management and outcome of patients on warfarin undergoing coronary stent implantation: results of the multicenter, prospective WARfarin and coronary STENTing (WAR-STENT) registry.

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Rubboli, Andrea; Sciahbasi, Alessandro; Briguori, Carlo; Saia, Francesco; Palmieri, Cataldo; Moroni, Luigi Andrea; Calabrò, Paolo; Leone, Antonio Maria; Franco, Nicoletta; Valgimigli, Marco; Varani, Elisabetta; Santi, Michela; Pasqualini, Paola; Capecchi, Alessandro; Piccalò, Giacomo; Margheri, Massimo; di Pasquale, Giuseppe; Galvani, Marcello; Bolognese, Leonardo; Gonzini, Lucio; Maggioni, Aldo Pietro

2013-04-01

The in-hospital management of patients on warfarin undergoing coronary stent implantation (PCI-S) is variable, and the in-hospital outcome incompletely defined. To determine the adherence to the current recommendations, and the incidence of adverse events, we carried out the prospective, multicenter, observational WARfarin and coronary STENTing (WAR-STENT) registry (ClinicalTrials.gov identifier NCT00722319). All consecutive patients on warfarin undergoing PCI-S at 37 Italian centers were enrolled and followed for 12 months. Outcome measures were: major adverse cardiovascular events (MACE), including cardiovascular death, non-fatal myocardial infarction, need for urgent revascularization, stroke, and venous thromboembolism, and major and minor bleeding. In this paper, we report the in-hospital findings. Out of the 411 patients enrolled, 92% were at non-low (ie, moderate or high) thromboembolic risk. The radial approach and bare-metal stents were used in 61% and 60% of cases, respectively. Drug-eluting stents were essentially reserved to patients with diabetes, which in turn, significantly predicted the implantation of drug-eluting stents (odds ratio [OR], 2.02; 95% confidence interval [CI], 1.29-3.17; P=.002). The in-hospital MACE and major bleeding rates were 2.7% and 2.1%, respectively. At discharge, triple therapy (TT) of warfarin, aspirin, and clopidogrel was prescribed to 76% of patients. Prescription of TT was significantly more frequent in the non-low thromboembolic risk group. Non-low thromboembolic risk, in turn, was a significant predictor of TT prescription (OR, 11.2; 95% CI, 4.83-26.3; P<.0001). In conclusion, real-world warfarin patients undergoing PCI-S are largely managed according to the current recommendations. As a consequence, the risk of in-hospital MACE and major bleedings appears limited and acceptable.

The IL--6 dependent effect of oral warfarin in heart valve replacement patients by measuring interacting clinical and demographic variables

International Nuclear Information System (INIS)

Shafiq, H.; Rashid, A.; Majeed, A.; Razah, S.; Asghar, I.

2016-01-01

Objective: To examine an inflammatory effect of warfarin and comparing with IL-6 levels along with different demographic and clinical variables. Study Design: Quasi experimental study. Place and Duration of Study: Center of Research in Experimental and Applied Medicine (CREAM), Army Medical College/National University of Sciences and Technology, Islamabad from Oct 2013 to Oct 2015. Material and Methods: The study design was Quasi Experimental study. Samples were collected by Non probability convenience sampling. Total 76 patients were included according to warfarin dose response in warfarin therapy patients, i.e. 32(42 percent) were taking 10mg/day of warfarin dose. Patient's demographic and clinical variables were noted i.e. age, gender, BMI, duration of therapy, INR history, hepatic, gastrointestinal and diabetic complications. Human IL-6 ELISA assay was performed. Results: The statistically significant difference was found between age groups (in years) and different levels of warfarin dose (p=0.046) along with IL-6 production. There is a negative correlation between warfarin dose and age group i.e. as age increases, the dose of warfarin decreases. Among the inter and intra-patient variability age and serum IL-6 levels were found to be statistically significant with warfarin dose response. BMI and warfarin dose were found to be weak positively correlated. Conclusion: A marked immunomodulatory response of warfarin was noted by measuring IL-6 levels. IL-6 levels retained a significant association with warfarin dose. (author)

Potential of a Pharmacogenetic-Guided Algorithm to Predict Optimal Warfarin Dosing in a High-Risk Hispanic Patient

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Dagmar F. Hernandez-Suarez MD

2016-12-01

Full Text Available Deep abdominal vein thrombosis is extremely rare among thrombotic events secondary to the use of contraceptives. A case to illustrate the clinical utility of ethno-specific pharmacogenetic testing in warfarin management of a Hispanic patient is reported. A 37-year-old Hispanic Puerto Rican, non-gravid female with past medical history of abnormal uterine bleeding on hormonal contraceptive therapy was evaluated for abdominal pain. Physical exam was remarkable for unspecific diffuse abdominal tenderness, and general initial laboratory results—including coagulation parameters—were unremarkable. A contrast-enhanced computed tomography showed a massive thrombosis of the main portal, splenic, and superior mesenteric veins. On admission the patient was started on oral anticoagulation therapy with warfarin at 5 mg/day and low-molecular-weight heparin. The prediction of an effective warfarin dose of 7.5 mg/day, estimated by using a recently developed pharmacogenetic-guided algorithm for Caribbean Hispanics, coincided with the actual patient’s warfarin dose to reach the international normalized ratio target. We speculate that the slow rise in patient’s international normalized ratio observed on the initiation of warfarin therapy, the resulting high risk for thromboembolic events, and the required warfarin dose of 7.5 mg/day are attributable in some part to the presence of the NQO1 *2 (g.559C>T, p.P187S polymorphism, which seems to be significantly associated with resistance to warfarin in Hispanics. By adding genotyping results of this novel variant, the predictive model can inform clinicians better about the optimal warfarin dose in Caribbean Hispanics. The results highlight the potential for pharmacogenetic testing of warfarin to improve patient care.

Comparison of the Effectiveness and Safety of Apixaban, Dabigatran, Rivaroxaban, and Warfarin in Newly Diagnosed Atrial Fibrillation.

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Hernandez, Inmaculada; Zhang, Yuting; Saba, Samir

2017-11-15

No studies have performed direct pairwise comparisons of the effectiveness and safety of warfarin and the new oral anticoagulants (NOACs) apixaban, dabigatran, and rivaroxaban. Using 2013 to 2014 claims from a 5% random sample of Medicare beneficiaries, we identified patients newly diagnosed with atrial fibrillation who initiated apixaban, dabigatran, rivaroxaban, warfarin, or no oral anticoagulation therapy in 2013 to 2014. Outcomes included the composite of ischemic stroke, systemic embolism (SE) and death, any bleeding event, gastrointestinal bleeding, intracranial bleeding, and treatment persistence. We constructed Cox proportional hazard models to compare outcomes between each pair of treatment groups. The composite risk of ischemic stroke, SE, and death was lower for NOACs than for warfarin: hazard ratio (HR) 0.86, 95% confidence interval (CI) 0.76 to 0.98 for apixaban; 0.73, 95% CI 0.63 to 0.86 for dabigatran; and 0.82, 95% CI 0.75 to 0.89 for rivaroxaban, all compared with warfarin. There were no differences in effectiveness across NOACs. The risk of any bleeding was lower with apixaban than with warfarin, but higher with rivaroxaban than with warfarin. Apixaban (HR 0.69, 95% CI 0.60 to 0.79) and dabigatran (HR 0.79, 95% CI 0.69 to 0.92) were associated with lower bleeding risk than rivaroxaban. Treatment persistence was highest for apixaban (82%), and lowest for dabigatran and warfarin (64%) (p value warfarin, NOACs are more effective in preventing stroke but their risk of bleeding varies, with rivaroxaban having higher risk than warfarin. Altogether, apixaban had the most favorable effectiveness, safety, and persistence profile. Copyright © 2017 Elsevier Inc. All rights reserved.

Preoperative warfarin reversal for early hip fracture surgery.

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Moores, Thomas Steven; Beaven, Alastair; Cattell, Andrew Edwin; Baker, Charles; Roberts, Philip John

2015-04-01

To evaluate our hospital protocol of low-dose vitamin K titration for preoperative warfarin reversal for early hip fracture surgery. Records of 16 men and 33 women aged 63 to 93 (mean, 81) years who were taking warfarin for atrial fibrillation (n=40), venous thromboembolism (n=9), cerebrovascular accident (n=3), and prosthetic heart valve (n=3) and underwent surgery for hip fractures were reviewed. The 3 patients with a prosthetic heart valve were deemed high risk for thromboembolism and the remainder low-risk. The international normalised ratio (INR) of patients was checked on admission and 6 hours after administration of vitamin K; an INR of fracture surgery within 36 to 48 hours of admission improves morbidity and mortality.

Shorter Hospital Stays and Lower Costs for Rivaroxaban Compared With Warfarin for Venous Thrombosis Admissions.

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Margolis, Jay M; Deitelzweig, Steven; Kline, Jeffrey; Tran, Oth; Smith, David M; Bookhart, Brahim; Crivera, Concetta; Schein, Jeff

2016-10-06

Venous thromboembolism, including deep vein thrombosis and pulmonary embolism, results in a substantial healthcare system burden. This retrospective observational study compared hospital length of stay (LOS) and hospitalization costs for patients with venous thromboembolism treated with rivaroxaban versus those treated with warfarin. Hospitalizations for adult patients with a primary diagnosis of deep vein thrombosis or pulmonary embolism who were initiated on rivaroxaban or warfarin were selected from MarketScan's Hospital Drug Database between November 1, 2012, and December 31, 2013. Patients treated with warfarin were matched 1:1 to patients treated with rivaroxaban using exact and propensity score matching. Hospital LOS, time from first dose to discharge, and hospitalization costs were reported descriptively and with generalized linear models (GLMs). The final study cohorts each included 1223 patients (751 with pulmonary embolism and 472 with deep vein thrombosis). Cohorts were well matched for demographic and clinical characteristics. Mean (±SD) LOS was 3.7±3.1 days for patients taking rivaroxaban and 5.2±3.7 days for patients taking warfarin, confirmed by GLM-adjusted results (rivaroxaban 3.7 days, warfarin 5.3 days, P<0.001). Patients with provoked venous thromboembolism admissions showed longer LOSs (rivaroxaban 5.1±4.5 days, warfarin 6.5±5.6 days, P<0.001) than those with unprovoked venous thromboembolism (rivaroxaban 3.3±2.4 days, warfarin 4.8±2.8 days, P<0.001). Days from first dose to discharge were 2.4±1.7 for patients treated with rivaroxaban and 3.9±3.7 for patients treated with warfarin when initiated with parenteral anticoagulants (P<0.001), and 2.7±1.7 and 3.7±2.1, respectively, when initiated without parenteral anticoagulants (P<0.001). Patients initiated on rivaroxaban incurred significantly lower mean total hospitalization costs ($8688±$9927 versus $9823±$9319, P=0.004), confirmed by modeling (rivaroxaban $8387 [95

Warfarin Use in Patients With Atrial Fibrillation Undergoing Hemodialysis: A Nationwide Population-Based Study.

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Yoon, Chang-Yun; Noh, Juhwan; Jhee, Jong Hyun; Chang, Tae Ik; Kang, Ea Wha; Kee, Youn Kyung; Kim, Hyoungnae; Park, Seohyun; Yun, Hae-Ryong; Jung, Su-Young; Oh, Hyung Jung; Park, Jung Tak; Han, Seung Hyeok; Kang, Shin-Wook; Kim, Changsoo; Yoo, Tae-Hyun

2017-09-01

The aim of this study is to elucidate the effects of warfarin use in patients with atrial fibrillation undergoing dialysis using a population-based Korean registry. Data were extracted from the Health Insurance Review and Assessment Service, which is a nationwide, mandatory social insurance database of all Korean citizens enrolled in the National Health Information Service between 2009 and 2013. Thromboembolic and hemorrhagic outcomes were analyzed according to warfarin use. Overall and propensity score-matched cohorts were analyzed by Cox proportional hazards models. Among 9974 hemodialysis patients with atrial fibrillation, the mean age was 66.6±12.2 years, 5806 (58.2%) were men, and 2921 (29.3%) used warfarin. After propensity score matching to adjust for all described baseline differences, 5548 subjects remained, and differences in baseline variables were distributed equally between warfarin users and nonusers. During a mean follow-up duration of 15.9±11.1 months, ischemic and hemorrhagic stroke occurred in 678 (6.8%) and 227 (2.3%) patients, respectively. In a multiple Cox model, warfarin use was significantly associated with an increased risk of hemorrhagic stroke (hazard ratio, 1.44; 95% confidence interval, 1.09-1.91; P =0.010) in the overall cohort. Furthermore, a significant relationship between warfarin use and hemorrhagic stroke was found in propensity-matched subjects (hazard ratio, 1.56; 95% confidence interval, 1.10-2.22; P =0.013). However, the ratios for ischemic stroke were not significantly different in either the propensity-matched (hazard ratio, 0.95; 95% confidence interval, 0.78-1.15; P =0.569) or overall cohort (hazard ratio, 1.06; 95% confidence interval, 0.90-1.26; P =0.470). Our findings suggest that warfarin should be used carefully in hemodialysis patients, given the higher risk of hemorrhagic events and the lack of ability to prevent thromboembolic complications. © 2017 American Heart Association, Inc.

Fate of [14C] warfarin in guinea-pigs: effect of a concomitant single dose of salicylate

International Nuclear Information System (INIS)

Wong, L.T.; Solomonraj, G.; Thomas, B.H.

1978-01-01

When a single dose of sodium salicylate (177.8 mg kg -1 , by mouth) was given with [ 14 C] warfarin (1 mg kg -1 , i.p.) to guinea-pigs, the salicylate depressed the blood concentrations of 14 C for 6 h. At 1 h, salicylate increased the distribution of 14 C in the liver and brain, but at 1 and 6 h it was decreased in the blood and kidney. A significant portion of the 14 C was excreted into the bile, but was subject to enterohepatic circulation and then excreted by the kidney. There was an enhancement of the biliary elimination of 14 C in the first 5 h after salicylate and a decrease in 14 C concentration in blood; the proportion of warfarin to its metabolites excreted in the urine and bile was unchanged. Salicylate displaced serum protein bound [ 14 C] warfarin in vitro. Salicylate increases the initial biliary elimination of warfarin by displacing some of that bound to plasma protein. This facilitated uptake of warfarin by the liver where it was metabolized. This effect of salicylate did not modify the hypoprothrombinaemia produced by warfarin. (author)

Out-of-range INR values and outcomes among new warfarin patients with non-valvular atrial fibrillation.

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Nelson, Winnie W; Wang, Li; Baser, Onur; Damaraju, Chandrasekharrao V; Schein, Jeffrey R

2015-02-01

Although efficacious in stroke prevention in non-valvular atrial fibrillation, many warfarin patients are sub-optimally managed. To evaluate the association of international normalized ratio control and clinical outcomes among new warfarin patients with non-valvular atrial fibrillation. Adult non-valvular atrial fibrillation patients (≥18 years) initiating warfarin treatment were selected from the US Veterans Health Administration dataset between 10/2007 and 9/2012. Valid international normalized ratio values were examined from the warfarin initiation date through the earlier of the first clinical outcome, end of warfarin exposure or death. Each patient contributed multiple in-range and out-of-range time periods. The relative risk ratios of clinical outcomes associated with international normalized ratio control were estimated. 34,346 patients were included for analysis. During the warfarin exposure period, the incidence of events per 100 person-years was highest when patients had international normalized ratio 3, patients had significantly increased risk of major bleeding (relative risk ratio: 1.5; 95 % confidence interval 1.2-2.0). In a Veterans Health Administration non-valvular atrial fibrillation population, exposure to out-of-range international normalized ratio values was associated with significantly increased risk of adverse clinical outcomes.

Safety and Efficacy of Warfarin Therapy in Remote Communities of the Top End of Northern Australia.

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Dennis, Jahde; Majoni, William; Tinsley, Jeffrey; Kangaharan, Nadarajah

2017-12-01

Warfarin remains a widely used anticoagulant but application in the remote context is not well documented. This study aimed to assess in more detail whether warfarin is being utilised effectively in Australia's most isolated and remote areas. Retrospective cohort analysis of 2013 captured international normalised ratio (INR) results from people engaged in long term warfarin usage within a number of remote Northern Australian communities. Assessment of monitoring, effectiveness of dosing and complication rates was undertaken. A cohort of 167 patients was established. On average, warfarin was utilised within therapeutic range 52% of the time. Monitoring frequency averaged 16 days. Major bleeding and thrombo-embolism occurred at rates of 5.8 and 4.1 per 100 patient years respectively. Therapeutic utilisation of warfarin in this setting is close to accepted rates but has room for improvement. Monitoring was acceptable and complication rates were not disproportionately high. This study indicates that warfarin is being used with reasonable safety and efficacy in remote regions, but further research is needed. Copyright © 2017 Australian and New Zealand Society of Cardiac and Thoracic Surgeons (ANZSCTS) and the Cardiac Society of Australia and New Zealand (CSANZ). All rights reserved.

Relative Expression of PBMC MicroRNA-133a Analysis in Patients Receiving Warfarin After Mechanical Heart Valve Replacement

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Kabiri Rad, Hamid; Mazaheri, Mahta; Dehghani Firozabadi, Ali

Background: MicroRNAs (miRNAs) are implicated in various biological processes including anticoagulation. However, the modulation of miRNA by pharmacological intervention such as warfarin treatment in patients receiving warfarin has not been disclosed yet. The aim of this study work was to assess the effect of warfarin drug on expression level of mir-133a-3p in patients with mechanical heart valve replacement. Methods: In this research, the expression level of miRNA-133a-3p was analyzed in Peripheral Blood Mononuclear Cells (PBMCs) from mechanical valve replacement patients who had received warfarin for at least 3 months continuously. Quantitative RT-PCR method was used for this assay. Results: Our findings indicated a significant diffrence between the rate of miR-133a-3p expression in individuals receiving warfarin and the control group (p<0.01). There was also a statistically significant difference in miR-133a-3p expression in patients with different ages (p<0.05) suggesting that the rate of miR-133a-3p expression in persons receiving warfarin is related to age. However, other variables like warfarin dose, International Normalized Ratio (INR), gender, and Body Mass Index (BMI) were not significantly effective on the miR-133a-3p experssion rate in individuals receving warfarin. Conclusion: Based on our results, it can be concluded that miR-133a-3p is involved in the coagulation pathway. The recent result indicates that warfarin affects the expression of miR-133a. This expression may be potentially important for treatment by anticoagulants. Awareness of the time course of miRNA expression profile can improve efficiency of response to warfarin. PMID:29296264

Factors influencing medication knowledge and beliefs on warfarin adherence among patients with atrial fibrillation in China

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Zhao S

2017-02-01

Full Text Available Shujuan Zhao,1 Hongwei Zhao,1 Xianpei Wang,2 Chuanyu Gao,2 Yuhua Qin,1 Haixia Cai,1 Boya Chen,1 Jingjing Cao1 1Department of Pharmacy, 2Department of Cardiovascular Medicine, People’s Hospital of Henan Province, Zhengzhou, Henan, People’s Republic of China Objectives: Warfarin is often used for ischemic stroke prevention in patients with atrial fibrillation (AF, but the factors affecting patient adherence to warfarin therapy have not been fully understood. Methods: A cross-sectional survey was conducted in AF patients undergoing warfarin therapy at least 6 months prior to the study. The clinical data collected using questionnaires by phone interviews included the following: 1 self-reported adherence measured by the Morisky Medication Adherence Scale-8©; 2 beliefs about medicines surveyed by Beliefs about Medicines Questionnaire (BMQ; and 3 drug knowledge as measured by the Warfarin Related Knowledge Test (WRKT. Demographic and clinical factors associated with warfarin adherence were identified using a logistic regression model. Results: Two hundred eighty-eight patients completed the survey and 93 (32.3% of them were classified as nonadherent (Morisky Medication Adherence Scale-8 score <6. Major factors predicting warfarin adherence included age, cardiovascular disorders, WRKT, and BMQ; WRKT and BMQ were independently correlated with adherence to warfarin therapy by multivariate logistic regression analysis. Adherents were more likely to have greater knowledge scores and stronger beliefs in the necessity of their specific medications ([odds ratio {OR} =1.81, 95% confidence interval {CI} =1.51–2.15] and [OR =1.17, 95% CI =1.06–1.29], respectively. Patients with greater concerns about adverse reactions and more negative views of general harm were more likely to be nonadherent ([OR =0.76, 95% CI =0.69–0.84] and [OR =0.82, 95% CI =0.73–0.92], respectively. Conclusion: BMK and WRKT are related with patient behavior toward warfarin

Association of Proton Pump Inhibitors With Reduced Risk of Warfarin-Related Serious Upper Gastrointestinal Bleeding.

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Ray, Wayne A; Chung, Cecilia P; Murray, Katherine T; Smalley, Walter E; Daugherty, James R; Dupont, William D; Stein, C Michael

2016-12-01

Proton pump inhibitors (PPIs) might reduce the risk of serious warfarin-related upper gastrointestinal bleeding, but the evidence of their efficacy for this indication is limited. A gastroprotective effect of PPIs would be particularly important for patients who take warfarin with antiplatelet drugs or nonselective nonsteroidal anti-inflammatory drugs (NSAIDs), which further increase the risk of gastrointestinal bleeding. This retrospective cohort study of patients beginning warfarin treatment in Tennessee Medicaid and the 5% National Medicare Sample identified 97,430 new episodes of warfarin treatment with 75,720 person-years of follow-up. The study end points were hospitalizations for upper gastrointestinal bleeding potentially preventable by PPIs and for bleeding at other sites. Patients who took warfarin without PPI co-therapy had 119 hospitalizations for upper gastrointestinal bleeding per 10,000 person-years of treatment. The risk decreased by 24% among patients who received PPI co-therapy (adjusted hazard ratio [HR], 0.76; 95% confidence interval [CI], 0.63-0.91). There was no significant reduction in the risk of other gastrointestinal bleeding hospitalizations (HR, 1.07; 95% CI, 0.94-1.22) or non-gastrointestinal bleeding hospitalizations (HR, 0.98; 95% CI, 0.84-1.15) in this group. Among patients concurrently using antiplatelet drugs or NSAIDs, those without PPI co-therapy had 284 upper gastrointestinal bleeding hospitalizations per 10,000 person-years of warfarin treatment. The risk decreased by 45% (HR, 0.55; 95% CI, 0.39-0.77) with PPI co-therapy. PPI co-therapy had no significant protective effect for warfarin patients not using antiplatelet drugs or NSAIDs (HR, 0.86; 95% CI, 0.70-1.06). Findings were similar in both study populations. In an analysis of patients beginning warfarin treatment in Tennessee Medicaid and the 5% National Medicare Sample, PPI co-therapy was associated with reduced risk of warfarin-related upper gastrointestinal bleeding; the

Biopsy of the prostate guided by transrectal ultrasound: relation between warfarin use and incidence of bleeding complications

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Ihezue, C.U. [Department of Radiology, Southampton General Hospital (United Kingdom); Smart, J. [Department of Radiology, Southampton General Hospital (United Kingdom); Dewbury, K.C. [Department of Radiology, Southampton General Hospital (United Kingdom)]. E-mail: keith.dewbury@suht.swest.nhs.uk; Mehta, R. [Department of Radiology, Southampton General Hospital (United Kingdom); Burgess, L. [Department of Radiology, Southampton General Hospital (United Kingdom)

2005-04-01

AIM: To determine the relation between warfarin use and the frequency of bleeding complications after biopsy of the prostate guided by transrectal ultrasound (TRUS). METHODS: Overall, 1022 consecutive patients with suspected prostatic disease were followed after biopsy. Warfarin and aspirin use was determined on the day of the procedure. A TRUS-guided biopsy was performed and patients were offered a questionnaire to complete 10 days after the procedure, to determine any immediate or delayed bleeding complications. Follow-up telephone calls were made to those who had not replied within the stipulated period. RESULTS: Of the 1000 patients who replied, 49 were receiving warfarin, 220 were receiving aspirin and 731 were not receiving any anticoagulant drugs. Of the 49 subjects reporting current use of warfarin, 18 (36.7%) experienced haematuria, compared with 440 (60.2%) of the patients receiving no anti-coagulant drugs who reported haematuria. This was statistically significant (p=0.001). Of the group receiving warfarin, 4 (8.2%) experienced haematospermia whereas 153 (21%) of the group receiving no anticoagulant medication reported haematospermia. This difference also was statistically significant (p=0.030). Rectal bleeding was experienced by 7 (14.3%) of the group receiving warfarin compared with 95 (13%) in the group without anticoagulant medication, but this was not statistically significant (p=0.80). We also demonstrated that there was no statistically significant association between the severity of the bleeding complications and medication with warfarin. CONCLUSION: None of the group receiving warfarin experienced clinically important bleeding complications. Our results suggest that the frequency and severity of bleeding complications were no worse in the warfarin group than in the control group and that discontinuing anticoagulation medication before prostate biopsy may be unnecessary.

The impact of pre-injury direct oral anticoagulants compared to warfarin in geriatric G-60 trauma patients.

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Barletta, J F; Hall, S; Sucher, J F; Dzandu, J K; Haley, M; Mangram, A J

2017-08-01

Pre-injury oral anticoagulants are associated with worse outcomes in geriatric (G-60) trauma patients, but there are limited data comparing warfarin with direct oral anticoagulants (DOAC). We sought to compare outcomes in G-60 trauma patients taking pre-injury DOACs vs. warfarin. All trauma patients, age ≥60 who were admitted to the hospital and taking an oral anticoagulant pre-injury were retrospectively identified. Patients were excluded if their reason for admission was a suicide attempt or penetrating extremity injury. Outcome measures included blood transfusions, hospital LOS, and mortality. A second analysis was performed, whereby patients were matched using ISS and age. There were 3,941 patients identified; 331 had documentation of anticoagulant use, pre-injury (warfarin, n = 237; DOAC, n = 94). Demographics were similar, but ISS [9 (4-13) vs. 8 (4-9), p = .027], initial INR [2.2 (1.8-2.9) vs. 1.2 (1.1-1.5), p warfarin group. There was no difference in the use of blood transfusions (24 vs. 17%, p = .164) or mortality (5.9 vs. 4.3%, p = .789) between warfarin and DOAC groups, respectively. However, LOS was longer in the warfarin group [5 (3-7.5) vs. 4 (2-6.3) days, p = .02]. Matched analysis showed no difference in blood transfusions (23 vs. 17%, p = .276), mortality (2.1 vs. 4.3%, p = .682) or LOS [5 (3-7) vs. 4 (2-6.3) days, p = .158] between warfarin and DOAC groups, respectively. Pre-injury DOACs are not associated with worse clinical outcomes compared to warfarin in G-60 trauma patients. Higher use of pharmacologic reversal agents with warfarin may be related to differences in mechanism of action and effect on INR.

Biopsy of the prostate guided by transrectal ultrasound: relation between warfarin use and incidence of bleeding complications

International Nuclear Information System (INIS)

Ihezue, C.U.; Smart, J.; Dewbury, K.C.; Mehta, R.; Burgess, L.

2005-01-01

AIM: To determine the relation between warfarin use and the frequency of bleeding complications after biopsy of the prostate guided by transrectal ultrasound (TRUS). METHODS: Overall, 1022 consecutive patients with suspected prostatic disease were followed after biopsy. Warfarin and aspirin use was determined on the day of the procedure. A TRUS-guided biopsy was performed and patients were offered a questionnaire to complete 10 days after the procedure, to determine any immediate or delayed bleeding complications. Follow-up telephone calls were made to those who had not replied within the stipulated period. RESULTS: Of the 1000 patients who replied, 49 were receiving warfarin, 220 were receiving aspirin and 731 were not receiving any anticoagulant drugs. Of the 49 subjects reporting current use of warfarin, 18 (36.7%) experienced haematuria, compared with 440 (60.2%) of the patients receiving no anti-coagulant drugs who reported haematuria. This was statistically significant (p=0.001). Of the group receiving warfarin, 4 (8.2%) experienced haematospermia whereas 153 (21%) of the group receiving no anticoagulant medication reported haematospermia. This difference also was statistically significant (p=0.030). Rectal bleeding was experienced by 7 (14.3%) of the group receiving warfarin compared with 95 (13%) in the group without anticoagulant medication, but this was not statistically significant (p=0.80). We also demonstrated that there was no statistically significant association between the severity of the bleeding complications and medication with warfarin. CONCLUSION: None of the group receiving warfarin experienced clinically important bleeding complications. Our results suggest that the frequency and severity of bleeding complications were no worse in the warfarin group than in the control group and that discontinuing anticoagulation medication before prostate biopsy may be unnecessary

Polymorphisms of vitamin K-related genes (EPHX1 and VKORC1L1) and stable warfarin doses.

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Chung, Jee-Eun; Lee, Kyung Eun; Chang, Byung Chul; Gwak, Hye Sun

2018-01-30

The aim of this study was to investigate the possible effects of EPHX1 and VKORC1L1 polymorphisms on variability of responses to warfarin. Sixteen single nucleotide polymorphisms (SNPs) in 201 patients with stable warfarin doses were analyzed including genes of VKORC1, CYP2C9, CYP4F2, GGCX, EPHX1 and VKORC1L1. Univariate analysis was conducted for the association of genotypes with stable warfarin doses. Multiple linear regression analysis was used to investigate factors that independently affected the inter-individual variability of warfarin dose requirements. The rs4072879 of VKORC1L1 (A>G) was significantly associated with stable warfarin doses; wild homozygote carriers (AA) required significantly lower stable warfarin doses than those with the variant G allele (5.02±1.56 vs. 5.96±2.01mg; p=0.001). Multivariate analysis showed that EPHX1 rs1877724 and VKORC1L1 rs4072879 accounted for 1.5% and 1.3% of the warfarin dose variability. Adding EPHX1 and VKORC1L1 SNPs to the base model including non-genetic variables (operation age, body weight and the therapy of ACEI or ARB) and genetic variables (VKORC1 rs9934438, CYP2C9 rs1057910, and CYP4F2 rs2108622) gave a number needed to genotype of 34. This study showed that polymorphisms of EPHX1 and VKORC1L1 could be determinants of stable warfarin doses. Copyright © 2017. Published by Elsevier B.V.

Review of potential drug interaction between Oseltamivir and Warfarin and why it is important for emergency medicine physicians.

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Shah, Siddharth P; Patel, Kinner M; Subedi, Rogin; Gambhir, Harvir Singh

2017-08-01

Oseltamivir is a very commonly prescribed anti-viral medication by the Emergency Medicine (EM) physicians for the prophylactic and therapeutic treatment of Influenza infection. While the drug interaction of Warfarin with various antibiotics is known, the drug interaction between Oseltamivir and Warfarin is not common. We present a case where an 83-year female patient, on Warfarin for Pulmonary Embolism, had worsening of coagulopathy after she was started on Oseltamivir. The INR was monitored daily in our patient and Warfarin was stopped when the INR became supra-therapeutic. Our patient did not have any minor or major bleeding complication. This is the first reported case of Oseltamivir related worsening coagulopathy in patient on Warfarin to the best of our knowledge. Keeping in mind the possible interaction between the two as it was evident in our case and few other published reports, we recommend monitoring the INR closely in patients using Warfarin after they are started on Oseltamivir therapy. Copyright © 2017 Elsevier Inc. All rights reserved.

Factors influencing medication knowledge and beliefs on warfarin adherence among patients with atrial fibrillation in China

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Zhao, Shujuan; Zhao, Hongwei; Wang, Xianpei; Gao, Chuanyu; Qin, Yuhua; Cai, Haixia; Chen, Boya; Cao, Jingjing

2017-01-01

Objectives Warfarin is often used for ischemic stroke prevention in patients with atrial fibrillation (AF), but the factors affecting patient adherence to warfarin therapy have not been fully understood. Methods A cross-sectional survey was conducted in AF patients undergoing warfarin therapy at least 6 months prior to the study. The clinical data collected using questionnaires by phone interviews included the following: 1) self-reported adherence measured by the Morisky Medication Adherence Scale-8©; 2) beliefs about medicines surveyed by Beliefs about Medicines Questionnaire (BMQ); and 3) drug knowledge as measured by the Warfarin Related Knowledge Test (WRKT). Demographic and clinical factors associated with warfarin adherence were identified using a logistic regression model. Results Two hundred eighty-eight patients completed the survey and 93 (32.3%) of them were classified as nonadherent (Morisky Medication Adherence Scale-8 score <6). Major factors predicting warfarin adherence included age, cardiovascular disorders, WRKT, and BMQ; WRKT and BMQ were independently correlated with adherence to warfarin therapy by multivariate logistic regression analysis. Adherents were more likely to have greater knowledge scores and stronger beliefs in the necessity of their specific medications ([odds ratio {OR} =1.81, 95% confidence interval {CI} =1.51–2.15] and [OR =1.17, 95% CI =1.06–1.29], respectively). Patients with greater concerns about adverse reactions and more negative views of general harm were more likely to be nonadherent ([OR =0.76, 95% CI =0.69–0.84] and [OR =0.82, 95% CI =0.73–0.92], respectively). Conclusion BMK and WRKT are related with patient behavior toward warfarin adherence. BMQ can be applied to identify patients at increased risk of nonadherence. PMID:28223782

Clinical Prediction Model for Time in Therapeutic Range While on Warfarin in Newly Diagnosed Atrial Fibrillation.

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Williams, Brent A; Evans, Michael A; Honushefsky, Ashley M; Berger, Peter B

2017-10-12

Though warfarin has historically been the primary oral anticoagulant for stroke prevention in newly diagnosed atrial fibrillation (AF), several new direct oral anticoagulants may be preferred when anticoagulation control with warfarin is expected to be poor. This study developed a prediction model for time in therapeutic range (TTR) among newly diagnosed AF patients on newly initiated warfarin as a tool to assist decision making between warfarin and direct oral anticoagulants. This electronic medical record-based, retrospective study included newly diagnosed, nonvalvular AF patients with no recent warfarin exposure receiving primary care services through a large healthcare system in rural Pennsylvania. TTR was estimated as the percentage of time international normalized ratio measurements were between 2.0 and 3.0 during the first year following warfarin initiation. Candidate predictors of TTR were chosen from data elements collected during usual clinical care. A TTR prediction model was developed and temporally validated and its predictive performance was compared with the SAMe-TT 2 R 2 score (sex, age, medical history, treatment, tobacco, race) using R 2 and c-statistics. A total of 7877 newly diagnosed AF patients met study inclusion criteria. Median (interquartile range) TTR within the first year of starting warfarin was 51% (32, 67). Of 85 candidate predictors evaluated, 15 were included in the final validated model with an R 2 of 15.4%. The proposed model showed better predictive performance than the SAMe-TT 2 R 2 score ( R 2 =3.0%). The proposed prediction model may assist decision making on the proper mode of oral anticoagulant among newly diagnosed AF patients. However, predicting TTR on warfarin remains challenging. © 2017 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.

Cost effectiveness of novel oral anticoagulants for stroke prevention in atrial fibrillation depending on the quality of warfarin anticoagulation control.

Science.gov (United States)

Janzic, Andrej; Kos, Mitja

2015-04-01

Vitamin K antagonists, such as warfarin, are standard treatments for stroke prophylaxis in patients with atrial fibrillation. Patient outcomes depend on quality of warfarin management, which includes regular monitoring and dose adjustments. Recently, novel oral anticoagulants (NOACs) that do not require regular monitoring offer an alternative to warfarin. The aim of this study was to evaluate whether cost effectiveness of NOACs for stroke prevention in atrial fibrillation depends on the quality of warfarin control. We developed a Markov decision model to simulate warfarin treatment outcomes in relation to the quality of anticoagulation control, expressed as percentage of time in the therapeutic range (TTR). Standard treatment with adjusted-dose warfarin and improved anticoagulation control by genotype-guided dosing were compared with dabigatran, rivaroxaban, apixaban and edoxaban. The analysis was performed from the Slovenian healthcare payer perspective using 2014 costs. In the base case, the incremental cost-effectiveness ratio for apixaban, dabigatran and edoxaban was below the threshold of €25,000 per quality-adjusted life-years compared with adjusted-dose warfarin with a TTR of 60%. The probability that warfarin was a cost-effective option was around 1%. This percentage rises as the quality of anticoagulation control improves. At a TTR of 70%, warfarin was the preferred treatment in half the iterations. The cost effectiveness of NOACs for stroke prevention in patients with nonvalvular atrial fibrillation who are at increased risk for stroke is highly sensitive to warfarin anticoagulation control. NOACs are more likely to be cost-effective options in settings with poor warfarin management than in settings with better anticoagulation control, where they may not represent good value for money.

Coordination properties of warfarin towards Pr(III) predicted from DFT and FT-IR studies

International Nuclear Information System (INIS)

Mihaylov, Tz.; Trendafilova, N.; Georgieva, I.; Kostova, I.

2010-01-01

Graphical abstract: The coordination behavior of warfarin towards Pr(III) in Pr(L) 3 .5H 2 O complex (L - warfarin) is investigated through molecular modeling at B3LYP/6-31G(d,p) level and consequent exhaustive comparative vibrational analysis of the ligand and the complex. The calculations predicted that the ligand binds to the metal through the deprotonated enol group and the keto C=O group in pseudo-octahedral polyhedron. The simulated vibrational spectrum of the model complex proposed is in excellent agreement with the experimental one. - Abstract: The coordination behavior of warfarin towards Pr(III) in Pr(L) 3 .5H 2 O complex (L - warfarin) is investigated through molecular modeling at B3LYP/6-31G(d,p) level and consequent exhaustive comparative vibrational analysis of the ligand and the complex. The calculated NPA charges, Fukui functions and MEP values of the anionic ligand in solution pointed out that the oxygen atoms of the deprotonated hydroxyl and the coumarin carbonyl groups are the most probable reactive sites upon coordination. The metal-ligand binding mode of warfarin is predicted through molecular modeling and energy estimation of different Pr(III)-warfarin structures. In the most stable model structure, the ligand-metal binding is realized through the oxygen of the deprotonated OH group and the oxygen of the keto C=O group in pseudo-octahedral polyhedron. The suggested metal-ligand binding mode is confirmed by comparative vibrational analysis of the free ligand and various model structures with different metal-ligand binding modes.

Coordination properties of warfarin towards Pr(III) predicted from DFT and FT-IR studies

Energy Technology Data Exchange (ETDEWEB)

Mihaylov, Tz., E-mail: tzmihay@svr.igic.bas.bg [Institute of General and Inorganic Chemistry, Bulgarian Academy of Sciences, Sofia (Bulgaria); Trendafilova, N.; Georgieva, I. [Institute of General and Inorganic Chemistry, Bulgarian Academy of Sciences, Sofia (Bulgaria); Kostova, I., E-mail: irenakostova@yahoo.com [Department of Chemistry, Faculty of Pharmacy, Medical University, Sofia (Bulgaria)

2010-08-23

Graphical abstract: The coordination behavior of warfarin towards Pr(III) in Pr(L){sub 3}.5H{sub 2}O complex (L - warfarin) is investigated through molecular modeling at B3LYP/6-31G(d,p) level and consequent exhaustive comparative vibrational analysis of the ligand and the complex. The calculations predicted that the ligand binds to the metal through the deprotonated enol group and the keto C=O group in pseudo-octahedral polyhedron. The simulated vibrational spectrum of the model complex proposed is in excellent agreement with the experimental one. - Abstract: The coordination behavior of warfarin towards Pr(III) in Pr(L){sub 3}.5H{sub 2}O complex (L - warfarin) is investigated through molecular modeling at B3LYP/6-31G(d,p) level and consequent exhaustive comparative vibrational analysis of the ligand and the complex. The calculated NPA charges, Fukui functions and MEP values of the anionic ligand in solution pointed out that the oxygen atoms of the deprotonated hydroxyl and the coumarin carbonyl groups are the most probable reactive sites upon coordination. The metal-ligand binding mode of warfarin is predicted through molecular modeling and energy estimation of different Pr(III)-warfarin structures. In the most stable model structure, the ligand-metal binding is realized through the oxygen of the deprotonated OH group and the oxygen of the keto C=O group in pseudo-octahedral polyhedron. The suggested metal-ligand binding mode is confirmed by comparative vibrational analysis of the free ligand and various model structures with different metal-ligand binding modes.

Association of Warfarin Use With Lower Overall Cancer Incidence Among Patients Older Than 50 Years.

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Haaland, Gry S; Falk, Ragnhild S; Straume, Oddbjørn; Lorens, James B

2017-12-01

In cancer models, warfarin inhibits AXL receptor tyrosine kinase-dependent tumorigenesis and enhances antitumor immune responses at doses not reaching anticoagulation levels. This study investigates the association between warfarin use and cancer incidence in a large, unselected population-based cohort. To examine the association between warfarin use and cancer incidence. This population-based cohort study with subgroup analysis used the Norwegian National Registry coupled with the Norwegian Prescription Database and the Cancer Registry of Norway. The cohort comprised all persons (N = 1 256 725) born between January 1, 1924, and December 31, 1954, who were residing in Norway from January 1, 2006, through December 31, 2012. The cohort was divided into 2 groups-warfarin users and nonusers; persons taking warfarin for atrial fibrillation or atrial flutter were the subgroup. Data were collected from January 1, 2004, to December 31, 2012. Data analysis was conducted from October 15, 2016, to January 31, 2017. Warfarin use was defined as taking at least 6 months of a prescription and at least 2 years from first prescription to any cancer diagnosis. If warfarin treatment started after January 1, 2006, each person contributed person-time in the nonuser group until the warfarin user criteria were fulfilled. Cancer diagnosis of any type during the 7-year observation period (January 1, 2006, through December 31, 2012). Of the 1 256 725 persons in the cohort, 607 350 (48.3%) were male, 649 375 (51.7%) were female, 132 687 (10.6%) had cancer, 92 942 (7.4%) were classified as warfarin users, and 1 163 783 (92.6%) were classified as nonusers. Warfarin users were older, with a mean (SD) age of 70.2 (8.2) years, and were predominantly men (57 370 [61.7%]) as compared with nonusers, who had a mean (SD) age of 63.9 (8.6) years and were mostly women (613 803 [52.7%]). Among warfarin users and compared with nonusers, there was a significantly lower age- and sex

Cost-effectiveness of apixaban compared with warfarin for stroke prevention in atrial fibrillation.

Directory of Open Access Journals (Sweden)

Soyon Lee

Full Text Available BACKGROUND: Apixaban was shown to be superior to adjusted-dose warfarin in preventing stroke or systemic embolism in patients with atrial fibrillation (AF and at least one additional risk factor for stroke, and associated with reduced rates of hemorrhage. We sought to determine the cost-effectiveness of using apixaban for stroke prevention. METHODS: Based on the results from the Apixaban Versus Warfarin in Patients with Atrial Fibrillation (ARISTOTLE trial and other published studies, we constructed a Markov model to evaluate the cost-effectiveness of apixaban versus warfarin from the Medicare perspective. The base-case analysis assumed a cohort of 65-year-old patients with a CHADS(2 score of 2.1 and no contraindication to oral anticoagulation. We utilized a 2-week cycle length and a lifetime time horizon. Outcome measures included costs in 2012 US$, quality-adjusted life-years (QALYs, life years saved and incremental cost-effectiveness ratios. RESULTS: Under base case conditions, quality adjusted life expectancy was 10.69 and 11.16 years for warfarin and apixaban, respectively. Total costs were $94,941 for warfarin and $86,007 for apixaban, demonstrating apixaban to be a dominant economic strategy. Upon one-way sensitivity analysis, these results were sensitive to variability in the drug cost of apixaban and various intracranial hemorrhage related variables. In Monte Carlo simulation, apixaban was a dominant strategy in 57% of 10,000 simulations and cost-effective in 98% at a willingness-to-pay threshold of $50,000 per QALY. CONCLUSIONS: In patients with AF and at least one additional risk factor for stroke and a baseline risk of ICH risk of about 0.8%, treatment with apixaban may be a cost-effective alternative to warfarin.

Cohort-specific imputation of gene expression improves prediction of warfarin dose for African Americans.

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Gottlieb, Assaf; Daneshjou, Roxana; DeGorter, Marianne; Bourgeois, Stephane; Svensson, Peter J; Wadelius, Mia; Deloukas, Panos; Montgomery, Stephen B; Altman, Russ B

2017-11-24

Genome-wide association studies are useful for discovering genotype-phenotype associations but are limited because they require large cohorts to identify a signal, which can be population-specific. Mapping genetic variation to genes improves power and allows the effects of both protein-coding variation as well as variation in expression to be combined into "gene level" effects. Previous work has shown that warfarin dose can be predicted using information from genetic variation that affects protein-coding regions. Here, we introduce a method that improves dose prediction by integrating tissue-specific gene expression. In particular, we use drug pathways and expression quantitative trait loci knowledge to impute gene expression-on the assumption that differential expression of key pathway genes may impact dose requirement. We focus on 116 genes from the pharmacokinetic and pharmacodynamic pathways of warfarin within training and validation sets comprising both European and African-descent individuals. We build gene-tissue signatures associated with warfarin dose in a cohort-specific manner and identify a signature of 11 gene-tissue pairs that significantly augments the International Warfarin Pharmacogenetics Consortium dosage-prediction algorithm in both populations. Our results demonstrate that imputed expression can improve dose prediction and bridge population-specific compositions. MATLAB code is available at https://github.com/assafgo/warfarin-cohort.

Association Between Dabigatran vs Warfarin and Risk of Osteoporotic Fractures Among Patients With Nonvalvular Atrial Fibrillation.

Science.gov (United States)

Lau, Wallis C Y; Chan, Esther W; Cheung, Ching-Lung; Sing, Chor Wing; Man, Kenneth K C; Lip, Gregory Y H; Siu, Chung-Wah; Lam, Joanne K Y; Lee, Alan C H; Wong, Ian C K

2017-03-21

The risk of osteoporotic fracture with dabigatran use in patients with nonvalvular atrial fibrillation (NVAF) is unknown. To investigate the risk of osteoporotic fracture with dabigatran vs warfarin in patients with NVAF. Retrospective cohort study using a population-wide database managed by the Hong Kong Hospital Authority. Patients newly diagnosed with NVAF from 2010 through 2014 and prescribed dabigatran or warfarin were matched by propensity score at a 1:2 ratio with follow-up until July 31, 2016. Dabigatran or warfarin use during the study period. Risk of osteoporotic hip fracture and vertebral fracture was compared between dabigatran and warfarin users using Poisson regression. The corresponding incidence rate ratio (IRR) and absolute risk difference (ARD) with 95% CIs were calculated. Among 51 496 patients newly diagnosed with NVAF, 8152 new users of dabigatran (n = 3268) and warfarin (n = 4884) were matched by propensity score (50% women; mean [SD] age, 74 [11] years). Osteoporotic fracture developed in 104 (1.3%) patients during follow-up (32 dabigatran users [1.0%]; 72 warfarin users [1.5%]). Results of Poisson regression analysis showed that dabigatran use was associated with a significantly lower risk of osteoporotic fracture compared with warfarin (0.7 vs 1.1 per 100 person-years; ARD per 100 person-years, -0.68 [95% CI, -0.38 to -0.86]; IRR, 0.38 [95% CI, 0.22 to 0.66]). The association with lower risk was statistically significant in patients with a history of falls, fractures, or both (dabigatran vs warfarin, 1.6 vs 3.6 per 100 person-years; ARD per 100 person-years, -3.15 [95% CI, -2.40 to -3.45]; IRR, 0.12 [95% CI, 0.04 to 0.33]), but not in those without a history (0.6 vs 0.7 per 100 person-years; ARD per 100 person-years, -0.04 [95% CI, 0.67 to -0.39]; IRR, 0.95 [95% CI, 0.45 to 1.96]) (P value for interaction, <.001). Among adults with NVAF receiving anticoagulation, the use of dabigatran compared with warfarin was associated with a

Fate of (/sup 14/C) warfarin in guinea-pigs: effect of a concomitant single dose of salicylate

Energy Technology Data Exchange (ETDEWEB)

Wong, L T; Solomonraj, G; Thomas, B H [Department of National Health and Welfare, Ottawa, Ontario (Canada). Health Protection Branch

1978-04-01

When a single dose of sodium salicylate (177.8 mg kg/sup -1/, by mouth) was given with (/sup 14/C) warfarin (1 mg kg/sup -1/, i.p.) to guinea-pigs, the salicylate depressed the blood concentrations of /sup 14/C for 6 h. At 1 h, salicylate increased the distribution of /sup 14/C in the liver and brain, but at 1 and 6 h it was decreased in the blood and kidney. A significant portion of the /sup 14/C was excreted into the bile, but was subject to enterohepatic circulation and then excreted by the kidney. There was an enhancement of the biliary elimination of /sup 14/C in the first 5 h after salicylate and a decrease in /sup 14/C concentration in blood; the proportion of warfarin to its metabolites excreted in the urine and bile was unchanged. Salicylate displaced serum protein bound (/sup 14/C) warfarin in vitro. Salicylate increases the initial biliary elimination of warfarin by displacing some of that bound to plasma protein. This facilitated uptake of warfarin by the liver where it was metabolized. This effect of salicylate did not modify the hypoprothrombinaemia produced by warfarin.

The Impact of Genetic and Non-Genetic Factors on Warfarin Dose Prediction in MENA Region: A Systematic Review.

Science.gov (United States)

Bader, Loulia Akram; Elewa, Hazem

2016-01-01

Warfarin is the most commonly used oral anticoagulant for the treatment and prevention of thromboembolic disorders. Pharmacogenomics studies have shown that variants in CYP2C9 and VKORC1 genes are strongly and consistently associated with warfarin dose variability. Although different populations from the Middle East and North Africa (MENA) region may share the same ancestry, it is still unclear how they compare in the genetic and non-genetic factors affecting their warfarin dosing. To explore the prevalence of CYP2C9 and VKORC1 variants in MENA, and the effect of these variants along with other non-genetic factors in predicting warfarin dose. In this systematic review, we included observational cross sectional and cohort studies that enrolled patients on stable warfarin dose and had the genetics and non-genetics factors associated with mean warfarin dose as the primary outcome. We searched PubMed, Medline, Scopus, PharmGKB, PHGKB, Google scholar and reference lists of relevant reviews. We identified 17 studies in eight different populations: Iranian, Israeli, Egyptian, Lebanese, Omani, Kuwaiti, Sudanese and Turkish. Most common genetic variant in all populations was the VKORC1 (-1639G>A), with a minor allele frequency ranging from 30% in Egyptians and up to 52% and 56% in Lebanese and Iranian, respectively. Variants in the CYP2C9 were less common, with the highest MAF for CYP2C9*2 among Iranians (27%). Variants in the VKORC1 and CYP2C9 were the most significant predictors of warfarin dose in all populations. Along with other genetic and non-genetic factors, they explained up to 63% of the dose variability in Omani and Israeli patients. Variants of VKORC1 and CYP2C9 are the strongest predictors of warfarin dose variability among the different populations from MENA. Although many of those populations share the same ancestry and are similar in their warfarin dose predictors, a population specific dosing algorithm is needed for the prospective estimation of warfarin

Comparison of benefit between dabigatran and warfarin among patients with atrial fibrillation: A systematic review

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Amal K Sulieman

2016-01-01

Full Text Available Warfarin is recognized as the standard antithrombotic agent for stroke prevention. However, new oral anticoagulant such as dabigatran constitutes huge improvement to compensate for the limitation of warfarin. A literature review was performed to compare and contrast the overall benefit of dabigatran and warfarin among patients with atrial fibrillation. We utilized HighWire as the data source for randomized controlled trials based on inclusion and exclusion criteria (from January 2007 to September 2013. Descriptive and quantitative information related to stroke and major bleeding were extracted from each trial. After a comprehensive screening of 298 search results, 17 studies which enrolled a total of 127,594 patients were included. Warfarin was found to have higher mean event rates for incidence of stroke, major bleeding, and net clinical benefit compared to dabigatran 110 mg and dabigatran 150 mg. Dabigatran 110 mg has higher rate of stroke and net clinical benefit than dabigatran 150 mg with less major hemorrhage. Overall, dabigatran had higher efficacy and safety profile than warfarin. Further research is required to determine the clinical feasibility of dabigatran in real-life practice.

Genetics and clinical response to warfarin and edoxaban in patients with venous thromboembolism.

Science.gov (United States)

Vandell, Alexander G; Walker, Joseph; Brown, Karen S; Zhang, George; Lin, Min; Grosso, Michael A; Mercuri, Michele F

2017-11-01

The aim of this study was to investigate whether genetic variants can identify patients with venous thromboembolism (VTE) at an increased risk of bleeding with warfarin. Hokusai-venous thromboembolism (Hokusai VTE), a randomised, multinational, double-blind, non-inferiority trial, evaluated the safety and efficacy of edoxaban versus warfarin in patients with VTE initially treated with heparin. In this subanalysis of Hokusai VTE, patients genotyped for variants in CYP2C9 and VKORC1 genes were divided into three warfarin sensitivity types (normal, sensitive and highly sensitive) based on their genotypes. An exploratory analysis was also conducted comparing normal responders to pooled sensitive responders (ie, sensitive and highly sensitive responders). The analysis included 47.7% (3956/8292) of the patients in Hokusai VTE. Among 1978 patients randomised to warfarin, 63.0% (1247) were normal responders, 34.1% (675) were sensitive responders and 2.8% (56) were highly sensitive responders. Compared with normal responders, sensitive and highly sensitive responders had heparin therapy discontinued earlier (pwarfarin dose (pwarfarin (sensitive responders HR 1.38 [95% CI 1.11 to 1.71], p=0.0035; highly sensitive responders 1.79 [1.09 to 2.99]; p=0.0252). In this study, CYP2C9 and VKORC1 genotypes identified patients with VTE at increased bleeding risk with warfarin. NCT00986154. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Comparison of initial loading doses of 5 mg and 10 mg for warfarin therapy

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Sidnei Lastória

2014-03-01

Full Text Available CONTEXT: The question of what is the best loading dosage of warfarin when starting anticoagulant treatment has been under discussion for ten years. We were unable to find any comparative studies of these characteristics conducted here in Brazil. OBJECTIVE: To compare the safety and efficacy of two initial warfarin dosage regimens for anticoagulant treatment. METHODS: One-hundred and ten consecutive patients of both sexes, with indications for anticoagulation because of venous or arterial thromboembolism, were analyzed prospectively. During the first 3 days of treatment, these patients were given adequate heparin to keep aPTT (activated partial thromboplastin time between 1.5 and 2.5, plus 5 mg of warfarin. From the fourth day onwards, their warfarin doses were adjusted using International Normalized Ratios (INR; target range: 2 to 3. This prospective cohort was compared with a historical series of 110 patients had been given 10 mg of warfarin on the first 2 days and 5 mg on the third day with adjustments based on INR thereafter. Outcomes analyzed were as follows: recurrence of thromboembolism, bleeding events and time taken to enter the therapeutic range. RESULTS: Efficacy, safety and length of hospital stay were similar in both samples. The sample that were given 10 mg entered the therapeutic range earlier (means: 4.5 days vs. 5.8 days, were on lower doses at discharge and had better therapeutic indicators at the first return appointment. CONCLUSIONS: The 10 mg dosage regimen took less time to attain the therapeutic range and was associated with lower warfarin doses at discharge and better INR at first out-patients follow-up visit.

A Korean Multi-Center Survey about Warfarin Management before Gastroenterological Endoscopy in Patients with a History of Mechanical Valve Replacement Surgery

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Kuk Hui Son

2016-10-01

Full Text Available Background: Guidelines for esophagogastroduodenoscopy (EGD in the West allow the continued use of warfarin under therapeutic international normalized ratio (INR level. In Korea, no guidelines have been issued regarding warfarin treatment before EGD. The authors surveyed Korean cardiac surgeons about how Korean cardiac surgeons handle warfarin therapy before EGD using a questionnaire. Participants were requested to make decisions regarding the continuation of warfarin therapy in two hypothetical cases. Methods: The questionnaire was administered to cardiac surgeons and consisted of eight questions, including two case scenarios. Results: Thirty- six cardiac surgeons at 28 hospitals participated in the survey, and 52.7% of the participants chose to stop warfarin before EGD in aortic valve replacement patients without risk factors for thromboembolism. When the patient’s INR level was 2, 31% of the participants indicated that they would choose to continue warfarin therapy. For EGD with biopsy, 72.2% of the participants chose warfarin withdrawal, and 25% of the participants chose heparin replacement. In mitral valve replacement patients, 47.2% of the participants chose to discontinue warfarin, and 22.2% of the participants chose heparin replacement. For EGD with biopsy in patients with a mitral valve replacement, 58.3% of the participants chose to stop warfarin, and 41.7% of the participants chose heparin replacement. Conclusion: This study demonstrated that attitudes regarding warfarin treatment for EGD are very different among Korean surgeons. Guidelines specific to the Korean population are required.

Factors influencing medication knowledge and beliefs on warfarin adherence among patients with atrial fibrillation in China.

Science.gov (United States)

Zhao, Shujuan; Zhao, Hongwei; Wang, Xianpei; Gao, Chuanyu; Qin, Yuhua; Cai, Haixia; Chen, Boya; Cao, Jingjing

2017-01-01

Warfarin is often used for ischemic stroke prevention in patients with atrial fibrillation (AF), but the factors affecting patient adherence to warfarin therapy have not been fully understood. A cross-sectional survey was conducted in AF patients undergoing warfarin therapy at least 6 months prior to the study. The clinical data collected using questionnaires by phone interviews included the following: 1) self-reported adherence measured by the Morisky Medication Adherence Scale-8 © ; 2) beliefs about medicines surveyed by Beliefs about Medicines Questionnaire (BMQ); and 3) drug knowledge as measured by the Warfarin Related Knowledge Test (WRKT). Demographic and clinical factors associated with warfarin adherence were identified using a logistic regression model. Two hundred eighty-eight patients completed the survey and 93 (32.3%) of them were classified as nonadherent (Morisky Medication Adherence Scale-8 score beliefs in the necessity of their specific medications ([odds ratio {OR} =1.81, 95% confidence interval {CI} =1.51-2.15] and [OR =1.17, 95% CI =1.06-1.29], respectively). Patients with greater concerns about adverse reactions and more negative views of general harm were more likely to be nonadherent ([OR =0.76, 95% CI =0.69-0.84] and [OR =0.82, 95% CI =0.73-0.92], respectively). BMK and WRKT are related with patient behavior toward warfarin adherence. BMQ can be applied to identify patients at increased risk of nonadherence.

Warfarin for the prevention of systemic embolism in patients with non-valvular atrial fibrillation

DEFF Research Database (Denmark)

Andersen, L V; Vestergaard, P; Deichgraeber, P

2008-01-01

Warfarin for stroke prevention in patients with atrial fibrillation (AF) is well documented. However, it has not been examined in the prevention of systemic embolism.......Warfarin for stroke prevention in patients with atrial fibrillation (AF) is well documented. However, it has not been examined in the prevention of systemic embolism....

Warfarin use and the risk of mortality, stroke, and bleeding in hemodialysis patients with atrial fibrillation.

Science.gov (United States)

Kai, Brandon; Bogorad, Yuliya; Nguyen, Leigh-Anh N; Yang, Su-Jau; Chen, Wansu; Spencer, Hillard T; Shen, Albert Y-J; Lee, Ming-Sum

2017-05-01

The optimal management of stroke prophylaxis in hemodialysis patients with atrial fibrillation is controversial. The purpose of this study was to determine the risk of mortality, stroke, and bleeding associated with the use of warfarin in hemodialysis patients with atrial fibrillation. This was a retrospective, population-based study of hemodialysis patients with atrial fibrillation between January 1, 2006, and September 30, 2015. Association of warfarin use with mortality, stroke, and bleeding was determined by propensity score-matched, Cox proportional hazard models. Among the 4286 patients with atrial fibrillation on hemodialysis, 989 (23%) were prescribed warfarin. Propensity score matching was used to identify 888 matched pairs with similar baseline characteristics. Warfarin use was associated with lower risk of all-cause death (hazard ratio [HR] 0.76, 95% confidence interval [CI] 0.69-0.84) and lower risk of ischemic stroke (HR 0.68, 95% CI 0.52-0.91). Warfarin use was not associated with a higher risk of hemorrhagic stroke (HR 1.2, 95% CI 0.6-2.2) or gastrointestinal bleeding (HR 0.97, 95% CI 0.77-1.2). The treatment effect was largest in the group with the best international normalized ratio control as measured by time in therapeutic range. Subgroup analyses showed warfarin use was associated with survival benefit in most subgroups. The 2 subgroups that did not benefit were patients with a history of hemorrhagic stroke and patients with concurrent aspirin use. Warfarin use is associated with lower all-cause mortality and ischemic stroke, without significantly increasing the risk of bleeding in hemodialysis patients with atrial fibrillation. Copyright © 2017 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.

Effect of Long Term Oral Warfarin Sodium Treatment on Bone Mineral Density Scores and Spinal Sagittal Alignment

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Kamil Eyvazov

2016-04-01

Full Text Available Objective: The aim of this study was to investigate the effect of long term oral warfarin sodium treatment on bone mineral density (BMD and spinal sagittal alignment. Materials and Methods: Sixty four participants were enrolled for this retrospective study. Participants were divided into two groups-participants who had taken warfarin sodium for at least two years (n=33 and participants who had never taken warfarin sodium (n=31. All of the individuals were evaluated at the same center. Dual X-ray absorptiometry (DXA was used for measuring BMD. Whole spine x-rays were obtained for sagittal assessment and the following parameters were measured: Cervical lordosis, thoracic kyphosis, lumbar lordosis, pelvic incidence, pelvic tilt, sacral slope and sagittal vertical axis (SVA. Results: The mean BMD value was significantly higher in participants who had not taken warfarin sodium compared to participants who had taken warfarin sodium. The differences between the average values were 0.1552 g/cm2 in BMD; 2.1 in T scores; 1.4 in Z scores. On the radiological evaluation of the spine, cervical lordosis was 7.1 degrees lower, lumbar lordosis was 4.7 degrees lower and thoracic kyphosis was 5.3 degrees higher in the patients using drug. C7 plumb line was interchanged forward in the patients using drug. Conclusions: This study shows that warfarin sodium use worsens bone quality in the lumbar region and does not affect bone quality in the femoral region. Furthermore, warfarin sodium use also reduces physiological lordosis and enhances thoracic kyphosis. Consequences of these changes are the likely cause of sagittal spinal anterior imbalance. Long-term oral warfarin sodium use affect bone mineral density and spinal alignment. Our conclusion about giving clear message and show exactly mechanism we need prospective randomized multicentre studies in future. We strongly believe this study will be pioneer for future researches.

Case Series Analysis of New Zealand Reports of Rapid Intense Potentiation of Warfarin by Roxithromycin.

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Savage, Ruth L; Tatley, Michael V

2018-05-01

We undertook an analysis of all the reports to the New Zealand Centre for Adverse Reactions Monitoring of a roxithromycin/warfarin interaction after two recent reports described intense rapid warfarin potentiation. The interaction was first published in 1995. Cytochrome P450 3A4 inhibition has been the proposed mechanism but has limited biologic plausibility. There are suggestions that the clinical significance of the interaction may be increased by severe illness, polypharmacy, renal dysfunction, older age and increased warfarin sensitivity. To investigate the potentiating effect of warfarin on roxithromycin in this New Zealand case series, the reports were reviewed to identify patients at risk, compare the reporting pattern with published Australian data and evaluate the appropriateness of current prescribing advice. Thirty patient reports were identified. The age range was 23-88 years, mean 66.8, median 73.0 (standard deviation 17.7) and the international normalised ratios after roxithromycin commencement ranged from 3.6 to 16.7 (mean 7.6, median 7.6, standard deviation 3.6). For eight patients with measurements on day 3, international normalised ratios were 4.3-16.7 (mean 10.4, median 8.8, standard deviation 4.4). Four patients had serious haemorrhage. Indications for roxithromycin were a range of respiratory tract infections. Anticoagulation was stable for most patients prior to acute infection. Serious infection occurred in 54.5% (12 of 22 patients with information). Polypharmacy (five or more medicines daily) was used by 36.7% of patients long term, increasing acutely to 83.3%, including additional potentially interacting medicines. Warfarin daily dose (1.5-13.0 mg, mean 4.4, median 4.0, standard deviation 2.2) was moderate to low. Pre-roxithromycin international normalised ratio values ranged from 1.4 to 3.7, mean and median 2.5, standard deviation 0.5. A high proportion of interactions were observed between warfarin and roxithromycin compared with other

Outcomes of Dabigatran and Warfarin for Atrial Fibrillation in Contemporary Practice: A Retrospective Cohort Study.

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Go, Alan S; Singer, Daniel E; Toh, Sengwee; Cheetham, T Craig; Reichman, Marsha E; Graham, David J; Southworth, Mary Ross; Zhang, Rongmei; Izem, Rima; Goulding, Margie R; Houstoun, Monika; Mott, Katrina; Sung, Sue Hee; Gagne, Joshua J

2017-12-19

Dabigatran (150 mg twice daily) has been associated with lower rates of stroke than warfarin in trials of atrial fibrillation, but large-scale evaluations in clinical practice are limited. To compare incidence of stroke, bleeding, and myocardial infarction in patients receiving dabigatran versus warfarin in practice. Retrospective cohort. National U.S. Food and Drug Administration Sentinel network. Adults with atrial fibrillation initiating dabigatran or warfarin therapy between November 2010 and May 2014. Ischemic stroke, intracranial hemorrhage, extracranial bleeding, and myocardial infarction identified from hospital claims among propensity score-matched patients starting treatment with dabigatran or warfarin. Among 25 289 patients starting dabigatran therapy and 25 289 propensity score-matched patients starting warfarin therapy, those receiving dabigatran did not have significantly different rates of ischemic stroke (0.80 vs. 0.94 events per 100 person-years; hazard ratio [HR], 0.92 [95% CI, 0.65 to 1.28]) or extracranial hemorrhage (2.12 vs. 2.63 events per 100 person-years; HR, 0.89 [CI, 0.72 to 1.09]) but were less likely to have intracranial bleeding (0.39 vs. 0.77 events per 100 person-years; HR, 0.51 [CI, 0.33 to 0.79]) and more likely to have myocardial infarction (0.77 vs. 0.43 events per 100 person-years; HR, 1.88 [CI, 1.22 to 2.90]). However, the strength and significance of the association between dabigatran use and myocardial infarction varied in sensitivity analyses and by exposure definition (HR range, 1.13 [CI, 0.78 to 1.64] to 1.43 [CI, 0.99 to 2.08]). Older patients and those with kidney disease had higher gastrointestinal bleeding rates with dabigatran. Inability to examine outcomes by dabigatran dose (unacceptable covariate balance between matched patients) or quality of warfarin anticoagulation (few patients receiving warfarin had available international normalized ratio values). In matched adults with atrial fibrillation treated in

Cohort-specific imputation of gene expression improves prediction of warfarin dose for African Americans

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Assaf Gottlieb

2017-11-01

Full Text Available Abstract Background Genome-wide association studies are useful for discovering genotype–phenotype associations but are limited because they require large cohorts to identify a signal, which can be population-specific. Mapping genetic variation to genes improves power and allows the effects of both protein-coding variation as well as variation in expression to be combined into “gene level” effects. Methods Previous work has shown that warfarin dose can be predicted using information from genetic variation that affects protein-coding regions. Here, we introduce a method that improves dose prediction by integrating tissue-specific gene expression. In particular, we use drug pathways and expression quantitative trait loci knowledge to impute gene expression—on the assumption that differential expression of key pathway genes may impact dose requirement. We focus on 116 genes from the pharmacokinetic and pharmacodynamic pathways of warfarin within training and validation sets comprising both European and African-descent individuals. Results We build gene-tissue signatures associated with warfarin dose in a cohort-specific manner and identify a signature of 11 gene-tissue pairs that significantly augments the International Warfarin Pharmacogenetics Consortium dosage-prediction algorithm in both populations. Conclusions Our results demonstrate that imputed expression can improve dose prediction and bridge population-specific compositions. MATLAB code is available at https://github.com/assafgo/warfarin-cohort

Contribution of rivaroxaban to the international normalized ratio when switching to warfarin for anticoagulation as determined by simulation studies.

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Siegmund, Hans-Ulrich; Burghaus, Rolf; Kubitza, Dagmar; Coboeken, Katrin

2015-06-01

This study evaluated the influence of rivaroxaban 20 mg once daily on international normalized ratio (INR) during the co-administration period when switching from rivaroxaban to warfarin. We developed a calibrated coagulation model that was qualified with phase I clinical data. Prothrombin time and INR values were simulated by use of phospholipid concentrations that matched Neoplastin Plus® and Innovin® reagents. To simulate the combined effects of rivaroxaban and warfarin on INR during switching, warfarin initiation was simulated by adjusting the magnitude of the warfarin effect to reach the desired target INRs over the course of 21 days. The warfarin effect values (obtained every 6 h) and the desired rivaroxaban plasma concentrations were used. Nomograms were generated from rivaroxaban induced increases in INR. The simulation had good prediction quality. Rivaroxaban induced increases in the total INR from the warfarin attributed INR were seen, which increased with rivaroxaban plasma concentration. When the warfarin only INR was 2.0-3.0, the INR contribution of rivaroxaban with Neoplastin Plus® was 0.5-1.2, decreasing to 0.3-0.6 with Innovin® at median trough rivaroxaban plasma concentrations (38 μg l(-1) ). The data indicate that measuring warfarin induced changes in INR are best performed at trough rivaroxaban concentrations (24 h after rivaroxaban dosing) during the co-administration period when switching from rivaroxaban to warfarin. Furthermore, Innovin® is preferable to Neoplastin Plus® because of its substantially lower sensitivity to rivaroxaban, thereby reducing the influence of rivaroxaban on the measured INR. © 2014 The British Pharmacological Society.

Cloud point extraction-fluorimetric combined methodology for the determination of trace warfarin based on the sensitization effect of supramolecule

Energy Technology Data Exchange (ETDEWEB)

Chang Zheng [Department of Applied Chemistry of College of Science, Xi' an University of Technology, Xi' an 710048 (China); College of Chemistry and Materials Science, Northwest University, 229 North Taibai Road, Xi' an 710069 (China); Yan Hongtao, E-mail: cz610@163.com [College of Chemistry and Materials Science, Northwest University, 229 North Taibai Road, Xi' an 710069 (China)

2012-03-15

Compared to the fluorescence spectra of warfarin in pure ethanol and in the presence of the nonionic surfactant Tergitol 15-S-7 after cloud point extraction (CPE), it can be seen that the fluorescence emission peak underwent an obvious red shift and the fluorescence intensity of warfarin was significantly increased in the presence of Tergitol 15-S-7. In order to confirm Tergitol 15-S-7-induced supramolecular effects, the investigations on the fluorescence quantum yields of warfarin in the micellar medium and pure ethanol were performed. The experimental results showed that the supramolecular interactions between Tergitol 15-S-7 and the warfarin excimers played a key role for improving the warfarin fluorescence properties. Based on these facts, a simple fluorometric method combined with CPE for the determination of trace warfarin was developed for the first time. Under optimized experimental conditions, the linear concentration range for warfarin was 3.0 Multiplication-Sign 1.0{sup -9}-1.0 Multiplication-Sign 10{sup -6} mol L{sup -1} and the detection limit was 3.3 Multiplication-Sign 10{sup -10} mol L{sup -1}. And, the proposed method was approved to be appropriate for monitoring warfarin in actual pharmaceutical formulations and biological fluid samples by recovery test, in comparison with other reported methods being satisfactory. - Highlights: Black-Right-Pointing-Pointer A CPE fluorescence method for trace warfarin was developed for the first time. Black-Right-Pointing-Pointer Supramolecule effects play a key role for improving the fluorescence property. Black-Right-Pointing-Pointer Notion presents an opportunity so far neglected area of CPE investigation. Black-Right-Pointing-Pointer Without previous treatment, urine species after CPE had no significant interference.

Cloud point extraction-fluorimetric combined methodology for the determination of trace warfarin based on the sensitization effect of supramolecule

International Nuclear Information System (INIS)

Chang Zheng; Yan Hongtao

2012-01-01

Compared to the fluorescence spectra of warfarin in pure ethanol and in the presence of the nonionic surfactant Tergitol 15-S-7 after cloud point extraction (CPE), it can be seen that the fluorescence emission peak underwent an obvious red shift and the fluorescence intensity of warfarin was significantly increased in the presence of Tergitol 15-S-7. In order to confirm Tergitol 15-S-7-induced supramolecular effects, the investigations on the fluorescence quantum yields of warfarin in the micellar medium and pure ethanol were performed. The experimental results showed that the supramolecular interactions between Tergitol 15-S-7 and the warfarin excimers played a key role for improving the warfarin fluorescence properties. Based on these facts, a simple fluorometric method combined with CPE for the determination of trace warfarin was developed for the first time. Under optimized experimental conditions, the linear concentration range for warfarin was 3.0×1.0 −9 –1.0×10 −6 mol L −1 and the detection limit was 3.3×10 −10 mol L −1 . And, the proposed method was approved to be appropriate for monitoring warfarin in actual pharmaceutical formulations and biological fluid samples by recovery test, in comparison with other reported methods being satisfactory. - Highlights: ► A CPE fluorescence method for trace warfarin was developed for the first time. ► Supramolecule effects play a key role for improving the fluorescence property. ► Notion presents an opportunity so far neglected area of CPE investigation. ► Without previous treatment, urine species after CPE had no significant interference.

The effects of ferulic acid on the pharmacokinetics of warfarin in rats after biliary drainage

Directory of Open Access Journals (Sweden)

Li H

2016-07-01

Full Text Available Haigang Li,1,2 Yang Wang,1 Rong Fan,1 Huiying Lv,3 Hua Sun,4 Haitang Xie,4 Tao Tang,1 Jiekun Luo,1 Zian Xia1 1Department of Integrated Traditional Chinese and Western Medicine, Laboratory of Ethnopharmacology, Xiangya Hospital, Central South University, 2Department of Pharmacy, Changsha Medical University, 3Hunan Agricultural Product Processing Institute, Hunan Academy of Agricultural Sciences, Changsha, 4Anhui Provincial Centre for Drug Clinical Evaluation, Yijishan Hospital of Wannan Medical College, Wuhu, People’s Republic of China Abstract: According to previous research studies, warfarin can be detected in human bile after oral administration. Ferulic acid (FA is the main bioactive component of many Chinese herbs for the treatment of cardiovascular disease. To elucidate the effects of FA on the pharmacokinetics of warfarin in rats after biliary drainage is necessary. Twenty rats were randomly divided into four groups: Group 1 (WN: healthy rats after the administration of warfarin sodium, Group 2 (WO: a rat model of biliary drainage after the administration of warfarin sodium, Group 3 (WFN: healthy rats after the administration of warfarin sodium and FA, and Group 4 (WFO: a rat model of biliary drainage after the administration of warfarin sodium and FA. Blood samples were collected at different time points after administration. The concentrations of blood samples were determined by ultraperformance liquid chromatography–tandem mass spectrometry. Comparisons between groups were performed according to the main pharmacokinetic parameters calculated by the DAS 2.1.1 software. The pharmacokinetic parameters showed a significant difference between the WN and WO groups, the WO group showed a decrease of 51% and 41.6% in area under the curve from 0 to time (AUC0–t and peak plasma concentration (Cmax, respectively, whereas time to Cmax (Tmax was delayed 3.27 folds. There were significant differences between the WFO and WFN groups, the WFO

Prostate cancer-specific survival among warfarin users in the Finnish Randomized Study of Screening for Prostate Cancer.

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Kinnunen, Pete T T; Murtola, Teemu J; Talala, Kirsi; Taari, Kimmo; Tammela, Teuvo L J; Auvinen, Anssi

2017-08-29

Venous thromboembolic events (VTE) are common in cancer patients and associated with higher mortality. In vivo thrombosis and anticoagulation might be involved in tumor growth and progression. We studied the association of warfarin and other anticoagulant use as antithrombotic medication and prostate cancer (PCa) death in men with the disease. The study included 6,537 men diagnosed with PCa during 1995-2009. Information on anticoagulant use was obtained from a national reimbursement registry. Cox regression with adjustment for age, PCa risk group, primary therapy and use of other medication was performed to compare risk of PCa death between warfarin users with 1) men using other types of anticoagulants and 2) non-users of anticoagulants. Medication use was analyzed as a time-dependent variable to minimize immortal time bias. In total, 728 men died from PCa during a median follow-up of 9 years. Compared to anticoagulant non-users, post-diagnostic use of warfarin was associated with an increased risk of PCa death (overall HR 1.47, 95% CI 1.13-1.93). However, this was limited to low-dose, low-intensity use. Otherwise, the risk was similar to anticoagulant non-users. Additionally, we found no risk difference between warfarin and other types of anticoagulants. Pre-diagnostic use of warfarin was not associated with the risk of PCa death. We found no reduction in risk of PCa death associated with warfarin use. Conversely, the risk was increased in short-term use, which is probably explained by a higher risk of thrombotic events prompting warfarin use in patients with terminal PCa.

Fatal cerebral blødning på grund af mulig interaktionmellem paracetamol og warfarin

DEFF Research Database (Denmark)

Vinsand Naver, Signe; Papina, Maria; Jimenez Solem, Espen

2015-01-01

This is a case report of an 83-year-old man in warfarin treatment with stable international normalised ratio (INR) after aortic valve replacement and atrial fibrillation. Due to back pain he took paracetamol (acetaminophen) 4 g/day, morphine 30 mg/day and diclofenac as rescue medication for two...... paracetamol and warfarin are discussed....

Cost Effectiveness of Genotype-Guided Warfarin Dosing in Patients with Mechanical Heart Valve Replacement Under the Fee-for-Service System.

Science.gov (United States)

Kim, Dong-Jin; Kim, Ho-Sook; Oh, Minkyung; Kim, Eun-Young; Shin, Jae-Gook

2017-10-01

Although studies assessing the cost effectiveness of genotype-guided warfarin dosing for the management of atrial fibrillation, deep vein thrombosis, and pulmonary embolism have been reported, no publications have addressed genotype-guided warfarin therapy in mechanical heart valve replacement (MHVR) patients or genotype-guided warfarin therapy under the fee-for-service (FFS) insurance system. The aim of this study was to evaluate the cost effectiveness of genotype-guided warfarin dosing in patients with MHVR under the FFS system from the Korea healthcare sector perspective. A decision-analytic Markov model was developed to evaluate the cost effectiveness of genotype-guided warfarin dosing compared with standard dosing. Estimates of clinical adverse event rates and health state utilities were derived from the published literature. The outcome measure was the incremental cost-effectiveness ratio (ICER) per quality-adjusted life-year (QALY). One-way and probabilistic sensitivity analyses were performed to explore the range of plausible results. In a base-case analysis, genotype-guided warfarin dosing was associated with marginally higher QALYs than standard warfarin dosing (6.088 vs. 6.083, respectively), at a slightly higher cost (US$6.8) (year 2016 values). The ICER was US$1356.2 per QALY gained. In probabilistic sensitivity analysis, there was an 82.7% probability that genotype-guided dosing was dominant compared with standard dosing, and a 99.8% probability that it was cost effective at a willingness-to-pay threshold of US$50,000 per QALY gained. Compared with only standard warfarin therapy, genotype-guided warfarin dosing was cost effective in MHVR patients under the FFS insurance system.

The impact of non-genetic and genetic factors on a stable warfarin dose in Thai patients.

Science.gov (United States)

Wattanachai, Nitsupa; Kaewmoongkun, Sutthida; Pussadhamma, Burabha; Makarawate, Pattarapong; Wongvipaporn, Chaiyasith; Kiatchoosakun, Songsak; Vannaprasaht, Suda; Tassaneeyakul, Wichittra

2017-08-01

The aim of this study was to investigate the contributions of non-genetic and genetic factors on the variability of stable warfarin doses in Thai patients. A total of 250 Thai patients with stable warfarin doses were enrolled in the study. Demographics and clinical data, e.g., age, body mass index, indications for warfarin and concomitant medications, were documented. Four single nucleotide polymorphisms in the VKORC1 - 1639G > A, CYP2C9*3, CYP4F2 rs2108622, and UGT1A1 rs887829 genes were detected from gDNA using TaqMan allelic discrimination assays. The patients with variant genotypes of VKORC1 - 1639G > A required significantly lower warfarin stable weekly doses (SWDs) than those with wild-type genotype (p warfarin SWDs than those with homozygous wild-type (p = 0.006). In contrast, there were no significant differences in the SWDs between the patients who carried variant alleles of CYP4F2 rs2108622 and UGT1A1 rs887829 as compared to wild-type allele carriers. Multivariate analysis, however, showed that CYP4F2 rs2108622 TT genotype accounted for a modest part of warfarin dose variability (1.2%). In contrast, VKORC1 - 1639G > A, CYP2C9*3, CYP4F2 rs2108622 genotypes and non-genetic factors accounted for 51.3% of dose variability. VKORC1 - 1639G > A, CYP2C9*3, and CYP4F2 rs2108622 polymorphisms together with age, body mass index, antiplatelet drug use, amiodarone use, and current smoker status explained 51.3% of individual variability in stable warfarin doses. In contrast, the UGT1A1 rs887829 polymorphism did not contribute to dose variability.

The Cost Differential Between Warfarin Versus Aspirin Treatment After a Fontan Procedure.

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Schilling, Chris; Dalziel, Kim; Iyengar, Ajay J; d'Udekem, Yves

2017-08-01

The use of aspirin versus warfarin for treatment of patients after a Fontan procedure remains contentious. Current preference-based models of treatment across Australia and New Zealand show variation in care that is unlikely to reflect patient differences and/or clinical risk. We combine data from the Australian and New Zealand Fontan Registry and a home INR (International Normalised Ratio) monitoring program (HINRMP) from the Royal Children's Hospital (RCH) Melbourne, to estimate the cost difference for Fontan recipients receiving aspirin versus warfarin for 2015. We adopt a societal perspective to costing which includes cost to the health system (e.g. medical consults, pathology tests) and costs to patients and carers (e.g. travel and time), but excludes costs of adverse events. Costs are presented in Australian 2015 dollars; any costs from previous years have been inflated using appropriate rates from the Australian Bureau of Statistics. We find that warfarin patients face additional costs of $825 per annum, with the majority ($584 or 71%) of those borne by the patient or family. If aspirin is as clinically as effective as warfarin, Fontan recipients could be enjoying far less costly, invasive and time-consuming treatment. While achieving such clinical consensus can be difficult, economics shows us that there are large costs associated with a failure to achieve it. Copyright © 2017. Published by Elsevier B.V.

Warfarin-induced toxic epidermal necrolysis in combination therapy of Henoch-Schönlein purpura nephritis: a case report.

Science.gov (United States)

Kasahara, Katsuaki; Gotoh, Yoshimitsu; Kuroyanagi, Yoshiyuki; Nagano, China

2017-07-14

Toxic epidermal necrolysis (TEN) is a rare life-threatening condition almost exclusively attributed to drugs. The main etiologic factors for TEN are sulphonamides, anticonvulsants, and antibiotics; however, there are no published reports of warfarin causing TEN. We present the case of a 3-year-old patient who developed TEN while receiving treatment for Henoch-Schönlein purpura nephritis (HSPN). With multiple-drug therapy comprising prednisolone, mizoribine, dipyridamole, and warfarin, it is difficult to detect which drug is the causative agent. While in most cases, diagnosis of the causative drug is based on clinical history without a lymphocyte transformation test (LTT), we performed the test three times and identified the causative drug as warfarin at the late phase. We continued HSPN treatment without warfarin, and results showed good renal function without life-threatening complications. To our knowledge, this is the first report about TEN caused by warfarin. Repeated LTTs could be useful for identifying TEN-causative drugs even in the late phase.

Assessment of warfarin therapy under full dose using indium-111 platelet scintigraphy in patients with intracardiac thrombi

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Yamada, Makoto; Onishi, Kenji; Fukunami, Masatake and others

1988-12-01

Twenty patients in whom intracardiac thrombi were detected by indium-111 platelet scintigraphy (the first platelet scintigraphy) were prospectively studied to examine the effect of warfarin therapy under full dose on the intracardiac thrombogenecity. Eleven patients (group I) who received 2-6 mg/day of warfarin and 9 patients (group II) who did not received warfarin had the second platelet scintigraphies 14-71 days after the first platelet scintigraphies. In group I, 10 platelet scintigraphies became negative and one remained positive for intracardiac thrombi after administration of warfarin, while in group II 8 platelet scintigraphies remained positive and only one changed to negative. The incidence of negative image at the second platelet scintigraphy was significantly lower in group II than that in group I. In group I, the degree of accumulation of platelets onto the surface of the thrombus (%IE), showed significant reduction (0.69+-0.48 to 0.11+-0.21) after warfarin therapy, while in group II %IE at the second scintigraphy (1.07+-1.03) were not significantly different from those at the first scintigraphy (1.13+-0.79). These results indicated that warfarin therapy under full dose inhibited the deposition of platelets on the intracardiac thrombi and thrombogenecity in the patients with intracardiac thrombi which were detected by indium-111 platelet scintigraphy.

Assessment of warfarin therapy under full dose using indium-111 platelet scintigraphy in patients with intracardiac thrombi

International Nuclear Information System (INIS)

Yamada, Makoto; Onishi, Kenji; Fukunami, Masatake

1988-01-01

Twenty patients in whom intracardiac thrombi were detected by indium-111 platelet scintigraphy (the first platelet scintigraphy) were prospectively studied to examine the effect of warfarin therapy under full dose on the intracardiac thrombogenecity. Eleven patients (group I) who received 2-6 mg/day of warfarin and 9 patients (group II) who did not received warfarin had the second platelet scintigraphies 14-71 days after the first platelet scintigraphies. In group I, 10 platelet scintigraphies became negative and one remained positive for intracardiac thrombi after administration of warfarin, while in group II 8 platelet scintigraphies remained positive and only one changed to negative. The incidence of negative image at the second platelet scintigraphy was significantly lower in group II than that in group I. In group I, the degree of accumulation of platelets onto the surface of the thrombus (%IE), showed significant reduction (0.69±0.48 to 0.11±0.21) after warfarin therapy, while in group II %IE at the second scintigraphy (1.07±1.03) were not significantly different from those at the first scintigraphy (1.13±0.79). These results indicated that warfarin therapy under full dose inhibited the deposition of platelets on the intracardiac thrombi and thrombogenecity in the patients with intracardiac thrombi which were detected by indium-111 platelet scintigraphy. (author)

Genetic variants associated with warfarin dose in African-American individuals: a genome-wide association study

Science.gov (United States)

Perera, Minoli A; Cavallari, Larisa H; Limdi, Nita A; Gamazon, Eric R; Konkashbaev, Anuar; Daneshjou, Roxana; Pluzhnikov, Anna; Crawford, Dana C; Wang, Jelai; Liu, Nianjun; Tatonetti, Nicholas; Bourgeois, Stephane; Takahashi, Harumi; Bradford, Yukiko; Burkley, Benjamin M; Desnick, Robert J; Halperin, Jonathan L; Khalifa, Sherief I; Langaee, Taimour Y; Lubitz, Steven A; Nutescu, Edith A; Oetjens, Matthew; Shahin, Mohamed H; Patel, Shitalben R; Sagreiya, Hersh; Tector, Matthew; Weck, Karen E; Rieder, Mark J; Scott, Stuart A; Wu, Alan HB; Burmester, James K; Wadelius, Mia; Deloukas, Panos; Wagner, Michael J; Mushiroda, Taisei; Kubo, Michiaki; Roden, Dan M; Cox, Nancy J; Altman, Russ B; Klein, Teri E; Nakamura, Yusuke; Johnson, Julie A

2013-01-01

Summary Background VKORC1 and CYP2C9 are important contributors to warfarin dose variability, but explain less variability for individuals of African descent than for those of European or Asian descent. We aimed to identify additional variants contributing to warfarin dose requirements in African Americans. Methods We did a genome-wide association study of discovery and replication cohorts. Samples from African-American adults (aged ≥18 years) who were taking a stable maintenance dose of warfarin were obtained at International Warfarin Pharmacogenetics Consortium (IWPC) sites and the University of Alabama at Birmingham (Birmingham, AL, USA). Patients enrolled at IWPC sites but who were not used for discovery made up the independent replication cohort. All participants were genotyped. We did a stepwise conditional analysis, conditioning first for VKORC1 −1639G→A, followed by the composite genotype of CYP2C9*2 and CYP2C9*3. We prespecified a genome-wide significance threshold of p<5×10−8 in the discovery cohort and p<0·0038 in the replication cohort. Findings The discovery cohort contained 533 participants and the replication cohort 432 participants. After the prespecified conditioning in the discovery cohort, we identified an association between a novel single nucleotide polymorphism in the CYP2C cluster on chromosome 10 (rs12777823) and warfarin dose requirement that reached genome-wide significance (p=1·51×10−8). This association was confirmed in the replication cohort (p=5·04×10−5); analysis of the two cohorts together produced a p value of 4·5×10−12. Individuals heterozygous for the rs12777823 A allele need a dose reduction of 6·92 mg/week and those homozygous 9·34 mg/week. Regression analysis showed that the inclusion of rs12777823 significantly improves warfarin dose variability explained by the IWPC dosing algorithm (21% relative improvement). Interpretation A novel CYP2C single nucleotide polymorphism exerts a clinically relevant

Renal function, time in therapeutic range and outcomes in warfarin-treated atrial fibrillation patients

DEFF Research Database (Denmark)

Bonde, Anders Nissen; Lip, Gregory Y H; Kamper, Anne-Lise

2017-01-01

Patients with severely reduced renal function have been excluded from randomized controlled trials of oral anticoagulation in atrial fibrillation (AF). Warfarin treatment in this population is controversial and data on anticoagulation control and the impact on adverse outcomes are needed. By indi......Patients with severely reduced renal function have been excluded from randomized controlled trials of oral anticoagulation in atrial fibrillation (AF). Warfarin treatment in this population is controversial and data on anticoagulation control and the impact on adverse outcomes are needed......) was calculated using the Rosendaal method. The risk of stroke and bleeding was estimated using multivariable Cox regression analyses with eGFR and TTR estimated time dependently throughout follow-up. We identified 10,423 warfarin-treated AF patients with available international normalized ratio and creatinine...

Validation and Application of a Simple UHPLC–MS-MS Method for the Enantiospecific Determination of Warfarin in Human Urine

Science.gov (United States)

Alshogran, Osama Y.; Ocque, Andrew J.; Leblond, François A.; Pichette, Vincent; Nolin, Thomas D.

2016-01-01

A simple and rapid liquid chromatographic–tandem mass spectrometric method has been developed and validated for the enantiospecific determination of R- and S-warfarin in human urine. Warfarin enantiomers were extracted from urine using methyl tert-butyl ether. Chromatographic separation of warfarin enantiomers and the internal standard d5-warfarin was achieved using a Astec Chirobiotic V column with gradient mobile phase at a flow rate of 400 µL/min over 10 min. Detection was performed on a TSQ Quantum Ultra triple quadrupole mass spectrometer equipped with a heated electrospray ionization source. Analytes were detected in negative ionization mode using selected reaction monitoring. Calibration curves were linear with a correlation coefficient of ≥0.996 for both enantiomers over a concentration range of 5–500 ng/mL. The intra- and interday accuracy and precision for both analytes were within ±9.0%. Excellent extraction efficiency and negligible matrix effects were observed. The applicability of the method was demonstrated by successful measurement of warfarin enantiomers in urine of patients with kidney disease. The method is simple, accurate and reproducible and is currently being used to support warfarin pharmacokinetic studies. PMID:26657732

Rivaroxaban compared with warfarin in patients with atrial fibrillation and previous stroke or transient ischaemic attack

DEFF Research Database (Denmark)

Hankey, Graeme J; Patel, Manesh R; Stevens, Susanna R

2012-01-01

In ROCKET AF, rivaroxaban was non-inferior to adjusted-dose warfarin in preventing stroke or systemic embolism among patients with atrial fibrillation (AF). We aimed to investigate whether the efficacy and safety of rivaroxaban compared with warfarin is consistent among the subgroups of patients ...

Dabigatran versus warfarin in patients with atrial fibrillation

NARCIS (Netherlands)

Connolly, Stuart J.; Ezekowitz, Michael D.; Yusuf, Salim; Eikelboom, John; Oldgren, Jonas; Parekh, Amit; Pogue, Janice; Reilly, Paul A.; Themeles, Ellison; Varrone, Jeanne; Wang, Susan; Alings, Marco; Xavier, Denis; Zhu, Jun; Diaz, Rafael; Lewis, Basil S.; Darius, Harald; Diener, Hans-Christoph; Joyner, Campbell D.; Wallentin, Lars; Connolly, S. J.; Ezekowitz, M. D.; Yusuf, S.; Eikelboom, J.; Oldgren, J.; Parekh, A.; Reilly, P. A.; Themeles, E.; Varrone, J.; Wang, S.; Palmcrantz-Graf, E.; Haehl, M.; Wallentin, L.; Alings, A. M. W.; Amerena, J. V.; Avezum, A.; Baumgartner, I.; Brugada, J.; Budaj, A.; Caicedo, V.; Ceremuzynski, L.; Chen, J. H.; Commerford, P. J.; Dans, A. L.; Darius, H.; Di Pasquale, G.; Diaz, R.; Erol, C.; Ferreira, J.; Flaker, G. C.; Flather, M. D.; Franzosi, M. G.; Gamboa, R.; Golitsyn, S. P.; Gonzalez Hermosillo, J. A.; Halon, D.; Heidbuchel, H.; Hohnloser, S. H.; Hori, M.; Huber, K.; Jansky, P.; Kamensky, G.; Keltai, M.; Kim, S.; Lau, C. P.; Le Heuzey, J. Y. F.; Lewis, B. S.; Liu, L. S.; Nanas, J.; Razali, O.; Pais, P. S.; Parkhomenko, A. N.; Pedersen, K. E.; Piegas, L. S.; Raev, D.; Simmers, T. A.; Smith, P. J.; Talajic, M.; Tan, R. S.; Tanomsup, S.; Toivonen, L.; Vinereanu, D.; Xavier, D.; Zhu, J.; Diener, H. C.; Joyner, C. D.; Diehl, A.; Ford, G.; Robinson, M.; Silva, J.; Sleight, P.; Wyse, D. G.; Collier, J.; de Mets, D.; Hirsh, J.; Lesaffre, E.; Ryden, L.; Sandercock, P.; Anastasiou-Nana, M. I.; Andersen, G.; Annex, B. H.; Atra, M.; Bornstein, N. M.; Boysen, G.; Brouwers, P. J. A. M.; Buerke, M.; Burrell, L. M.; Chan, Y. K.; Chen, W. H.; Cheung, R. T. F.; Divakaramenon, S.; Donnan, G. A.; Duray, G. Z.; Dvorakova, H.; Fiedler, J.; Gardinale, E.; Gates, P. C.; Goshev, E. G.; Goto, S.; Gross, B.; Guimaraes, H. P.; Gulkevych, O.; Haberl, R. L.; Hankey, G.; Hartikainen, J.; Healey, J.; Iliesiu, A. M.; Irkin, O.; Jaxa-Chamiec, T.; Jolly, S.; Kaste, K. A. M.; Kies, B.; Kostov, K. D.; Kristensen, K. S.; Labovitz, A. J.; Lassila, R. P. T.; Lee, K. L. F.; Lutay, Y. M.; Magloire, P.; Mak, K. H.; Meijer, A.; Mihov, L.; Morillo, C. A.; Morillo, L. E.; Nair, G. M.; Norrving, B.; Ntalianis, A.; Ntsekhe, M.; Olah, L.; Pasco, P. M. D.; Peeters, A.; Perovic, V.; Petrov, I.; Pizzolato, G.; Rafti, F.; Rey, N. R.; Ribas, S.; Rokoss, M.; Sarembock, I. J.; Sheth, T.; Shuaib, A.; Sitkei, E.; Sorokin, E.; Srámek, M.; Strozynska, E.; Tanne, D.; Thijs, V. N. S.; Tomek, A.; Turazza, F.; Vanhooren, G.; Vizel, S. A.; Vos, J.; Wahlgren, N.; Weachter, R.; Zaborska, B.; Zaborski, J.; Zimlichman, R.; Cong, J.; Fendt, K.; Muldoon, S.; Bajkor, S.; Grinvalds, A.; Malvaso, M.; Pogue, J.; Simek, K.; Yang, S.; Alzogaray, M. F.; Bono, J. O.; Caccavo, A.; Cartasegna, L.; Casali, W. P.; Cuello, J. L.; Cuneo, C. A.; Elizari, M. V.; Fernandez, A. A.; Ferrari, A. E.; Gabito, A. J.; Goicoechea, R. F.; Gorosito, V. M.; Hirschson, A.; Hominal, M. A.; Hrabar, A. D.; Liberman, A.; Mackinnon, I. J.; Manzano, R. D.; Muratore, C. A.; Nemi, S. A.; Rodriguez, M. A.; Sanchez, A. S.; Secchi, J.; Vogel, D. R.; Colquhoun, D. M.; Crimmins, D. S.; Dart, A. M.; Davis, S. M.; Hand, P. J.; Kubler, P. A.; Lehman, R. G.; McBain, G.; Morrison, H. C.; New, G.; Singh, B. B.; Spence, C. Z.; Waites, J. H.; Auer, J.; Doweik, L.; Freihoff, F.; Gaul, G.; Gazo, F.; Geiger, H.; Giacomini, G.; Huber, G. W.; Jukic, I.; Lamm, G.; Niessner, H.; Podczeck, A.; Schuh, J.; Siostrzonek, P.; Steger, C.; Vogel, B.; Watzak, R.; Weber, H. S.; Weihs, W.; Blankoff, I.; Boland, J. L.; Brike, C.; Carlier, M.; Cools, F.; de Meester, A.; de Raedt, H. J.; de Wolf, L.; Dhooghe, G. M.; Dilling-Boer, D.; Elshot, S. R.; Fasseaux, S.; Goethals, M.; Goethals, P.; Gurne, O.; Hellemans, S.; Ivan, B.; Jottrand, M.; Kersschot, I.; Lecoq, E.; Marcovitch, O.; Melon, D.; Miljoen, H.; Missault, L.; Pierard, L. A.; Provenier, F.; Rousseau, M. F.; Stockman, D.; Tran-Ngoc, E.; van Mieghem, W.; Vandekerckhove, Y.; Vandervoort, P.; Verrostte, J.; Vijgen, J.; Armaganijan, D.; Braga, C.; Braga, J. C. 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S.; Orfanidis, Z.; Papamichalis, M.; Peltekis, L.; Savvas, S.; Skoumpourdis, E. A.; Stakos, D. A.; Styliadis, I.; Triposkiadis, F.; Tsounis, D.; Tziakas, D. N.; Zafiridis, T.; Zarifis, J. H.; Chan, G. C. P.; Chan, W. K.; Chan, W. S.; Lau, C. L.; Tse, H. F.; Tsui, P. T.; Yu, C. M.; Yue, C. S.; Fugedi, K.; Garai, B.; Jánosi, A.; Kadar, A.; Karpati, P.; Keltai, K.; Kosa, I.; Kovacs, I.; Laszlo, Z.; Mezei, L.; Rapi, J.; Regos, L. I.; Szakal, I.; Szigyarto, I.; Toth, K.; Zsa'ry, A.; Agarwal, D. K.; Aggarwal, R. K.; Arulvenkatesh, R.; Bharani, A.; Bhuvaneswaran, J. S.; Byrapaneni, R. B.; Chandwani, P.; Chopra, S.; Desai, N.; Deshpande, V.; Golla, N. P.; Gupta, J. B.; Haridas, K. K.; Hiremath, J.; Jain, A. S.; Jain, M.; Jhala, D. A.; Joseph, J.; Kaila, M.; Kannaiyan, A.; Kumar, S.; Kuruvila, P.; Mahorkar, V. K.; Metha, A.; Naik, A. M.; Narayanan, S.; Panwar, R. B.; Reddy, C.; Sawhney, J. P. S.; Shah, S. M.; Sharma, S.; Shetty, G. S.; Sinha, N.; Sontakke, N. N.; Srinivas, A.; Trivedi, M. R.; Vadagenalli, P. S.; Vijayakumar, M.; Ben-Aharon, Y.; Benhorin, J.; Bogomolny, N.; Botwin-Shimko, S.; Bova, I.; Brenner, B.; Burstein, M.; Butnaru, A.; Caspi, A.; Danenberg, H. D.; Dayan, M.; Eldar, M.; Elian, D.; Elias, M.; Elis, A.; Esanu, G.; Genin, I.; Goldstein, L. H.; Grossman, E.; Hamoud, S.; Hayek, T.; Ilani, N.; Ilia, R.; Klainman, E. I.; Leibowitz, A.; Leibowitz, D.; Levin, I.; Lishner, M.; Lotan, C.; Mahagney, A.; Marmor, A.; Motro, M.; Peres, D.; Plaev, T.; Reisen, L. H.; Rogowski, O.; Schwammenthal, E.; Schwammenthal, Y.; Shechter, M.; Shochat, M.; Shotan, A.; Strasberg, B.; Sucher, E.; Telman, G.; Turgeman, Y.; Tzoran, I.; Weiss, A. T.; Weitsman, T.; Weller, B.; Wexler, D. 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G.; Pirelli, S.; Renda, G.; Santini, M.; Tavarozzi, I.; Terrosu, P.; Uneddu, F.; Viccione, M.; Zanini, R.; Zingarini, G.; Aoyagi, T.; Eguma, H.; Fujii, K.; Fukuchi, M.; Fukunami, M.; Furukawa, Y.; Furuya, J.; Haneda, K.; Hara, S.; Hiroe, M.; Iesaka, Y.; Iijima, T.; Ishibashi, Y.; Iwade, K.; Kajiya, T.; Kakinoki, S.; Kamakura, S.; Katayama, Y.; Kihara, Y.; Kimura, K.; Kobayashi, S.; Kono, K.; Koretsune, Y.; Marui, N.; Matsuyama, T.; Meno, H.; Miyamoto, N.; Morikawa, S.; Myojin, K.; Nakamura, T.; Nishi, Y.; Ogawa, T.; Onaka, H.; Sakakibara, T.; Sakurai, S.; Sasaki, Y.; Sato, H.; Sugii, M.; Sumii, K.; Suzuki, S.; Takagi, M.; Takenaka, T.; Takeuchi, K.; Tanaka, S.; Tanouchi, J.; Ueda, K.; Ueyama, Y.; Ujihira, T.; Usui, M.; Yagi, M.; Yamada, T.; Yamamoto, H.; Yokochi, M.; Zen, E.; Abd Ghaphar, A. K.; Ang, C. K.; Chee, K. H.; Fong, A. F. Y.; Ismail, O.; Jeyaindran, S.; Kaur, S.; Lee, T. C.; Sandhu, R. S.; Shah, R. 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H.; Wang, S. F.; Yang, S. P.; Kiatchoosakun, S.; Krittayaphong, R.; Kuanprasert, S.; Ngarmukos, T.; Simtharakaew, T.; Sukanandachai, B.; Sukonthasam, A.; Suwanagool, A.; Tatsanavivat, P.; Atmaca, Y.; Baris, N.; Boyaci, B.; Demir, M.; Guneri, S.; Usal, A.; Yalcin, R.; Amosova, K. M.; Beregova, O. P.; Besaga, Y. E. M.; Ikorkin, M. R.; Karapetyan, K.; Karpenko, O. I.; Kononenko, L.; Kuryata, O.; Martynova, L.; Motylevska, T.; Okhryamkina, O.; Pavlyk, S. S.; Perepelytsya, M. V.; Rudenko, L. V.; Skarzhevsky, O. A.; Tkachenko, L. A.; Tseluyko, V.; Usan, N.; Voronkov, L. G.; Yshchenko, K. V.; Zharinov, O. J.; Bryson, V. G.; Butler, R.; Cargill, R. I.; Chahal, N. S.; Cleland, J. G.; Cohen, A. T.; Cruddas, E. M.; Davey, P.; Davies, J.; Ford, S. L.; Griffith, K.; Haynes, R.; Hill, S.; Javed, M.; Kadr, H. H.; Lip, G. H.; Machin, J.; McEneaney, D. J.; McInnes, G. T.; McNeill, A. J.; Moriarty, A. J.; Muir, S.; O'Callaghan, J.; Purvis, J. A.; Pye, M.; Senior, R.; Sutton, D. A.; Thomas, S. H. L.; Wilkinson, P. R.; Wilmott, R.; Wrigley, M. J.; Abadier, R.; Abbud, Z. A.; Adams, K. V.; Adler, S. W.; Agarwal, S.; Ahmed, A. M.; Ahmed, I. S.; Aiuto, M. A.; Albrittun, T. D.; Aliyar, P.; Allan, J. J.; Allen, D. P.; Allen, S. L.; Altschuller, A.; Amin, M.; Anand, I. S.; Antolick, A. B.; Arora, R.; Arouni, A. J.; Arslanian, C. L.; Asinger, R. W.; Aycock, G. R.; Bariciano, R. J.; Baron, S. B.; Barr, M. A.; Bartkowiak, A. J.; Baruch, L.; Basignani, C.; Bass, M. L.; Bean, B.; Bedwell, N. W.; Belber, A. D.; Belew, K.; Bell, Y. C.; Bellinger, R. L.; Bennett, W. T.; Bensimhon, D. R.; Benton, R.; Benton, R. E.; Ben-Yehuda, O.; Bertolet, B. D.; Betkowski, A. S.; Bilazarian, S. D.; Bissette, J. K.; Bobade, M. B.; Bolster, D. E.; Bomba, J.; Book, D. M.; Boscia, J. A.; Bouchard, A.; Bowman, L. M.; Bradley, A. J.; Brandt, H. D.; Bricker, C. R.; Brobyn, T. L.; Brock, R. I.; Broderick, T. M.; Broedlin, K.; Brown, A. M.; Browne, K. F.; Burke, S. W.; Burton, M. E.; Buser, G. A.; Capasso, M. K.; Caplan, W. E.; Cappelli, J.; Cardona, C.; Cardona, F.; Carlson, T.; Carr, K. W.; Casey, T.; Cashion, W. R.; Cass, D. T.; Chandrashekar, Y. S.; Changlani, M.; Chapla, P. G.; Chappell, J. H.; Chen, C.; Chen, Y.; Cho, N. R.; Cieszkowski, J. H.; Clark, D. M.; Clayton, R.; Clogston, C. W.; Cockrell, D. J.; Cohen, A. I.; Cohen, T. J.; Cole, J. F.; Conway, G.; Cook, V. R.; Cornish, A. L.; Cossu, S. F.; Costello, D. L.; Courtade, D. J.; Covelli, H. C.; Crenshaw, B. S.; Crews, L. A.; Crossley, G. H.; Culp, S. C.; Curtis, B. M.; Darrow, K.; de Raad, R. E.; DeGregorio, M.; DelNegro, A. A.; Denny, D. M.; Desai, V. S.; Deumite, N. J.; Dewey, L.; Dharawat, R. N.; Dobbs, B.; Donahue, S. M.; Downey, B.; Downing, J.; Drehobl, M. A.; Drewes, W. A.; Drucker, M. N.; Duff, R.; Duggal, M.; Dunlap, S. H.; Dunning, D. W.; DuThinh, V.; Dykstra, G. T.; East, C.; Eblaghie, M. C.; Edelstein, J.; Edmiston, W. A.; Eisen, H. J.; Eisenberg, S. J.; Ellis, J. R.; Ellison, H. S.; Ellsworth, S.; Elshahawy, M.; Emlein, G.; Entcheva, M.; Essandoh, L. K.; Estrada, A. Q.; Ewing, B.; Faillace, R. T.; Fanelli, A.; Farrell, P. W.; Farris, S. W.; Fattal, P. G.; Feigenblum, D. Y.; Feldman, G. J.; Fialkow, J. A.; Fiddler, K. M.; Fields, R. H.; Finkel, M. S.; Finn, C.; Fischell, T. A.; Fishbach, M.; Fishbein, G. J.; Fisher, M. M.; Fleischhauer, F. J.; Folk, T. G.; Folkerth, S. D.; Fortman, R. R.; Frais, M. A.; Friedman, D. C.; Fuchs, G.; Fuller, F.; Garibian, G.; Gee, F. H.; Gelernt, M. D.; Genovely, H. C.; Gerber, J. R.; Germano, J. J.; Giardina, J. J.; Gilbert, J. M.; Gillespie, E. L.; Gilman, E. M.; Gitler, B.; Givens, D. H.; Glover, R.; Gogia, H. S.; Gohn, D. C.; Goldberg, R. K.; Goldberger, J. J.; Goldscher, D. A.; Goldstein, M.; Goraya, T.; Gordon, D. F.; Gottlieb, D.; Grafner, H. L.; Graham, M.; Graves, M. W.; Graziano, M.; Greco, S. N.; Greenberg, M. L.; Greenspon, A. J.; Greer, G. S.; Griffin, D. D.; Grogan, E. W.; Groo, V. L.; Guarnieri, T.; Gupta, A.; Gupta, J.; Hack, T. C.; Hall, B.; Hallak, O.; Halpern, S. W.; Hamburg, C.; Hamroff, G. S.; Han, J.; Handel, F.; Hankins, S. R.; Hanovich, G. D.; Hanrahan, J. A.; Haque, I. U.; Hargrove, J. L.; Harnick, P. E.; Harris, J. L.; Hartley, P. A.; Haskel, E. J.; Hatch, D.; Haught, W. H.; Hearne, S.; Hearne, S. E.; Hemphill, J. A.; Henderson, D. A.; Henes, C. H.; Hengerer-Yates, T.; Hermany, P. R.; Herzog, W. R.; Hickey, K.; Hilton, T. C.; Hockstad, E. S.; Hodnett, P.; Hoffmeister, R.; Holland, J.; Hollenweger, L.; Honan, M. B.; Hoopes, D. A.; Hordes, A. R.; Hotchkiss, D. A.; Howard, M. A.; Howard, V. N.; Hulyalkar, A. R.; Hurst, P.; Hutchison, L. C.; Ingram, J.; Isakov, T.; Ison, R. K.; Israel, C. N.; Jackson, B. K.; Jackson, K. N.; Jacobson, A. K.; Jain, S.; Jarmukli, N. F.; Joffe, I.; Johnson, L. E.; Johnson, S. A.; Johnson, S. L.; Jones, A. A.; Joyce, D. B.; Judson, P. L.; Juk, S. S.; Kaatz, S.; Kaddaha, R. M.; Kaplan, K. J.; Karunaratne, H. B.; Kennett, J. D.; Kenton, D. M.; Kettunen, J. A.; Khan, M. A.; Khant, R. N.; Kirkwood, M. D.; Knight, B. P.; Knight, P. O.; Knutson, T. J.; Kobayashi, J. F.; Kogan, A.; Kogan, A. D.; Koren, M. J.; Kosinski, E. J.; Kosolcharoen, P.; Kostis, J. B.; Kramer, J. H.; Kramer, S. D.; Kron, J.; Kuchenrither, C. R.; Kulback, S. J.; Kumar, A.; Kushner, D.; Kutscher, A.; Lai, C. K.; Lam, J. B.; Landau, C.; Landzberg, J. S.; Lang, D. T.; Lang, J. M.; Lanzarotti, C. J.; Lascewski, D. L.; Lau, T. K.; Lee, J. K.; Lee, S.; Leimbach, W. N.; LePine, A. M.; Lesser, M. F.; Leuchak, S. H.; Levy, R. M.; Lewis, W. R.; Lincoln, T. L.; Lingerfelt, W. M.; Liston, M.; Liu, Z. G.; Lloret, R. L.; Lohrbauer, L.; Longoria, D. C.; Lott, B. M.; Louder, D. R.; Loukinen, K. L.; Lovell, J.; Lue, S.; Mackall, J. A.; Maletz, L.; Marlow, L.; Martin, R. C.; Matsumura, M.; McCartney, M. J.; McDuffie, D.; McGough, M. F.; McGrew, F. A.; McGuinn, Wm P.; McMillen, M. D.; McNeff, J.; McPherson, C. A.; Meengs, M. E.; Meengs, W. L.; Meholick, A. W.; Meisner, J. S.; Melucci, M. B.; Mercando, A.; Merlino, J. D.; Meymandi, S. K.; Miele, M. B.; Miller, R. H.; Miller, S. H.; Minor, S. T.; Mitchell, M. R.; Modi, M.; Mody, F. V.; Moeller, C. L.; Moloney, J. F.; Moran, J. E.; Morcos, N. C.; Morgan, A.; Mukherjee, S. K.; Mullinax, K.; Murphy, A. L.; Mustin, A. J.; Myers, G. I.; Naccarelli, G. V.; Nadar, V. K.; Nallasivan, M.; Navas, J. P.; Niazi, I. K.; Nsah, E. N.; Nunamaker, J. L.; Ochalek, T. B.; O'dea, D. J.; Ogilvie, P. D.; Olliff, B.; Omalley, A. K.; O'Neill, P. G.; Onufer, J. R.; Orchard, R. C.; Orihuela, L. A.; Ortiz, E. C.; O'Sullivan, M. T.; Padanilam, B. J.; Pandey, P.; Patel, D. V.; Patel, R. J.; Patel, V. B.; Patlola, R. R.; Pennock, G. D.; Perlman, R.; Peters, P. H.; Petrillo, A. V.; Pezzella, S.; Phillips, D.; Pierre-Louis, J. R.; Pilcher, G.; Pillai, C.; Pollock, S. G.; Pond, M. S.; Porterfield, J. K.; Presant, L.; Pressler, J.; Pribble, A. H.; Promisloff, S. D.; Pudi, K. K.; Putnam, D. L.; Quartner, J.; Quinn, J. C.; Quinnell, C. M.; Raad, G. L.; Rasmussen, L. A.; Ray, C.; Reiffel, J. A.; Reynertson, S.; Richardson, J. W.; Riley, C. P.; Rippy, J. S.; Rittelmeyer, J. T.; Roberts, D. M.; Robertson, R.; Robinson, V. J. B.; Rocco, T. A.; Rosenbaum, D.; Roth, E. M.; Rottman, J. N.; Rough, R. R.; Rubenstein, J. J.; Sakkal, A. M.; Saleem, T.; Salerno, D. M.; Samendinger, M. L.; Sandeno, S.; Santilli, T. M.; Santucci, P.; Sattar, P.; Saxman, K. A.; Schaefer, S.; Schmidt, J.; Schneider, R. M.; Schocken, D. D.; Schrader, M. K.; Schramm, B. A.; Schultz, R. W.; Schussheim, A. E.; Schwarz, E. F.; Seamon, M. C.; Sestero, J. D.; Shah, M. P.; Shah, R.; Shalaby, A.; Shanes, J. G.; Sheftel, G. L.; Sheikh, K. H.; Shein, A. B.; Shemonsky, N. K.; Shepler, A.; Sheridan, E.; Shipwash, T. M.; Shopnick, R. I.; Short, W. G.; Shoukfeh, M. F.; Sibia, R. S.; Siler, T. M.; Silva, J. A.; Simons, G. R.; Simpson, A. G.; Simpson, H. R.; Simpson, V. J.; Singh, B. N.; Singh, N.; Singh, V. N.; Sitz, C. J.; Skatrud, L.; Sklar, J.; Slotwiner, D. J.; Smith, P. F.; Smith, P. N.; Smith, R. H.; Smith, J. E.; Sodowick, B. C.; Solomon, A. J.; Soltero, E. A.; Sonel, A. F.; Sperling, R.; Spiller, C.; Spink, B. Z.; Sprinkle, L. W.; Spyropoulos, A. C.; Stamos, T. D.; Steljes, A. D.; Stillabower, M. E.; Stover, T.; Strain, J. E.; Strickland, T. L.; Suresh, D. P.; Takata, T. S.; Taylor, J. S.; Taylor, M.; Teague, S. M.; Teixeia, J. M.; Telfer, E. A.; Terry, P. S.; Terry, R. W.; Thai, H. M.; Thalin, M.; Thomas, V. N.; Thompson, C. A.; Thompson, M. A.; Thornton, J. W.; Tidman, R. E.; Toler, B. S.; Traina, M. I.; Trippi, J. A.; Ujiiye, D. L.; Usedom, J. E.; van de Graaff, E.; van de Wall, L. R.; Vaughn, J. W.; Ver Steeg, D.; Vicari, R. M.; Vijay, N.; Vitale, C. B.; Vlastaris, A. G.; Voda, J.; Vora, K. N.; Voyles, W. F.; Vranian, R. B.; Vrooman, P. S.; Waack, P.; Waldo, A. L.; Walker, J. L.; Wallace, M. A.; Walsh, E. A.; Walsh, R. L.; Walton, A.; Washam, M.; Wehner, P. S.; Wei, J. Y.; Weiner, S.; Weiss, R. J.; Wells, D. M.; Wera-Archakul, W.; Wertheimer, J. H.; West, S. A.; Whitaker, J. H.; White, M. L.; White, R. H.; Whitehill, J. N.; Wiegman, P. J.; Wiesel, J.; Williams, J.; Williams, L. E.; Williams, M. L.; Williamson, V. K.; Wilson, V. E.; Wilson, W. W.; Woodfield, S. L.; Wulff, C. W.; Yates, S. W.; Yousuf, K. A.; Zakhary, B. G.; Zambrano, R.; Zimetbaum, P.; Zoble, R.; Zopo, A. R.; Zwerner, P. L.

2009-01-01

BACKGROUND: Warfarin reduces the risk of stroke in patients with atrial fibrillation but increases the risk of hemorrhage and is difficult to use. Dabigatran is a new oral direct thrombin inhibitor. METHODS: In this noninferiority trial, we randomly assigned 18,113 patients who had atrial

Edoxaban versus warfarin in patients with atrial fibrillation

NARCIS (Netherlands)

Giugliano, R.P.; Ruff, C.T.; Braunwald, E.; Murphy, S.A.; Wiviott, S.D.; Halperin, J.L.; Waldo, A.L.; Ezekowitz, M.D.; Weitz, J.I.; Spinar, J.; Ruzyllo, W.; Ruda, M.; Koretsune, Y.; Betcher, J.; Shi, M.; Grip, L.T.; Patel, S.P.; Patel, I.; Hanyok, J.J.; Mercuri, M.; Antman, E.M.; Verheugt, F.W.A.; et al.,

2013-01-01

BACKGROUND: Edoxaban is a direct oral factor Xa inhibitor with proven antithrombotic effects. The long-term efficacy and safety of edoxaban as compared with warfarin in patients with atrial fibrillation is not known. METHODS: We conducted a randomized, double-blind, double-dummy trial comparing two

Edoxaban versus Warfarin in Patients with Atrial Fibrillation

NARCIS (Netherlands)

Giugliano, Robert P.; Ruff, Christian T.; Braunwald, Eugene; Murphy, Sabina A.; Wiviott, Stephen D.; Halperin, Jonathan L.; Waldo, Albert L.; Ezekowitz, Michael D.; Weitz, Jeffrey I.; Špinar, Jindřich; Ruzyllo, Witold; Ruda, Mikhail; Koretsune, Yukihiro; Betcher, Joshua; Shi, Minggao; Grip, Laura T.; Patel, Shirali P.; Patel, Indravadan; Hanyok, James J.; Mercuri, Michele; Antman, Elliott M.; Braunwald, E.; Antman, E. M.; Giugliano, R. P.; Ruff, C. T.; Morin, S. E.; Hoffman, E. B.; Murphy, S. A.; Deenadayalu, N.; Grip, L.; Mercuri, M.; Lanz, H.; Patel, I.; Curt, V.; Duggal, A.; Hanyok, J.; Davé, J.; Morgan, D.; Choi, Y.; Shi, M.; Jin, J.; Xie, J.; Crerand, W.; Kappelhof, J.; Maxwell, W.; Zhang, X.; Zhang, Z.; de Groot, J. [=Joris R.; de Vos, R.; Hoekstra, J.

2013-01-01

BackgroundEdoxaban is a direct oral factor Xa inhibitor with proven antithrombotic effects. The long-term efficacy and safety of edoxaban as compared with warfarin in patients with atrial fibrillation is not known. MethodsWe conducted a randomized, double-blind, double-dummy trial comparing two

Effects of VKORC1 Genetic Polymorphisms on Warfarin Maintenance Dose Requirement in a Chinese Han Population

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Yan, Xiaojuan; Yang, Feng; Zhou, Hanyun; Zhang, Hongshen; Liu, Jianfei; Ma, Kezhong; Li, Yi; Zhu, Jun; Ding, Jianqiang

2015-01-01

Background VKORC1 is reported to be capable of treating several diseases with thrombotic risk, such as cardiac valve replacement. Some single-nucleotide polymorphisms (SNPs) in VKORC1 are documented to be associated with clinical differences in warfarin maintenance dose. This study explored the correlations of VKORC1–1639 G/A, 1173 C/T and 497 T/G genetic polymorphisms with warfarin maintenance dose requirement in patients undergoing cardiac valve replacement. Material/Methods A total of 298 patients undergoing cardiac valve replacement were recruited. During follow-up, clinical data were recorded. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method was applied to detect VKORC1–1639 G/A, 1173 C/T and 497 T/G polymorphisms, and genotypes were analyzed. Results Correlations between warfarin maintenance dose and baseline characteristics revealed statistical significances of age, gender and operation methods with warfarin maintenance dose (all PWarfarin maintenance dose in VKORC1–1639 G/A AG + GG carriers was obviously higher than in AA carriers (Pwarfarin maintenance dose was apparently higher in patients with CT genotype (Pwarfarin maintenance dose (all Pwarfarin maintenance dose in patients undergoing cardiac valve replacement; meanwhile, gender, operation method and method for heart valve replacement might also be correlate with warfarin maintenance dose. PMID:26583785

Taking warfarin (Coumadin, Jantoven) - what to ask your doctor

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... MA: Elsevier; 2016:702-737. Bristol-Myers Squibb Company. Coumadin (warfarin sodium) Information. Updated September 2016. Bmsmedinfo. ... Hurd, MD, Professor of Endocrinology and Health Care Ethics, Xavier University, Cincinnati, OH. Review provided by VeriMed ...

Accuracy assessment of pharmacogenetically predictive warfarin dosing algorithms in patients of an academic medical center anticoagulation clinic.

Science.gov (United States)

Shaw, Paul B; Donovan, Jennifer L; Tran, Maichi T; Lemon, Stephenie C; Burgwinkle, Pamela; Gore, Joel

2010-08-01

The objectives of this retrospective cohort study are to evaluate the accuracy of pharmacogenetic warfarin dosing algorithms in predicting therapeutic dose and to determine if this degree of accuracy warrants the routine use of genotyping to prospectively dose patients newly started on warfarin. Seventy-one patients of an outpatient anticoagulation clinic at an academic medical center who were age 18 years or older on a stable, therapeutic warfarin dose with international normalized ratio (INR) goal between 2.0 and 3.0, and cytochrome P450 isoenzyme 2C9 (CYP2C9) and vitamin K epoxide reductase complex subunit 1 (VKORC1) genotypes available between January 1, 2007 and September 30, 2008 were included. Six pharmacogenetic warfarin dosing algorithms were identified from the medical literature. Additionally, a 5 mg fixed dose approach was evaluated. Three algorithms, Zhu et al. (Clin Chem 53:1199-1205, 2007), Gage et al. (J Clin Ther 84:326-331, 2008), and International Warfarin Pharmacogenetic Consortium (IWPC) (N Engl J Med 360:753-764, 2009) were similar in the primary accuracy endpoints with mean absolute error (MAE) ranging from 1.7 to 1.8 mg/day and coefficient of determination R (2) from 0.61 to 0.66. However, the Zhu et al. algorithm severely over-predicted dose (defined as >or=2x or >or=2 mg/day more than actual dose) in twice as many (14 vs. 7%) patients as Gage et al. 2008 and IWPC 2009. In conclusion, the algorithms published by Gage et al. 2008 and the IWPC 2009 were the two most accurate pharmacogenetically based equations available in the medical literature in predicting therapeutic warfarin dose in our study population. However, the degree of accuracy demonstrated does not support the routine use of genotyping to prospectively dose all patients newly started on warfarin.

Apixaban vs. warfarin with concomitant aspirin in patients with atrial fibrillation: insights from the ARISTOTLE trial

NARCIS (Netherlands)

Alexander, J.H.; Lopes, R.D.; Thomas, L.; Alings, M.; Atar, D.; Aylward, P.; Goto, S.; Hanna, M.; Huber, K.; Husted, S.; Lewis, B.S.; McMurray, J.J.; Pais, P.; Pouleur, H.; Steg, P.G.; Verheugt, F.W.A.; Wojdyla, D.M.; Granger, C.B.; Wallentin, L.

2014-01-01

AIMS: We assessed the effect of concomitant aspirin use on the efficacy and safety of apixaban compared with warfarin in patients with atrial fibrillation (AF). METHODS AND RESULTS: In ARISTOTLE, 18 201 patients were randomized to apixaban 5 mg twice daily or warfarin. Concomitant aspirin use was

Effect of Genetic Variants, Especially CYP2C9 and VKORC1, on the Pharmacology of Warfarin

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Fung, Erik; Patsopoulos, Nikolaos A.; Belknap, Steven M.; O’Rourke, Daniel J.; Robb, John F.; Anderson, Jeffrey L.; Shworak, Nicholas W.; Moore, Jason H.

2014-01-01

The genes encoding the cytochrome P450 2C9 enzyme (CYP2C9) and vitamin K-epoxide reductase complex unit 1 (VKORC1) are major determinants of anticoagulant response to warfarin. Together with patient demographics and clinical information, they account for approximately one-half of the warfarin dose variance in individuals of European descent. Recent prospective and randomized controlled trial data support pharmacogenetic guidance with their use in warfarin dose initiation and titration. Benefits from pharmacogenetics-guided warfarin dosing have been reported to extend beyond the period of initial dosing, with supportive data indicating benefits to at least 3 months. The genetic effects of VKORC1 and CYP2C9 in African and Asian populations are concordant with those in individuals of European ancestry; however, frequency distribution of allelic variants can vary considerably between major populations. Future randomized controlled trials in multiethnic settings using population-specific dosing algorithms will allow us to further ascertain the generalizability and cost-effectiveness of pharmacogenetics-guided warfarin therapy. Additional genome-wide association studies may help us to improve and refine dosing algorithms and potentially identify novel biological pathways. PMID:23041981

Rivaroxaban limits complement activation compared with warfarin in antiphospholipid syndrome patients with venous thromboembolism.

Science.gov (United States)

Arachchillage, D R J; Mackie, I J; Efthymiou, M; Chitolie, A; Hunt, B J; Isenberg, D A; Khamashta, M; Machin, S J; Cohen, H

2016-11-01

Essentials Complement activation has a pathogenic role in thrombotic antiphospholipid syndrome (APS). Coagulation proteases such as factor Xa can activate complement proteins. Complement activation markers were elevated in anticoagulated thrombotic APS patients. Complement activation decreased in APS patients switching from warfarin to rivaroxaban. Background Complement activation may play a major role in the pathogenesis of thrombotic antiphospholipid syndrome (APS). Coagulation proteases such as factor Xa can activate complement proteins. Aims To establish whether rivaroxaban, a direct factor Xa inhibitor, limits complement activation compared with warfarin in APS patients with previous venous thromboembolism (VTE). Methods A total of 111 APS patients with previous VTE, on warfarin target INR 2.5, had blood samples taken at baseline and at day 42 after randomization in the RAPS (Rivaroxaban in Antiphospholipid Syndrome) trial. Fifty-six patients remained on warfarin and 55 switched to rivaroxaban. Fifty-five normal controls (NC) were also studied. Markers of complement activation (C3a, C5a, terminal complement complex [SC5b-9] and Bb fragment) were assessed. Results APS patients had significantly higher complement activation markers compared with NC at both time-points irrespective of the anticoagulant. There were no differences between the two patient groups at baseline, or patients remaining on warfarin at day 42. In 55 patients randomized to rivaroxaban, C3a, C5a and SC5b-9 were lower at day 42 (median (ng mL -1 ) [confidence interval] 64 [29-125] vs. 83 [35-147], 9 [2-15] vs. 12 [4-18] and 171 [56-245] vs. 201 [66-350], respectively) but levels of Bb fragment were unchanged. There were no correlations between rivaroxaban levels and complement activation markers. Conclusions APS patients with previous VTE on warfarin exhibit increased complement activation, which is likely to occur via the classical pathway and is decreased by rivaroxaban administration

Comparative safety of direct oral anticoagulants and warfarin in venous thromboembolism: multicentre, population based, observational study.

Science.gov (United States)

Jun, Min; Lix, Lisa M; Durand, Madeleine; Dahl, Matt; Paterson, J Michael; Dormuth, Colin R; Ernst, Pierre; Yao, Shenzhen; Renoux, Christel; Tamim, Hala; Wu, Cynthia; Mahmud, Salaheddin M; Hemmelgarn, Brenda R

2017-10-17

Objective  To determine the safety of direct oral anticoagulant (DOAC) use compared with warfarin use for the treatment of venous thromboembolism. Design  Retrospective matched cohort study conducted between 1 January 2009 and 31 March 2016. Setting  Community based, using healthcare data from six jurisdictions in Canada and the United States. Participants  59 525 adults (12 489 DOAC users; 47 036 warfarin users) with a new diagnosis of venous thromboembolism and a prescription for a DOAC or warfarin within 30 days of diagnosis. Main outcome measures  Outcomes included hospital admission or emergency department visit for major bleeding and all cause mortality within 90 days after starting treatment. Propensity score matching and shared frailty models were used to estimate adjusted hazard ratios of the outcomes comparing DOACs with warfarin. Analyses were conducted independently at each site, with meta-analytical methods used to estimate pooled hazard ratios across sites. Results  Of the 59 525 participants, 1967 (3.3%) had a major bleed and 1029 (1.7%) died over a mean follow-up of 85.2 days. The risk of major bleeding was similar for DOAC compared with warfarin use (pooled hazard ratio 0.92, 95% confidence interval 0.82 to 1.03), with the overall direction of the association favouring DOAC use. No difference was found in the risk of death (pooled hazard ratio 0.99, 0.84 to 1.16) for DOACs compared with warfarin use. There was no evidence of heterogeneity across centres, between patients with and without chronic kidney disease, across age groups, or between male and female patients. Conclusions  In this analysis of adults with incident venous thromboembolism, treatment with DOACs, compared with warfarin, was not associated with an increased risk of major bleeding or all cause mortality in the first 90 days of treatment. Trial registration  Clinical trials NCT02833987. Published by the BMJ Publishing Group Limited. For permission to use (where not

Prediction of warfarin maintenance dose in Han Chinese patients using a mechanistic model based on genetic and non-genetic factors.

Science.gov (United States)

Lu, Yuan; Yang, Jinbo; Zhang, Haiyan; Yang, Jin

2013-07-01

Many attempts have been made to predict the warfarin maintenance dose in patients beginning warfarin therapy using a descriptive model based on multiple linear regression. Here we report the first attempt to develop a comprehensive mechanistic model integrating in vitro-in vivo extrapolation (IVIVE) with a pharmacokinetic-pharmacodynamic model to predict the warfarin maintenance dose in Han Chinese patients. The model incorporates demographic factors [sex, age, body weight (BW)] and the genetic polymorphisms of cytochrome P450 (CYP) 2C9 (CYP2C9) and vitamin K epoxide reductase complex subunit 1 (VKORC1). Information on the various factors, mean warfarin daily dose and International Normalized Ratio (INR) was available for a cohort of 197 Han Chinese patients. Based on in vitro enzyme kinetic parameters for S-warfarin metabolism, demographic data for Han Chinese and some scaling factors, the S-warfarin clearance (CL) was predicted for patients in the cohort with different CYP2C9 genotypes using IVIVE. The plasma concentration of S-warfarin after a single oral dose was simulated using a one-compartment pharmacokinetic model with first-order absorption and a lag time and was combined with a mechanistic coagulation model to simulate the INR response. The warfarin maintenance dose was then predicted based on the demographic data and genotypes of CYP2C9 and VKORC1 for each patient and using the observed steady-state INR (INRss) as a target value. Finally, sensitivity analysis was carried out to determine which factor(s) affect the warfarin maintenance dose most strongly. The predictive performance of this mechanistic model is not inferior to that of our previous descriptive model. There were significant differences in the mean warfarin daily dose in patients with different CYP2C9 and VKORC1 genotypes. Using IVIVE, the predicted mean CL of S-warfarin for patients with CYP2C9*1/*3 (0.092 l/h, n = 11) was 57 % less than for those with wild-type *1/*1 (0.215 l/h, n

Rivaroxaban vs Warfarin and Risk of Post-Thrombotic Syndrome among Patients with Venous Thromboembolism

DEFF Research Database (Denmark)

Søgaard, Mette; Nielsen, Peter Brønnum; Skjøth, Flemming

2018-01-01

BACKGROUND: The effectiveness of rivaroxaban to reduce post-thrombotic syndrome in patients with venous thromboembolism is largely unknown. We compared rates of post-thrombotic syndrome in patients given rivaroxaban versus warfarin in a cohort of routine clinical care patients with incident venous...... thromboembolism. METHODS: We linked Danish nationwide registries to identify all patients with incident venous thromboembolism who were new users of rivaroxaban or warfarin and compared rates of post-thrombotic syndrome using an inverse probability of treatment weighting approach to account for baseline...... confounding. RESULTS: We identified 19,939 oral anticoagulation naive patients with incident venous thromboembolism treated with warfarin or rivaroxaban (mean age 64 years, 48% females, 45.5% with pulmonary embolism). The propensity-weighted rate of post-thrombotic syndrome at 3 years follow-up was 0...

Clinical implications of antiretroviral drug interactions with warfarin: a case-control study.

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Esterly, John S; Darin, Kristin M; Gerzenshtein, Lana; Othman, Fidah; Postelnick, Michael J; Scarsi, Kimberly K

2013-06-01

Warfarin, a frequently prescribed anticoagulant with a narrow therapeutic index, is susceptible to drug-drug interactions with antiretroviral therapy (ART). This study compared the warfarin maintenance dose (WMD) between patients receiving and not receiving ART and evaluated predictors of warfarin dosage among those on ART. This was a case-control (1:2) study. Cases were HIV-infected patients receiving warfarin and protease inhibitor (PI)- and/or non-nucleoside reverse transcriptase inhibitor (NNRTI)-based ART. Controls were randomly selected HIV-uninfected patients receiving warfarin. The WMD was compared between cases and controls and between cases on varying ART regimens. Bivariate comparisons were performed and a linear regression model was developed to identify predictors of WMD. We identified 18 case and 36 control patients eligible for inclusion. Cases were younger than controls (mean age: 45.8 versus 63.1 years, P African American (50.0% versus 22.2%, P=0.04). ART was classified as PI-based (n=9), NNRTI-based (n=7) and PI + NNRTI-based (n=2). The WMD (mean ± SD) differed between cases and controls (8.6  ±  3.4 mg versus 5.1 ± 1.5 mg, P ART regimens (PI: 8.8  ±  4.5 mg; NNRTI: 8.6   ± 1.8 mg; PI + NNRTI: 7.3  ±  3.3 mg; P = 0.86). Race and ritonavir dose were independent predictors of WMD, predicting an increase of 3.9 mg (95% CI: 0.88-6.98, P = 0.02) if a patient was African American or 3.7 mg (95% CI: 0.53-6.89, P = 0.03) if the total daily ritonavir dose was 200 mg. The required WMD was significantly higher in patients receiving ART. Prompt dose titration to achieve a higher WMD with vigilant monitoring may be required due to these drug-drug interactions.

Comparison of Direct Oral Anticoagulants and Warfarin in the Treatment of Deep Venous Thrombosis in the Chronic Phase.

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Wakakura, Shingo; Hara, Fumihiko; Fujino, Tadashi; Hamai, Asami; Ohara, Hiroshi; Kabuki, Takayuki; Harada, Masahiko; Ikeda, Takanori

2018-01-27

We assessed the efficacy and safety of direct oral anticoagulants (DOACs) for the treatment of deep venous thrombosis (DVT) in the chronic phase through comparison with conventional warfarin therapy.A total of 807 consecutive patients who were diagnosed with having DVT in the chronic phase were included (484 patients to warfarin therapy and 323 patients to DOAC therapy). The condition of leg veins was assessed 3 to 6 months after starting the therapies by ultrasound examination. Major bleeding and mortality during the therapies were followed-up.There was no significant difference between the two groups in the thrombosis improvement rate (DOAC group: 91.2% versus warfarin group: 88.9%). There was no significant difference between the two groups in major bleeding (DOAC group: 1.8% versus warfarin group: 1.8%). In patients with active cancer, the DOAC group had a borderline higher thrombosis improvement rate than the warfarin group (92.1% versus 80.0%, P = 0.05). The proportion of major bleeding in the patients with active cancer was slightly higher in the warfarin group than in the DOAC group (4.3% versus 2.8%; P = 0.71). Active cancer was not an independent risk factor for major bleeding and recurrence in the DOAC group (OR 2.68, 95% CI 0.51-14.1; P = 0.24 and OR 0.65, 95% CI 0.20-2.07; P = 0.47).In treatment using oral anticoagulants for DVT in the chronic phase, DOACs exhibited equal efficacy and safety as warfarin did. Particularly DOACs appear to be an attractive therapeutic option for cancer-associated DVT in chronic phase, with relatively low anticipated rates of recurrence and major bleeding.

Factor VII R353Q genetic polymorphism is associated with altered warfarin sensitivity among CYP2C9 *1/*1 carriers.

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Mlynarsky, Liat; Bejarano-Achache, Idit; Muszkat, Mordechai; Caraco, Yoseph

2012-05-01

Warfarin responsiveness is characterized by marked interindividual variability. A major portion of this variability is attributed to CYP2C9 and VKORC1 polymorphisms, but almost 50% is still unaccounted for. This paper reports the first prospective study on the association between factor VII R353Q polymorphism and warfarin responsiveness during induction. Genotyping for factor VII R353Q and 323D/I polymorphisms was performed in a cohort consisting of 374 patients (198 CYP2C9*1/*1) treated with warfarin who were prospectively followed from warfarin initiation. Compared with *1/*1-R/R and *1/*1-R/Q genotype carriers, *1/*1-Q/Q homozygotes achieved higher International Normalized Ratio (INR) values while consuming lower warfarin doses. The greater sensitivity was illustrated by 82.1% higher Warfarin Sensitivity Index During Induction (WSIDI) (0.14 ± 0.11 vs. 0.08 ± 0.50 mg⁻¹ Mann-Whitney, P = 0.043). Multiple regression analysis consisting of both genetic and nongenetic factors explained 26% of WSIDI variability, with R353Q genetic polymorphism having a modest yet significant effect and accounting for 1.7% of the overall variability. Moreover, the incidence of overanticoagulation (i.e., INR > 4) was 6.94-fold higher among *1/*1-Q/Q vs. *1/*1-R/R&R/Q carriers during warfarin induction (Pearson chi-square, P = 0.005). These findings were not accounted for by a chance difference in the distribution of VKORC1 genotypes. Analysis of these parameters among the entire cohort, including CYP2C9*2 and CYP2C9*3 variant allele carriers, did not reach statistical significance. Warfarin responsiveness during induction was unrelated to factor VII 323D/I genetic polymorphism. The response to warfarin during induction is influenced by factor VII R353Q polymorphism. The prospective use of this polymorphism, along with CYP2C9 and VKORC1, may enhance the accuracy of warfarin loading. However, the impact of R353Q polymorphism on overall warfarin response is subtle, and it is therefore

Warfarin Management and Outcomes in Patients with Nonvalvular Atrial Fibrillation Within an Integrated Health Care System.

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An, JaeJin; Niu, Fang; Zheng, Chengyi; Rashid, Nazia; Mendes, Robert A; Dills, Diana; Vo, Lien; Singh, Prianka; Bruno, Amanda; Lang, Daniel T; Le, Paul T; Jazdzewski, Kristin P; Aranda, Gustavus

2017-06-01

Warfarin is a common treatment option to manage patients with nonvalvular atrial fibrillation (NVAF) in clinical practice. Understanding current pharmacist-led anticoagulation clinic management patterns and associated outcomes is important for quality improvement; however, currently little evidence associating outcomes with management patterns exists. To (a) describe warfarin management patterns and (b) evaluate associations between warfarin treatment and clinical outcomes for patients with NVAF in an integrated health care system. A retrospective cohort study was conducted among NVAF patients with warfarin therapy between January 1, 2006, and December 31, 2011, using Kaiser Permanente Southern California data, and followed until December 31, 2013. Management patterns related to international normalized ratio (INR) monitoring, anticoagulation clinic pharmacist intervention (consultation), and warfarin dose adjustments were investigated along with yearly attrition rates, time-in-therapeutic ranges (TTRs), and clinical outcomes (stroke or systemic embolism and major bleeding). Descriptive statistics and multivariable Cox proportional hazard models were used to determine associations between TTR and clinical outcomes. A total of 32,074 NVAF patients on warfarin treatment were identified and followed for a median of 3.8 years. About half (49%) of the patients were newly initiating warfarin therapy. INR monitoring and pharmacist interventions were conducted roughly every 3 weeks after 6 months of warfarin treatment. Sixty-three percent of the study population had ≥ 1 warfarin dose adjustments with a mean (SD) of 6.7 (6.3) annual dose adjustments. Warfarin dose adjustments occurred at a median of 1 day (interquartile ranges [IQR] 1-3) after the INR measurement. Yearly attrition rate was from 3.3% to 6.3% during the follow-up, and median (IQR) TTR was 61% (46%-73%). Patients who received frequent INR monitoring (≥ 27 times per year), pharmacist interventions (≥ 24

Genotyping three SNPs affecting warfarin drug response by isothermal real-time HDA assays.

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Li, Ying; Jortani, Saeed A; Ramey-Hartung, Bronwyn; Hudson, Elizabeth; Lemieux, Bertrand; Kong, Huimin

2011-01-14

The response to the anticoagulant drug warfarin is greatly affected by genetic polymorphisms in the VKORC1 and CYP2C9 genes. Genotyping these polymorphisms has been shown to be important in reducing the time of the trial and error process for finding the maintenance dose of warfarin thus reducing the risk of adverse effects of the drug. We developed a real-time isothermal DNA amplification system for genotyping three single nucleotide polymorphisms (SNPs) that influence warfarin response. For each SNP, real-time isothermal Helicase Dependent Amplification (HDA) reactions were performed to amplify a DNA fragment containing the SNP. Amplicons were detected by fluorescently labeled allele specific probes during real-time HDA amplification. Fifty clinical samples were analyzed by the HDA-based method, generating a total of 150 results. Of these, 148 were consistent between the HDA-based assays and a reference method. The two samples with unresolved HDA-based test results were repeated and found to be consistent with the reference method. The HDA-based assays demonstrated a clinically acceptable performance for genotyping the VKORC1 -1639G>A SNP and two SNPs (430C>T and 1075A>C) for the CYP2C9 enzyme (CYP2C9*2 and CYP2C9*3), all of which are relevant in warfarin pharmacogenentics. Copyright © 2010 Elsevier B.V. All rights reserved.

A Novel Admixture-Based Pharmacogenetic Approach to Refine Warfarin Dosing in Caribbean Hispanics.

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Jorge Duconge

Full Text Available This study is aimed at developing a novel admixture-adjusted pharmacogenomic approach to individually refine warfarin dosing in Caribbean Hispanic patients.A multiple linear regression analysis of effective warfarin doses versus relevant genotypes, admixture, clinical and demographic factors was performed in 255 patients and further validated externally in another cohort of 55 individuals.The admixture-adjusted, genotype-guided warfarin dosing refinement algorithm developed in Caribbean Hispanics showed better predictability (R2 = 0.70, MAE = 0.72mg/day than a clinical algorithm that excluded genotypes and admixture (R2 = 0.60, MAE = 0.99mg/day, and outperformed two prior pharmacogenetic algorithms in predicting effective dose in this population. For patients at the highest risk of adverse events, 45.5% of the dose predictions using the developed pharmacogenetic model resulted in ideal dose as compared with only 29% when using the clinical non-genetic algorithm (p<0.001. The admixture-driven pharmacogenetic algorithm predicted 58% of warfarin dose variance when externally validated in 55 individuals from an independent validation cohort (MAE = 0.89 mg/day, 24% mean bias.Results supported our rationale to incorporate individual's genotypes and unique admixture metrics into pharmacogenetic refinement models in order to increase predictability when expanding them to admixed populations like Caribbean Hispanics.ClinicalTrials.gov NCT01318057.

Warfarin-induced Primary Dissection of Lower Peripheral Arteries: A Case Report

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Lee, Jae A; You, He Chul; Han, Young Min; Kwak, Hyo Sung [Chonbuk National University Hospital and Medical School, Jeonju (Korea, Republic of)

2010-12-15

Primary dissection of a peripheral artery without involvement of the aorta is a rare entity. Warfarin is currently used as the standard oral anticoagulant in a variety of clinical settings. We report here on a case of focal dissection of the common iliac artery and the superficial femoral artery following prophylactic treatment with warfarin for a prosthetic heart valve. The patient's laboratory results showed a high international normalized ratio and prolongation of the activated partial thromboplastin time. Angiography showed a dissection of the left common iliac artery and the right superficial femoral artery. His symptoms immediately disappeared after deploying stents to the arterial dissections

Warfarin-induced Primary Dissection of Lower Peripheral Arteries: A Case Report

International Nuclear Information System (INIS)

Lee, Jae A; You, He Chul; Han, Young Min; Kwak, Hyo Sung

2010-01-01

Primary dissection of a peripheral artery without involvement of the aorta is a rare entity. Warfarin is currently used as the standard oral anticoagulant in a variety of clinical settings. We report here on a case of focal dissection of the common iliac artery and the superficial femoral artery following prophylactic treatment with warfarin for a prosthetic heart valve. The patient's laboratory results showed a high international normalized ratio and prolongation of the activated partial thromboplastin time. Angiography showed a dissection of the left common iliac artery and the right superficial femoral artery. His symptoms immediately disappeared after deploying stents to the arterial dissections

Low warfarin resistance frequency in Norway rats in two cities in China after 30 years usage of anticoagulant rodenticides.

Science.gov (United States)

Ma, Xiaohui; Wang, Da-Wei; Li, Ning; Liu, Lan; Tian, Lin; Luo, Chan; Cong, Lin; Feng, Zhiyong; Liu, Xiao-Hui; Song, Ying

2018-04-17

Anticoagulant rodenticides have been widely used in rodent control in China for over 30 years and resistant Norway rats have been reported. Mutations in the vitamin K epoxide reductase complex, subunit 1 (Vkorc1) gene can cause anticoagulant resistance in rodents. In this study, we analyzed the Vkorc1 polymorphisms of 681 Norway rats collected in Zhanjiang and Harbin City in China from 2008 to 2015 and evaluated the warfarin resistance frequency. Analysis revealed 4 mutations including 3 not previously reported. Two new synonymous mutations His68His and Leu105Leu are not associated with warfarin resistance. One new nonsynonymous mutation Ala140Thr was found in Zhanjiang rat samples collected in 3 years with low frequencies (3.3%-4.0%) and is likely associated with warfarin resistance. Laboratory resistance tests suggested low warfarin resistance frequencies in rats from Zhanjiang (4.9%-17.1%) and Harbin City (0-2.5%). Both genetic analysis and laboratory resistance tests suggested low warfarin resistance frequencies in rats from Zhanjiang and Harbin City. The alternative usage of FGARs and SGARs might represent an effective strategy against the development of warfarin resistance in Norway rats in China. This article is protected by copyright. All rights reserved.

Validation and Application of a Simple UHPLC-MS-MS Method for the Enantiospecific Determination of Warfarin in Human Urine.

Science.gov (United States)

Alshogran, Osama Y; Ocque, Andrew J; Leblond, François A; Pichette, Vincent; Nolin, Thomas D

2016-04-01

A simple and rapid liquid chromatographic-tandem mass spectrometric method has been developed and validated for the enantiospecific determination of R- and S-warfarin in human urine. Warfarin enantiomers were extracted from urine using methyl tert-butyl ether. Chromatographic separation of warfarin enantiomers and the internal standard d5-warfarin was achieved using a Astec Chirobiotic V column with gradient mobile phase at a flow rate of 400 µL/min over 10 min. Detection was performed on a TSQ Quantum Ultra triple quadrupole mass spectrometer equipped with a heated electrospray ionization source. Analytes were detected in negative ionization mode using selected reaction monitoring. Calibration curves were linear with a correlation coefficient of ≥0.996 for both enantiomers over a concentration range of 5-500 ng/mL. The intra- and interday accuracy and precision for both analytes were within ±9.0%. Excellent extraction efficiency and negligible matrix effects were observed. The applicability of the method was demonstrated by successful measurement of warfarin enantiomers in urine of patients with kidney disease. The method is simple, accurate and reproducible and is currently being used to support warfarin pharmacokinetic studies. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

TRial of an Educational intervention on patients' knowledge of Atrial fibrillation and anticoagulant therapy, INR control, and outcome of Treatment with warfarin (TREAT

Directory of Open Access Journals (Sweden)

Pattison Helen M

2010-05-01

Full Text Available Abstract Background Atrial fibrillation (AF patients with a high risk of stroke are recommended anticoagulation with warfarin. However, the benefit of warfarin is dependent upon time spent within the target therapeutic range (TTR of their international normalised ratio (INR (2.0 to 3.0. AF patients possess limited knowledge of their disease and warfarin treatment and this can impact on INR control. Education can improve patients' understanding of warfarin therapy and factors which affect INR control. Methods/Design Randomised controlled trial of an intensive educational intervention will consist of group sessions (between 2-8 patients containing standardised information about the risks and benefits associated with OAC therapy, lifestyle interactions and the importance of monitoring and control of their International Normalised Ratio (INR. Information will be presented within an 'expert-patient' focussed DVD, revised educational booklet and patient worksheets. 200 warfarin-naïve patients who are eligible for warfarin will be randomised to either the intervention or usual care groups. All patients must have ECG-documented AF and be eligible for warfarin (according to the NICE AF guidelines. Exclusion criteria include: aged Discussion More data is needed on the clinical benefit of educational intervention with AF patients receiving warfarin. Trial registration ISRCTN93952605

Comparison of warfarin therapy clinical outcomes following implementation of an automated mobile phone-based critical laboratory value text alert system.

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Lin, Shu-Wen; Kang, Wen-Yi; Lin, Dong-Tsamn; Lee, James; Wu, Fe-Lin; Chen, Chuen-Liang; Tseng, Yufeng J

2014-01-01

Computerized alert and reminder systems have been widely accepted and applied to various patient care settings, with increasing numbers of clinical laboratories communicating critical laboratory test values to professionals via either manual notification or automated alerting systems/computerized reminders. Warfarin, an oral anticoagulant, exhibits narrow therapeutic range between treatment response and adverse events. It requires close monitoring of prothrombin time (PT)/international normalized ratio (INR) to ensure patient safety. This study was aimed to evaluate clinical outcomes of patients on warfarin therapy following implementation of a Personal Handy-phone System-based (PHS) alert system capable of generating and delivering text messages to communicate critical PT/INR laboratory results to practitioners' mobile phones in a large tertiary teaching hospital. A retrospective analysis was performed comparing patient clinical outcomes and physician prescribing behavior following conversion from a manual laboratory result alert system to an automated system. Clinical outcomes and practitioner responses to both alert systems were compared. Complications to warfarin therapy, warfarin utilization, and PT/INR results were evaluated for both systems, as well as clinician time to read alert messages, time to warfarin therapy modification, and monitoring frequency. No significant differences were detected in major hemorrhage and thromboembolism, warfarin prescribing patterns, PT/INR results, warfarin therapy modification, or monitoring frequency following implementation of the PHS text alert system. In both study periods, approximately 80% of critical results led to warfarin discontinuation or dose reduction. Senior physicians' follow-up response time to critical results was significantly decreased in the PHS alert study period (46.3% responded within 1 day) compared to the manual notification study period (24.7%; P = 0.015). No difference in follow-up response time

Effect of Warfarin Treatment on Survival of Patients With Pulmonary Arterial Hypertension (PAH) in the Registry to Evaluate Early and Long-Term PAH Disease Management (REVEAL).

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Preston, Ioana R; Roberts, Kari E; Miller, Dave P; Sen, Ginny P; Selej, Mona; Benton, Wade W; Hill, Nicholas S; Farber, Harrison W

2015-12-22

Long-term anticoagulation is recommended in idiopathic pulmonary arterial hypertension (IPAH). In contrast, limited data support anticoagulation in pulmonary arterial hypertension (PAH) associated with systemic sclerosis (SSc-PAH). We assessed the effect of warfarin anticoagulation on survival in IPAH and SSc-PAH patients enrolled in Registry to Evaluate Early and Long-term PAH Disease Management (REVEAL), a longitudinal registry of group I PAH. Patients who initiated warfarin on study (n=187) were matched 1:1 with patients never on warfarin, by enrollment site, etiology, and diagnosis status. Descriptive analyses were conducted to compare warfarin users and nonusers by etiology. Survival analyses with and without risk adjustment were performed from the time of warfarin initiation or a corresponding quarterly update in matched pairs to avoid immortal time bias. Time-varying covariate models were used as sensitivity analyses. Mean warfarin treatment was 1 year; mean international normalized ratios were 1.9 (IPAH) and 2.0 (SSc-PAH). Two-thirds of patients initiating warfarin discontinued treatment before the last study assessment. There was no survival difference with warfarin in IPAH patients (adjusted hazard ratio, 1.37; P=0.21) or in SSc-PAH patients (adjusted hazard ratio, 1.60; P=0.15) in comparison with matched controls. However, SSc-PAH patients receiving warfarin within the previous year (hazard ratio, 1.57; P=0.031) or any time postbaseline (hazard ratio, 1.49; P=0.046) had increased mortality in comparison with warfarin-naïve patients. No significant survival advantage was observed in IPAH patients who started warfarin. In SSc-PAH patients, long-term warfarin was associated with poorer survival than in patients not receiving warfarin, even after adjusting for confounders. URL: http://www.clinicaltrials.gov. Unique identifier: NCT00370214. © 2015 The Authors.

Patients with Moderate and Severe Traumatic Brain Injury: Impact of Preinjury Platelet Inhibitor or Warfarin Treatment.

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Tollefsen, Marie Hexeberg; Vik, Anne; Skandsen, Toril; Sandrød, Oddrun; Deane, Susan Frances; Rao, Vidar; Moen, Kent Gøran

2018-06-01

We aimed to examine the effect of preinjury antithrombotic medication on clinical and radiologic neuroworsening in traumatic brain injury (TBI) and study the effect on outcome. A total of 184 consecutive patients ≥50 years old with moderate and severe TBI admitted to a level 1 trauma center were included. Neuroworsening was assessed clinically by using the Glasgow Coma Scale (GCS) score and radiologically by using the Rotterdam CT score on repeated time points. Functional outcome was assessed with the Glasgow Outcome Scale Extended 6 months after injury. The platelet inhibitor group (mean age, 77.3 years; n = 43) and the warfarin group (mean age, 73.2 years; n = 20) were significantly older than the nonuser group (mean age, 63.7 years; n = 121; P ≤ 0.001). In the platelet inhibitor group 74% and in the warfarin group, 85% were injured by falls. Platelet inhibitors were not significantly associated with clinical or radiologic neuroworsening (P = 0.37-1.00), whereas warfarin increased the frequency of worsening in GCS score (P = 0.001-0.028) and Rotterdam CT score (P = 0.004). In-hospital mortality was higher in the platelet inhibitor group (28%; P = 0.030) and the warfarin group (50%; P warfarin predicted both mortality and worse outcome. In this study of patients with moderate and severe TBI, preinjury platelet inhibitors did not cause neuroworsening or predict higher mortality or worse outcome. In contrast, preinjury warfarin caused neuroworsening and was an independent risk factor for mortality and worse outcome at 6 months. Hence, fall prevention and liberal use of computed tomography examinations is important in this patient group. Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.

Warfarin Dosing Algorithms Underpredict Dose Requirements in Patients Requiring ≥7 mg Daily: A Systematic Review and Meta-analysis.

Science.gov (United States)

Saffian, S M; Duffull, S B; Wright, Dfb

2017-08-01

There is preliminary evidence to suggest that some published warfarin dosing algorithms produce biased maintenance dose predictions in patients who require higher than average doses. We conducted a meta-analysis of warfarin dosing algorithms to determine if there exists a systematic under- or overprediction of dose requirements for patients requiring ≥7 mg/day across published algorithms. Medline and Embase databases were searched up to September 2015. We quantified the proportion of over- and underpredicted doses in patients whose observed maintenance dose was ≥7 mg/day. The meta-analysis included 47 evaluations of 22 different warfarin dosing algorithms from 16 studies. The meta-analysis included data from 1,492 patients who required warfarin doses of ≥7 mg/day. All 22 algorithms were found to underpredict warfarin dosing requirements in patients who required ≥7 mg/day by an average of 2.3 mg/day with a pooled estimate of underpredicted doses of 92.3% (95% confidence interval 90.3-94.1, I 2 = 24%). © 2017 American Society for Clinical Pharmacology and Therapeutics.

Cervical spine abnormalities and instability with myelopathy in warfarin-related chondrodysplasia: 17-year follow-up

International Nuclear Information System (INIS)

Takano, Hideyuki; Smith, W.L.; Sato, Yutaka; Kao, S.C.S.

1998-01-01

A patient with warfarin embryopathy developed progressive cervical spinal myelopathy owing to bony cervical spinal damage. While there are several descriptions of warfarin embryopathy, the long-term complication of cervical spinal instability has not been reported. This cervical instability may, as in our patient, cause severe neurological dysfunction or even sudden death; therefore, it is important that pediatric radiologists should be alert to this condition. (orig.)

Consequence of patient substitution of nattokinase for warfarin after aortic valve replacement with a mechanical prosthesis.

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Elahi, Maqsood M; Choi, Charles H; Konda, Subbareddy; Shake, Jay G

2015-01-01

This report describes a patient's self-substitution of nattokinase for the vitamin K antagonist warfarin after aortic valve replacement with a mechanical prosthesis. Nattokinase is an enzyme derived from a popular fermented soybean preparation in Japan (natto), which has fibrinolytic properties and is gaining popularity in nontraditional health journals and nonmedical health websites as an over-the-counter thrombolytic. After nearly a year of use of nattokinase without warfarin, the patient developed thrombus on the mechanical valve and underwent successful repeat valve replacement. We believe this is the first documented case of nattokinase being used as a substitute for warfarin after valve replacement, and we strongly discourage its use for this purpose.

Quality of anticoagulation management with warfarin among outpatients in a tertiary hospital in Addis Ababa, Ethiopia: a retrospective cross-sectional study.

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Fenta, Teferi Gedif; Assefa, Tamrat; Alemayehu, Bekele

2017-06-06

Warfarin is the most widely used anticoagulant in the world. The difficulty of managing warfarin contributes to great potential for patient harm, both from excessive anticoagulation and insufficient anticoagulation. This study assessed the International Normalized Ratio (INR) control outcome measures and warfarin dose adjustment practices at cardiology and hematology outpatient clinics at a teaching hospital in Addis Ababa, Ethiopia. The study was based on a cross - sectional study design involving 360 retrospective patients' chart review among outpatients who received warfarin for its various indications. The mean frequency of INR monitoring per patient was 62.9 days (17.2-143.7 days). Patients spent 52.2%, 29.0% and 18.8% of the time in sub-therapeutic, therapeutic and supra-therapeutic ranges, respectively. The daily warfarin dose was increased 50.9% and 36.9% and decreased in 52.8% and 60.9% of the time for occurrences of sub-therapeutic and supra-therapeutic INRs to achieve target ranges of 2.0-3.0 and 2.5-3.5, respectively. The quality of anticoagulation management with warfarin among outpatients in Tikur Anbessa Specialized Hospital was sub-optimal. This was reflected by low Time in Therapeutic Range (TTR), longer than recommended INR monitoring frequency, and minimal actions taken to adjust warfarin dose after occurrences of non-therapeutic INRs.

Warfarin dose and INR related to genotypes of CYP2C9 and VKORC1 in patients with myocardial infarction

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Seljeflot Ingebjørg

2008-06-01

Full Text Available Abstract Background Warfarin treatment has a narrow therapeutic range, requiring meticulous monitoring and dosage titration. Individual dosage requirement has recently partly been explained by genetic variation of the warfarin metabolizing enzyme CYP2C9 and the Vitamin K-activating enzyme VKORC1. In the WARIS-II study, comparing three different antithrombotic regimens after myocardial infarction, warfarin treatment reduced thrombotic events, but was associated with more frequent bleeding than use of acetylsalisylic acid (ASA alone. Aims The primary aim of the present study was to investigate the relation between genotypes of CYP2C9 and VKORC1 and warfarin maintenance dose in myocardial infarction. The secondary aim was to relate the genotypes to international normalized ratio (INR. Methods Genotyping was performed in 212 myocardial infarction patients from the WARIS-II study by robotic isolation of DNA from EDTA whole blood (MagNa Pure LC before PCR amplification (LightCycler and melting point analysis. Results The 420 C>T substitution of CYP2C9*2, the 1075 A>C substitution of CYP2C9*3 and the 1173 C>T substitution of VKORC1 had minor allele frequencies of, 11.3%, 5.7% and 36.6% respectively. Warfarin weekly dose varied between 17 mg and 74 mg among the patients. INR did not vary between genotypes. Warfarin dosage requirement was significantly associated with CYP2C9 and VKORC1 genotypes, treatment group and age. The VKORC1 genotype contributed 24.5% to the interindividual variation in warfarin dosage, whereas the combined CYP2C9 genotypes were only responsible for 7.2% of the dose variation. Conclusion CYP2C9 and VKORC1 genotype frequencies in myocardial infarction patients appear similar to other patient groups and have similar impact on warfarin maintenance dose.

Impact of Computer-Aided Warfarin Dosing in a Saudi Arabian ...

African Journals Online (AJOL)

Pharmacotherapy Group, Faculty of Pharmacy, University of Benin, Benin City, 300001 Nigeria. All rights .... anticoagulant therapy in the form warfarin and were ... difference between the dosing of the ... individual patients are matched to a.

In situ detection of warfarin using time-correlated single-photon counting

Energy Technology Data Exchange (ETDEWEB)

Rosengren, Annika M.; Karlsson, Bjoern C.G. [Bioorganic and Biophysical Chemistry Laboratory, School of Natural Sciences, Linnaeus University, SE-391 82 Kalmar (Sweden); Naeslund, Inga; Andersson, Per Ola [Swedish Defence Research Agency, FOI, CBRN Defence and Security, SE-901 82 Umea (Sweden); Nicholls, Ian A., E-mail: ian.a.nicholls@bioorg.uu.se [Bioorganic and Biophysical Chemistry Laboratory, School of Natural Sciences, Linnaeus University, SE-391 82 Kalmar (Sweden); Department of Biochemistry and Organic Chemistry Laboratory, Uppsala University, SE-751 23 Uppsala (Sweden)

2011-04-01

Highlights: {yields} Direct in situ measurement of specific isomeric forms of the anticoagulant warfarin. {yields} TCSPC spectroscopy in conjunction with synthetic Sudlow I binding site receptors. {yields} Development of sensor principle for use in clinical and environmental monitoring. -- Abstract: Here we report on a novel method for the direct in situ measurement of specific isomeric forms of the anticoagulant warfarin using time correlated single-photon counting (TCSPC) spectroscopy in conjunction with synthetic Sudlow I binding site receptors. The method is highly robust over the clinically significant concentration range, and demonstrates the potential of the binding site mimics in conjunction with the spectroscopic strategy employed here for the determination of this important pharmaceutical in clinical or even environmental samples.

In situ detection of warfarin using time-correlated single-photon counting

International Nuclear Information System (INIS)

Rosengren, Annika M.; Karlsson, Bjoern C.G.; Naeslund, Inga; Andersson, Per Ola; Nicholls, Ian A.

2011-01-01

Highlights: → Direct in situ measurement of specific isomeric forms of the anticoagulant warfarin. → TCSPC spectroscopy in conjunction with synthetic Sudlow I binding site receptors. → Development of sensor principle for use in clinical and environmental monitoring. -- Abstract: Here we report on a novel method for the direct in situ measurement of specific isomeric forms of the anticoagulant warfarin using time correlated single-photon counting (TCSPC) spectroscopy in conjunction with synthetic Sudlow I binding site receptors. The method is highly robust over the clinically significant concentration range, and demonstrates the potential of the binding site mimics in conjunction with the spectroscopic strategy employed here for the determination of this important pharmaceutical in clinical or even environmental samples.

Pionerer bag vitamin K, dikumarol og warfarin

DEFF Research Database (Denmark)

Norn, Svend; Permin, Henrik; Kruse, Edith

2014-01-01

. The discovery was initiated by Dam, by a lucky choice of chicks in the dissertation of sterol metabolism, since the vitamin is not formed by intestinal bacteria in these animals. In these experiments the lack of an unknown factor in the synthetic diet caused internal bleeding similar to that found in scurvy......- through in the treatment of thromboembolic diseases. Today new oral anticoagulants are competing with warfarin....

Outcomes Associated With Resuming Warfarin Treatment After Hemorrhagic Stroke or Traumatic Intracranial Hemorrhage in Patients With Atrial Fibrillation.

Science.gov (United States)

Nielsen, Peter Brønnum; Larsen, Torben Bjerregaard; Skjøth, Flemming; Lip, Gregory Y H

2017-04-01

The increase in the risk for bleeding associated with antithrombotic therapy causes a dilemma in patients with atrial fibrillation (AF) who sustain an intracranial hemorrhage (ICH). A thrombotic risk is present; however, a risk for serious harm associated with resumption of anticoagulation therapy also exists. To investigate the prognosis associated with resuming warfarin treatment stratified by the type of ICH (hemorrhagic stroke or traumatic ICH). This nationwide observational cohort study included patients with AF who sustained an incident ICH event during warfarin treatment from January 1, 1998, through February 28, 2016. Follow-up was completed April 30, 2016. Resumption of warfarin treatment was evaluated after hospital discharge. No oral anticoagulant treatment or resumption of warfarin treatment, included as a time-dependent exposure. One-year observed event rates per 100 person-years were calculated, and treatment strategies were compared using time-dependent Cox proportional hazards regression models with adjustment for age, sex, length of hospital stay, comorbidities, and concomitant medication use. A total of 2415 patients with AF in this cohort (1481 men [61.3%] and 934 women [38.7%]; mean [SD] age, 77.1 years [9.1 years]) sustained an ICH event. Of these events, 1325 were attributable to hemorrhagic stroke and 1090 were secondary to trauma. During the first year, 305 patients with a hemorrhagic stroke (23.0%) died, whereas 210 in the traumatic ICH group (19.3%) died. Among patients with hemorrhagic stroke, resuming warfarin therapy was associated with a lower rate of ischemic stroke or systemic embolism (SE) (adjusted hazard ratio [AHR], 0.49; 95% CI, 0.24-1.02) and an increased rate of recurrent ICH (AHR, 1.31; 95% CI, 0.68-2.50) compared with not resuming warfarin therapy, but these differences did not reach statistical significance. For patients with traumatic ICH, resuming warfarin therapy also was associated with a lower rate of ischemic stroke

Effects on bone metabolism markers and arterial stiffness by switching to rivaroxaban from warfarin in patients with atrial fibrillation.

Science.gov (United States)

Namba, Sayaka; Yamaoka-Tojo, Minako; Kakizaki, Ryota; Nemoto, Teruyoshi; Fujiyoshi, Kazuhiro; Hashikata, Takehiro; Kitasato, Lisa; Hashimoto, Takuya; Kameda, Ryo; Meguro, Kentaro; Shimohama, Takao; Tojo, Taiki; Ako, Junya

2017-08-01

In recent years, direct oral anticoagulants (DOACs) of dabigatran, rivaroxaban, apixaban, edoxaban, which are all alternatives to warfarin, have been released. The use of DOACs is becoming more widespread in the clinical management of thrombotic stroke risk in patients with atrial fibrillation (AF). In large-scale clinical trials of each drug, DOACs were reported to inhibit intracranial hemorrhage, stroke, and death compared to warfarin. Warfarin is an endogenous vitamin K antagonist; therefore, patients who are taking warfarin must be prohibited from taking vitamin K. Vitamin K is an essential cofactor required for the ɤ-carboxylation of vitamin K-dependent proteins including coagulation factors, osteocalcin (OC), matrix Gla protein (MGP), and the growth arrest-specific 6 (GAS6). OC is a key factor for bone matrix formation. MGP is a local inhibitor of soft tissue calcification in the vessel wall. GAS6 prevents the apoptosis of vascular smooth muscle cells. Therefore, decrease of blood vitamin K levels may cause osteoporosis, vascular calcification, and the inhibition of vessels angiogenesis. This study aimed to evaluate the effects of changing from warfarin to rivaroxaban on bone mineral metabolism, vascular calcification, and vascular endothelial dysfunction. We studied 21 consecutive patients with persistent or chronic AF, who were treated with warfarin at least for 12 months. Warfarin administration was changed to rivaroxaban (10 or 15 mg/day) in all patients. Osteopontin (OPN), bone alkaline phosphatase (BAP), and under-carboxylated osteocalcin (ucOC) were measured. Pulse wave velocity (PWV) and augmentation index (AI) were also measured as atherosclerosis assessments. All measurements were done before and six months after the rivaroxaban treatment. There was a significant increase in serum level of BAP compared to baseline (12.5 ± 4.6 to 13.4 ± 4.1 U/L, P warfarin in patients with atrial fibrillation was associated with an increase of bone

Warfarin Anticoagulation Therapy in Caribbean Hispanics of Puerto Rico: A Candidate Gene Association Study.

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Claudio-Campos, Karla; Labastida, Aurora; Ramos, Alga; Gaedigk, Andrea; Renta-Torres, Jessicca; Padilla, Dariana; Rivera-Miranda, Giselle; Scott, Stuart A; Ruaño, Gualberto; Cadilla, Carmen L; Duconge-Soler, Jorge

2017-01-01

Existing algorithms account for ~50% of observed variance in warfarin dose requirements after including common polymorphisms. However, they do not perform as well in populations other than Caucasians, in part because some ethno-specific genetic variants are overlooked. The objective of the present study was to identify genetic polymorphisms that can explain variability in warfarin dose requirements among Caribbean Hispanics of Puerto Rico. Next-Generation Sequencing of candidate genes CYP2C9 and VKORC1 and genotyping by DMET® Plus Assay of cardiovascular patients were performed. We also aimed at characterizing the genomic structure and admixture pattern of this study cohort. Our study used the Extreme Discordant Phenotype approach to perform a case-control association analysis. The CYP2C9 variant rs2860905, which was found in all the major haplotypes occurring in the Puerto Rican population, showed stronger association with warfarin sensitivity (A; CYP2C9 rs1856908; ABCB1 c.IVS9-44A>G/ rs10276036; CES2 c.269-965A>G/ rs4783745) and non-genetic factors (i.e., hypertension, diabetes and age) showed better prediction of warfarin dose requirements than CYP2C9 * 2 and CYP2C9 * 3 combined (partial R 2 = 0.132 vs. 0.023 and 0.007, respectively, p Puerto Ricans in the study cohort showed a tri-hybrid admixture pattern, with a slightly higher than expected contribution of Native American ancestry (25%). The genomic diversity of Puerto Ricans is highlighted by the presence of four different major haplotype blocks in the CYP2C9 locus. Although, our findings need further replication, this study contributes to the field by identifying novel genetic variants that increase predictability of stable warfarin dosing among Caribbean Hispanics.

Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for Pharmacogenetics-Guided Warfarin Dosing: 2017 Update.

Science.gov (United States)

Johnson, J A; Caudle, K E; Gong, L; Whirl-Carrillo, M; Stein, C M; Scott, S A; Lee, M T; Gage, B F; Kimmel, S E; Perera, M A; Anderson, J L; Pirmohamed, M; Klein, T E; Limdi, N A; Cavallari, L H; Wadelius, M

2017-09-01

This document is an update to the 2011 Clinical Pharmacogenetics Implementation Consortium (CPIC) guideline for CYP2C9 and VKORC1 genotypes and warfarin dosing. Evidence from the published literature is presented for CYP2C9, VKORC1, CYP4F2, and rs12777823 genotype-guided warfarin dosing to achieve a target international normalized ratio of 2-3 when clinical genotype results are available. In addition, this updated guideline incorporates recommendations for adult and pediatric patients that are specific to continental ancestry. © 2017 American Society for Clinical Pharmacology and Therapeutics.

Stroke risks and patterns of warfarin therapy among atrial fibrillation patients post radiofrequency ablation: A real-world experience.

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Zhang, Juan; Liu, Xingpeng; Liu, Xiaoqing; Yin, Xiandong; Wang, Yanjiang; Lu, Xiaoying; Yang, Xinchun

2017-11-01

We assessed the thromboembolic risks of atrial fibrillation (AF) patients who had undergone radiofrequency ablation (RFA) using the CHADS2-VASc risk scoring system and further investigated the patterns of warfarin use for thromboprophylaxis according to patient thromboembolic risk scores.In this study, we analyzed the stroke risks of patients who had undergone RFA for AF at our hospital between March 2014 and June 2016 using the CHADS2, CHADS2-VASc, and Hypertension, Abnormal renal/liver function, Stroke, Bleeding history or predisposition, Labile international normalized ratio, Elderly (> 65 years) (HAS-BLED) scoring systems. We retrieved medications, co-morbidities, and initial warfarin dosage data. The primary outcome was the percentage of patients initiated with warfarin therapy for stroke prophylaxis in AF who had a CHADS2-VASc score of 0.Totally, 309 patients were initiated with warfarin therapy for stroke prophylaxis in AF post-RFA. The baseline warfarin dosage was 2.76 ± 0.61 mg. The baseline CHADS2-VASC score was 2.93 ± 1.96 and 40 (12.95%) had a CHADS2-VASC score of 0, 42 (13.6%) had a CHADS2-VASCscore of 1, and 227 (73.5%) had a CHADS2-VASC score ≥2. The baseline CHADS2 score was 2.17 ± 1.55 and 48 (15.5%) had a CHADS2 score of 0, 68 (22.0%) had a CHADS2 score of 1, and 193 (62.5%) had a CHADS2 score ≥2. The baseline HAS-BLED score was 1.25 ± 0.91 and 69 (22.3%) had a HAS-BLED score of 0, 121 (39.2%) had a HAS-BLED score of 1, and 119 (38.5%) had a HAS-BLED score ≥2. Patients aged warfarin thromboprophylaxis in accordance with national guidelines. Our findings suggest that low and intermediate stroke risk patients should be evaluated for stroke risks and risk factors so that tailored warfarin thromboprophylaxis therapy can be given and inappropriate use of warfarin in AF patients can be avoided. Copyright © 2017 The Authors. Published by Wolters Kluwer Health, Inc. All rights reserved.

Cervical spine abnormalities and instability with myelopathy in warfarin-related chondrodysplasia: 17-year follow-up

Energy Technology Data Exchange (ETDEWEB)

Takano, Hideyuki; Smith, W.L.; Sato, Yutaka; Kao, S.C.S. [Department of Radiology, The University of Iowa Clinics and Hospitals, 200 Hawkins Dr., F3966 JPP, Iowa City, IA 52242-1077 (United States)

1998-07-01

A patient with warfarin embryopathy developed progressive cervical spinal myelopathy owing to bony cervical spinal damage. While there are several descriptions of warfarin embryopathy, the long-term complication of cervical spinal instability has not been reported. This cervical instability may, as in our patient, cause severe neurological dysfunction or even sudden death; therefore, it is important that pediatric radiologists should be alert to this condition. (orig.) With 5 figs., 9 refs.

Should warfarin or aspirin be stopped prior to prostate biopsy? An analysis of bleeding complications related to increasing sample number regimes

International Nuclear Information System (INIS)

Chowdhury, R.; Abbas, A.; Idriz, S.; Hoy, A.; Rutherford, E.E.; Smart, J.M.

2012-01-01

Aim: To determine whether patients undergoing transrectal ultrasound (TRUS)-guided prostate biopsy with increased sampling numbers are more likely to experience bleeding complications and whether warfarin or low-dose aspirin are independent risk factors. Materials and methods: 930 consecutive patients with suspected prostatic cancer were followed up after biopsy. Warfarin/low-dose aspirin was not stopped prior to the procedure. An eight to 10 sample regime TRUS-guided prostate biopsy was performed and patients were offered a questionnaire to complete 10 days after the procedure, to determine any immediate or delayed bleeding complications. Results: 902 patients returned completed questionnaires. 579 (64.2%) underwent eight core biopsies, 47 (5.2%) underwent nine, and 276 (30.6%) underwent 10. 68 were taking warfarin [mean international normalized ratio (INR) = 2.5], 216 were taking low-dose aspirin, one was taking both, and 617 were taking neither. 27.9% of those on warfarin and 33.8% of those on aspirin experienced haematuria. 37% of those on no blood-thinning medication experienced haematuria. 13.2% of those on warfarin and 14.4% of those on aspirin experienced rectal bleeding. 11.5% of those on no blood-thinning medication experienced rectal bleeding. 7.4% of those on warfarin and 12% of those on aspirin experienced haematospermia. 13.8% of those on neither experienced haematospermia. Regression analysis showed a significant association between increasing sampling number and occurrence of all bleeding complication types. There was no significant association between minor bleeding complications and warfarin use; however, there was a significant association between minor bleeding complications and low-dose aspirin use. There was no severe bleeding complication. Conclusion: There is an increased risk of bleeding complications following TRUS-guided prostate biopsy with increased sampling numbers but these are minor. There is also an increased risk with low

Performance of commercial platforms for rapid genotyping of polymorphisms affecting warfarin dose.

Science.gov (United States)

King, Cristi R; Porche-Sorbet, Rhonda M; Gage, Brian F; Ridker, Paul M; Renaud, Yannick; Phillips, Michael S; Eby, Charles

2008-06-01

Initiation of warfarin therapy is associated with bleeding owing to its narrow therapeutic window and unpredictable therapeutic dose. Pharmacogenetic-based dosing algorithms can improve accuracy of initial warfarin dosing but require rapid genotyping for cytochrome P-450 2C9 (CYP2C9) *2 and *3 single nucleotide polymorphisms (SNPs) and a vitamin K epoxide reductase (VKORC1) SNP. We evaluated 4 commercial systems: INFINITI analyzer (AutoGenomics, Carlsbad, CA), Invader assay (Third Wave Technologies, Madison, WI), Tag-It Mutation Detection assay (Luminex Molecular Diagnostics, formerly Tm Bioscience, Toronto, Canada), and Pyrosequencing (Biotage, Uppsala, Sweden). We genotyped 112 DNA samples and resolved any discrepancies with bidirectional sequencing. The INFINITI analyzer was 100% accurate for all SNPs and required 8 hours. Invader and Tag-It were 100% accurate for CYP2C9 SNPs, 99% accurate for VKORC1 -1639/3673 SNP, and required 3 hours and 8 hours, respectively. Pyrosequencing was 99% accurate for CYP2C9 *2, 100% accurate for CYP2C9 *3, and 100% accurate for VKORC1 and required 4 hours. Current commercial platforms provide accurate and rapid genotypes for pharmacogenetic dosing during initiation of warfarin therapy.

A case report of a patient carrying CYP2C9*3/4 genotype with extremely low warfarin dose requirement.

Science.gov (United States)

Lee, Soo Youn; Nam, Myung Hyun; Kim, June Soo; Kim, Jong Won

2007-06-01

We report a case of intolerance to warfarin dosing due to impaired drug metabolism in a patient with CYP2C9*3/*4. A 73-yr-old woman with atrial fibrilation was taking warfarin. She attained a high prothrombin time international normalized ratio (INR) at the standard doses during the induction of anticoagulation and extremely low dose of warfarin (6.5 mg/week) was finally chosen to reach the target INR. Genotyping for CYP2C9 revealed that this patient had a genotype CYP2C9*3/*4. This is the first Korean compound heterozygote for CYP2C9*3 and *4. This case suggests the clinical usefulness of pharmacogenetic testing for individualized dosage adjustments of warfarin.

Evaluation of clinical outcomes among nonvalvular atrial fibrillation patients treated with rivaroxaban or warfarin, stratified by renal function
.

Science.gov (United States)

Weir, Matthew R; Haskell, Lloyd; Berger, Jeffrey S; Ashton, Veronica; Laliberté, François; Crivera, Concetta; Brown, Kip; Lefebvre, Patrick; Schein, Jeffrey

2018-05-01

Renal dysfunction increases the risk of thromboembolic and bleeding events in patients with nonvalvular atrial fibrillation (NVAF). Adult NVAF patients with ≥ 6 months prior to first warfarin or rivaroxaban dispensing were selected from the IMS Health Real-World Data Adjudicated Claims database (05/2011 - 06/2015) with electronic medical records. Ischemic stroke events, thromboembolic events (venous thromboembolism, myocardial infarction, or ischemic stroke), and major bleeding events were compared between patients by renal function identified by 1) relevant ICD-9-CM diagnosis codes and 2) estimated creatinine clearance (eCrCl). Baseline confounders were adjusted using inverse probability of treatment weights. The diagnosis-based analysis included 39,872 rivaroxaban and 48,637 warfarin users (3,572 and 8,230 with renal dysfunction, respectively). The eCrCl-based analysis included 874 rivaroxaban and 1,069 warfarin users (66 and 208 with eCrCl < 60 mL/min, respectively). In the diagnosis-based analysis, rivaroxaban users with renal dysfunction had a significantly lower stroke rate (HR = 0.55, p = 0.0004) compared to warfarin users; rivaroxaban users with and without renal dysfunction had significantly lower thromboembolic event rates (HR = 0.62, p < 0.0001; and HR = 0.64, p < 0.0001, respectively), and similar major bleeding rates to warfarin users. In the eCrCl-based analysis, rivaroxaban users with eCrCl ≥ 60 mL/min had a significantly lower thromboembolic event rate, but other outcomes were not statistically significant. Rivaroxaban-treated NVAF patients with diagnosed renal dysfunction had a significantly lower stroke rate compared to warfarin-treated patients. Regardless of renal dysfunction diagnoses, rivaroxaban users had lower thromboembolic event rates compared to warfarin users, and a similar rate of major bleeding. eCrCl-based analysis was limited by a small sample size.
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Increased short-term risk of thrombo-embolism or death after interruption of warfarin treatment in patients with atrial fibrillation.

Science.gov (United States)

Raunsø, Jakob; Selmer, Christian; Olesen, Jonas Bjerring; Charlot, Mette Gitz; Olsen, Anne-Marie S; Bretler, Ditte-Marie; Nielsen, Jørn Dalsgaard; Dominguez, Helena; Gadsbøll, Niels; Køber, Lars; Gislason, Gunnar H; Torp-Pedersen, Christian; Hansen, Morten Lock

2012-08-01

It is presently unknown whether patients with atrial fibrillation (AF) are at increased risk of thrombo-embolic adverse events after interruption of warfarin treatment. The purpose of this study was to assess the risk and timing of thrombo-embolism after warfarin treatment interruption. A retrospective, nationwide cohort study of all patients in Denmark treated with warfarin after a first hospitalization with AF in the period 1997-2008. Incidence rate ratios (IRRs) of thrombo-embolic events and all-cause mortality were calculated using the Poisson regression analyses. In total, 48 989 AF patients receiving warfarin treatment were included. Of these, 35 396 patients had at least one episode of warfarin treatment interruption. In all, 8255 deaths or thrombo-embolic events occurred during treatment interruption showing an initial clustering of events with 2717, 835, 500, and 427 events occurring during 0-90, 91-180, 181-270, and 271-360 days after treatment interruption, respectively. Correspondingly, the crude incidence rates were 31.6, 17.7, 12.3, and 11.4 events per 100 patient-years. In a multivariable analysis, the first 90-day interval of treatment interruption was associated with a markedly higher risk of death or thrombo-embolism (IRR 2.5; 95% confidence interval 2.3-2.8) vs. the interval of 271-360 days. In patients with AF, an interruption of warfarin treatment is associated with a significantly increased short-term risk of death or thrombo-embolic events within the first 90 days of treatment interruption.

The accuracy of warfarin dosage based on VKORC1 and CYP2C9 phenotypes in a Chinese population

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Agustinus Wijaya

2012-05-01

Full Text Available Background: The aim of this study is to assess the accuracy of warfarin dosage based on VKORC1 and CYP2C9 genotype in Chinese population.Methods: Blood samples were taken from 37 patients. We compared the warfarin dosage obtained from genotype (according to www.warfarindosing.org and treatment dosage with international normalized ratio (INR value within 2.0-3.0.Results: The majority of Chinese people in our study are VKORC1 homozygous AA (89.2%, rarely VKORC1 heterozygous AG and we cannot find a patient with homozygous GG. For CYP2C9 genotype, most patients have the wildtype variants (CYP2C9*2 CC and CYP2C9*3 AA. The warfarin dosage for patients with VKORC1 AA and CYP2C9*3 AC is lower than for patients with other genotype variants.Conclusion: There is no significant difference between pharmacogenetic algorithm (www.warfarindosing.org and our treatment dosage. Our conclusion is that the pharmacogenetic algorithm is accurate to predict the warfarin dose. (Med J Indones. 2012;21:108-12Keywords: CYP2C9, pharmacogenetic algorithm, VKORC1, warfarin

Introduction of a carbon paste electrode based on nickel carbide for investigation of interaction between warfarin and vitamin K1.

Science.gov (United States)

Torkashvand, Maryam; Gholivand, Mohammad Bagher; Taherpour, Avat Arman; Boochani, Arash; Akhtar, Arsalan

2017-05-30

In this paper a novel electrochemical sensor based on nickel carbide (Ni 3 C) nanoparticles as a new modifier was constructed. Ni 3 C nanoparticle was synthesized and characterized by scanning electron microscopy, X-ray diffraction and first-principles study. Electrochemical impedance spectroscopy (EIS) and cyclic voltammetry (CV) studies confirmed the electrode modification. Afterwards, the new electrode for the first time was used for interaction study between vitamin K1 and warfarin as an anticoagulant drug by differential pulse voltammetry. The adduct formation between the drug and vitamin K1 was improved by decreasing in anodic peak current of warfarin in the presence of different amounts of vitamin K1. The binding constant between warfarin and vitamin K1 was obtained by voltammetric and UV-vis and fluorescence spectroscopic methods. The molecular modeling method was also performed to explore the structural features and binding mechanism of warfarin to vitamin K1. The different aspects of modeling of vitamin K1 and warfarin and their adduct structures confirmed the adduct formation by hydrogen bonding. Copyright © 2017 Elsevier B.V. All rights reserved.

Integrated analysis of genetic variation and gene expression reveals novel variant for increased warfarin dose requirement in African Americans

NARCIS (Netherlands)

Hernandez, W.; Gamazon, E. R.; Aquino-Michaels, K.; Smithberger, E.; O'Brien, T. J.; Harralson, A. F.; Tuck, M.; Barbour, A.; Cavallari, L. H.; Perera, M. A.

2017-01-01

Essentials Genetic variants controlling gene regulation have not been explored in pharmacogenomics. We tested liver expression quantitative trait loci for association with warfarin dose response. A novel predictor for increased warfarin dose response in African Americans was identified. Precision

Patients' Perceptions of a Game About Warfarin and Vitamin K: A Pilot Study.

Science.gov (United States)

Faddoul, Badia; Kelemen, Arpad; Connerney, Ingrid; Grover, Brian; Hoffman, Janice

2012-10-01

Digital games to promote healthy behaviors are rapidly expanding in the healthcare industry. One area where health game can be useful is in educating patients about oral anticoagulants such as warfarin. The goal of this pilot study was to develop a game about warfarin and vitamin K interactions and evaluate its usability among adult patients receiving warfarin therapy. The game was developed by an interdisciplinary team. The content of the game was based on published evidence-based practice about anticoagulation education. Kolb's experiential learning theory served as the theoretical foundation of the game, which we developed in Flash and Actionscript 2(®) (Adobe Systems, San Jose, CA) programming and scripting languages, and it is playable on various platforms, including Windows and Macintosh, via Internet Explorer, Mozilla Firefox, and Safari Web browsers. Twenty patients were surveyed using a 7-point Likert scale to evaluate their experience on the Perceived Health Web Site Usability Questionnaire (PHWSUQ). The PHWSUQ measures satisfaction, ease of learning the site, and usefulness. Possible responses ranged from 1 (very unsatisfied) to 7 (very satisfied) and from strongly disagree (1) to strongly agree (7). The overall mean score on the PHWSUQ was 53.6 out of 70 (SD, 11.3), or 76.6 percent. The mean scores for "satisfaction," "ease of use," and "usefulness" subscales were 80.2 percent, 71.2 percent, and 77.4 percent, respectively. The findings suggest that patients were satisfied with the game, which indicates that adult patients on warfarin are open to game use as an educational tool to learn health information.

Theory‐based pharmacokinetics and pharmacodynamics of S‐ and R‐warfarin and effects on international normalized ratio: influence of body size, composition and genotype in cardiac surgery patients

Science.gov (United States)

Xue, Ling; Holford, Nick; Ding, Xiao‐liang; Shen, Zhen‐ya; Huang, Chen‐rong; Zhang, Hua; Zhang, Jing‐jing; Guo, Zhe‐ning; Xie, Cheng; Zhou, Ling; Chen, Zhi‐yao; Liu, Lin‐sheng

2016-01-01

Aims The aims of this study are to apply a theory‐based mechanistic model to describe the pharmacokinetics (PK) and pharmacodynamics (PD) of S‐ and R‐warfarin. Methods Clinical data were obtained from 264 patients. Total concentrations for S‐ and R‐warfarin were measured by ultra‐high performance liquid tandem mass spectrometry. Genotypes were measured using pyrosequencing. A sequential population PK parameter with data method was used to describe the international normalized ratio (INR) time course. Data were analyzed with NONMEM. Model evaluation was based on parameter plausibility and prediction‐corrected visual predictive checks. Results Warfarin PK was described using a one‐compartment model. CYP2C9 *1/*3 genotype had reduced clearance for S‐warfarin, but increased clearance for R‐warfarin. The in vitro parameters for the relationship between prothrombin complex activity (PCA) and INR were markedly different (A = 0.560, B = 0.386) from the theory‐based values (A = 1, B = 0). There was a small difference between healthy subjects and patients. A sigmoid Emax PD model inhibiting PCA synthesis as a function of S‐warfarin concentration predicted INR. Small R‐warfarin effects was described by competitive antagonism of S‐warfarin inhibition. Patients with VKORC1 AA and CYP4F2 CC or CT genotypes had lower C50 for S‐warfarin. Conclusion A theory‐based PKPD model describes warfarin concentrations and clinical response. Expected PK and PD genotype effects were confirmed. The role of predicted fat free mass with theory‐based allometric scaling of PK parameters was identified. R‐warfarin had a minor effect compared with S‐warfarin on PCA synthesis. INR is predictable from 1/PCA in vivo. PMID:27763679

Hospital Admissions, Costs, and 30-Day Readmissions Among Newly Diagnosed Nonvalvular Atrial Fibrillation Patients Treated with Dabigatran Etexilate or Warfarin.

Science.gov (United States)

Fonseca, Eileen; Sander, Stephen D; Hess, Gregory P; Ghosh, Sabyasachi

2015-11-01

Oral anticoagulation such as warfarin and dabigatran is indicated for atrial fibrillation (AF) patients at risk of ischemic stroke. Dabigatran etexilate was developed to address the limitations of warfarin, including the need for regular blood monitoring, which has the potential to lead to higher health care resource use, particularly in hospitalized patients. To evaluate whether hospitalization cost, length of hospital stay (LOS), likelihood of readmission within 30 days, and cost of readmissions differed across inpatient encounters among nonvalvular atrial fibrillation (NVAF) patients that were newly diagnosed and newly treated with either dabigatran or warfarin. A retrospective cohort study was conducted using IMS Health's Charge Detail Master (CDM) database. Hospitalizations were identified based on a primary or secondary AF diagnosis, dabigatran or warfarin use, and a discharge date from January 2011 through March 2012. The identified patients without valvular procedures and transient AF were required to have a minimum of 12 months of pharmacy and private practitioner records prior to the inpatient encounter to ensure that they were newly treated on dabigatran or warfarin. Propensity score matching was used to balance baseline characteristics between treatment cohorts. Outcomes assessed were LOS, 30-day readmissions, and costs. Because individual patients could have more than 1 hospital observation, generalized estimating equations (GEE) with a gamma distribution (log link) were used for the analysis of continuous outcome measures (e.g., LOS and costs) and a binominal distribution for dichotomous outcomes (hospital readmissions). Two cohorts were propensity score matched (1:2) on demographic and clinical characteristics. The dabigatran cohort included 646 hospitalizations, and the warfarin cohort included 1,292 hospitalizations. Hospitalizations were on average 13% shorter (4.8 vs. 5.5 days, P  less than  0.001) and cost 12% less ($14,794 vs. $16,826, P�

Frequency of different disorders requiring warfarin therapy and its outcome in terms of dosage and inr value in pakistani population

International Nuclear Information System (INIS)

Qayyum, A.; Najmi, M.H.

2014-01-01

To determine the frequency of different disorders requiring warfarin therapy and to see the target INR and warfarin dose requirement in Pakistani population. Study Design:Descriptive study. Setting and Duration of Study: The study was carried out at Armed Forces Institut e of Cardiology (AFIC) Rawalpindi, Military Hospital Rawalpindi and National Institute of Cardiovascular Diseases (NICVD), Karachi, Pakistan from October 2010 to March 2012. Patients and Methods: Stable patients taking warfarin therapy were recruited after detailed medical history, physical examination and laboratory tests. The demographic and clinical data of individuals were entered in a pre-structured proforma. Patients suffering from hepatic and renal disease, any co-morbid disease or taking any concurrent medication or diet which would have affected warfarin therapy, were excluded. Data was analyzed using PSS version 20.0. Results: A total of 607 stable patients fulfilling the eligibility criteria, participated in the study. There were 297 (48.9%) male and 310 (51.1%) female patients. The mean age was 37.93 +- 12.23 years (range 18-65 years). The most common indication for warfarin therapy was valvular heart diseases (93.4%) followed by atrial fibrillation (2.3%) whereas other indications for warfarin use are less commonly seen in our study population. Patients had mean international normalized ratio (INR) value of 2.3 +9- 0.8 (range 1.5-3.5). Mean daily dose of warfarin calculated in 607 patients was 5.62 and 1.98 mg with the range of 0.36-15 g whereas mean weekly dose was 39.36 +- 13.8 mg with the range of 2.5-105 mg. Conclusion: In Pakistani population the most common indications for warfarin use are valvular heart diseases followed by atrial fibrillation. The mean INR values were within recommended range of 2-3. The mean daily dose observed in long-term therapy is comparable to the empirical dose of 5 mg routinely started in clinical practice. (author)

Edoxaban versus warfarin for the treatment of symptomatic venous thromboembolism

NARCIS (Netherlands)

Büller, Harry R; Décousus, Hervé; Grosso, Michael A; Mercuri, Michele; Middeldorp, Saskia; Prins, Martin H; Raskob, Gary E; Schellong, Sebastian M; Schwocho, Lee; Segers, Annelise; Shi, Minggao; Verhamme, Peter; Wells, Phil; Kamphuisen, P.W.

2013-01-01

BACKGROUND: Whether the oral factor Xa inhibitor edoxaban can be an alternative to warfarin in patients with venous thromboembolism is unclear. METHODS: In a randomized, double-blind, noninferiority study, we randomly assigned patients with acute venous thromboembolism, who had initially received

No Dose Adjustment is Recommended for Digoxin, Warfarin, Atorvastatin or a Combination Oral Contraceptive When Coadministered with Dulaglutide.

Science.gov (United States)

de la Peña, Amparo; Cui, Xuewei; Geiser, Jeanne; Loghin, Corina

2017-11-01

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) for the treatment of type 2 diabetes mellitus are known to delay gastric emptying (GE). The potential effect of the GLP-1 RA dulaglutide on the pharmacokinetics (PK) of four orally administered drugs and on the pharmacodynamic (PD) effect of warfarin was investigated. In four separate clinical pharmacology studies, digoxin, warfarin, atorvastatin and Ortho-Cyclen ® were orally administered to healthy subjects with and without a subcutaneous dose of dulaglutide 1.5 mg. The effect of dulaglutide coadministration was assessed based on the PK parameters of key analytes. For warfarin PD, the effect of dulaglutide on the international normalized ratio (INR) was evaluated. Areas under the concentration-time curves (AUCs) with and without dulaglutide were similar for all analytes except atorvastatin, where it was reduced by 21%. Maximum concentrations (C max ) were generally lower following coadministration with dulaglutide, with statistically significant reductions (90% confidence intervals of geometric least squares means ratios outside 0.80-1.25) for all analytes except R-warfarin. For all analytes, there was a general trend for the time to C max (t max ) to increase following coadministration with dulaglutide. For warfarin, dulaglutide coadministration had no statistically significant effect on the maximum INR (INR max ); however, a 2% increase in area under the INR curve (AUC INR ) was observed. Dulaglutide did not affect the absorption of the tested medications to a clinically relevant degree. Based on the PK and PD evaluations, no dose adjustments for digoxin, warfarin, atorvastatin and Ortho-Cyclen ® are recommended when coadministered with dulaglutide. NCT01458210, NCT01436201, NCT01432938, and NCT01250834.

Provider and pharmacist responses to warfarin drug–drug interaction alerts: a study of healthcare downstream of CPOE alerts

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Boro, Maureen S; Korman, Nancy E; Davoren, J Ben

2011-01-01

Objective To categorize the appropriateness of provider and pharmacist responses to warfarin critical drug–drug interaction (cDDI) alerts, assess responses and actions to the cDDI, and determine the occurrence of warfarin adverse drug events (ADE) after alerts. Design An 18-month, retrospective study of acute care admissions at a single Veterans Affairs medical center using computerized provider order entry (CPOE). Measurements Patients included had at least one warfarin cDDI alert. Chart reviews included baseline laboratory values and demographics, provider actions, patient outcomes, and associated factors, including other interacting medications and number of simultaneously processed alerts. Results 137 admissions were included (133 unique patients). Amiodarone, vitamin E in a multivitamin, sulfamethoxazole, and levothyroxine accounted for 75% of warfarin cDDI. Provider responses were clinically appropriate in 19.7% of admissions and pharmacist responses were appropriate in 9.5% of admissions. There were 50 ADE (36.6% of admissions) with warfarin; 80% were rated as having no or mild clinical effect. An increased number of non-critical alerts at the time of the reference cDDI alert was the only variable associated with an inappropriate provider response (p=0.01). Limitations This study was limited by being a retrospective review and the possibility of confounding variables, such as other interacting medications. Conclusion The large number of CPOE alerts may lead to inappropriate responses by providers and pharmacists. The high rate of ADE suggests a need for improved medication management systems for patients on warfarin. This study highlights the possibility of alert fatigue contributing to the high prevalence of inappropriate alert over-ride text responses. PMID:22037888

Warfarin Anticoagulation Therapy in Caribbean Hispanics of Puerto Rico: A Candidate Gene Association Study

Directory of Open Access Journals (Sweden)

Karla Claudio-Campos

2017-06-01

Full Text Available Existing algorithms account for ~50% of observed variance in warfarin dose requirements after including common polymorphisms. However, they do not perform as well in populations other than Caucasians, in part because some ethno-specific genetic variants are overlooked. The objective of the present study was to identify genetic polymorphisms that can explain variability in warfarin dose requirements among Caribbean Hispanics of Puerto Rico. Next-Generation Sequencing of candidate genes CYP2C9 and VKORC1 and genotyping by DMET® Plus Assay of cardiovascular patients were performed. We also aimed at characterizing the genomic structure and admixture pattern of this study cohort. Our study used the Extreme Discordant Phenotype approach to perform a case-control association analysis. The CYP2C9 variant rs2860905, which was found in all the major haplotypes occurring in the Puerto Rican population, showed stronger association with warfarin sensitivity (<4 mg/day than common variants CYP2C9*2 and CYP2C9*3. Although, CYP2C9*2 and CYP2C9*3 are separately contained within two of the haplotypes, 10 subjects with the sensitive phenotype were carriers of only the CYP2C9 rs2860905 variant. Other polymorphisms in CES2 and ABCB1 were found to be associated with warfarin resistance. Incorporation of rs2860905 in a regression model (R2 = 0.63, MSE = 0.37 that also includes additional genetics (i.e., VKORC1-1639 G>A; CYP2C9 rs1856908; ABCB1 c.IVS9-44A>G/ rs10276036; CES2 c.269-965A>G/ rs4783745 and non-genetic factors (i.e., hypertension, diabetes and age showed better prediction of warfarin dose requirements than CYP2C9*2 and CYP2C9*3 combined (partial R2 = 0.132 vs. 0.023 and 0.007, respectively, p < 0.001. The genetic background of Puerto Ricans in the study cohort showed a tri-hybrid admixture pattern, with a slightly higher than expected contribution of Native American ancestry (25%. The genomic diversity of Puerto Ricans is highlighted by the presence of

Population Impact of Drug Interactions with Warfarin: A Real-World Data Approach.

Science.gov (United States)

Martín-Pérez, Mar; Gaist, David; de Abajo, Francisco J; Rodríguez, Luis A García

2018-03-01

 To investigate the population impact of previously reported interactions between warfarin and other drugs on international normalized ratio (INR) levels.  Using The Health Improvement Network (THIN), a United Kingdom primary care database, a cohort of warfarin users between 2005 and 2013 ( N  = 121,962) was followed until the first qualifying prescription for the potential interacting drugs was evaluated. Sixteen sub-cohorts, one for each study drug, and a control sub-cohort of warfarin were ascertained. Short-term changes in INR levels were assessed by comparing INR values measured before and after initiation of the interacting drug with paired Student's t -test. We also evaluated the proportion of patients with INR values outside the therapeutic range (INR: 2-3).  Miconazole use was associated with the highest mean increase in INR (+3.35), followed by amiodarone (+1.28), fluconazole (+0.79), metronidazole (+0.75) and nystatin (+0.65). After subtracting the natural INR variation observed in the control sub-cohort, supra-therapeutic levels (INR > 3) were found in 53.2% (miconazole), 45.5% (amiodarone), 23.3% (metronidazole), 23.2% (fluconazole) and 17.6% (nystatin) of patients initiating treatment with these drugs. Carbamazepine use was associated with a mean INR decrease of -0.63 and infra-therapeutic levels (INR < 2) were observed in 46.2% of patients initiating carbamazepine. For all other drugs, the change was small to moderate, in absolute INR units (+0.23 to +0.55) and in the proportion of patients with INR levels out of therapeutic range (<16%).  Clinically potentially important interactions were observed in several study drugs. The majority of them, although confirmed, had little impact after adjusting for standard INR variability in the general population of warfarin users. Schattauer GmbH Stuttgart.

A review of a priori regression models for warfarin maintenance dose prediction.

Directory of Open Access Journals (Sweden)

Ben Francis

Full Text Available A number of a priori warfarin dosing algorithms, derived using linear regression methods, have been proposed. Although these dosing algorithms may have been validated using patients derived from the same centre, rarely have they been validated using a patient cohort recruited from another centre. In order to undertake external validation, two cohorts were utilised. One cohort formed by patients from a prospective trial and the second formed by patients in the control arm of the EU-PACT trial. Of these, 641 patients were identified as having attained stable dosing and formed the dataset used for validation. Predicted maintenance doses from six criterion fulfilling regression models were then compared to individual patient stable warfarin dose. Predictive ability was assessed with reference to several statistics including the R-square and mean absolute error. The six regression models explained different amounts of variability in the stable maintenance warfarin dose requirements of the patients in the two validation cohorts; adjusted R-squared values ranged from 24.2% to 68.6%. An overview of the summary statistics demonstrated that no one dosing algorithm could be considered optimal. The larger validation cohort from the prospective trial produced more consistent statistics across the six dosing algorithms. The study found that all the regression models performed worse in the validation cohort when compared to the derivation cohort. Further, there was little difference between regression models that contained pharmacogenetic coefficients and algorithms containing just non-pharmacogenetic coefficients. The inconsistency of results between the validation cohorts suggests that unaccounted population specific factors cause variability in dosing algorithm performance. Better methods for dosing that take into account inter- and intra-individual variability, at the initiation and maintenance phases of warfarin treatment, are needed.

A review of a priori regression models for warfarin maintenance dose prediction.

Science.gov (United States)

Francis, Ben; Lane, Steven; Pirmohamed, Munir; Jorgensen, Andrea

2014-01-01

A number of a priori warfarin dosing algorithms, derived using linear regression methods, have been proposed. Although these dosing algorithms may have been validated using patients derived from the same centre, rarely have they been validated using a patient cohort recruited from another centre. In order to undertake external validation, two cohorts were utilised. One cohort formed by patients from a prospective trial and the second formed by patients in the control arm of the EU-PACT trial. Of these, 641 patients were identified as having attained stable dosing and formed the dataset used for validation. Predicted maintenance doses from six criterion fulfilling regression models were then compared to individual patient stable warfarin dose. Predictive ability was assessed with reference to several statistics including the R-square and mean absolute error. The six regression models explained different amounts of variability in the stable maintenance warfarin dose requirements of the patients in the two validation cohorts; adjusted R-squared values ranged from 24.2% to 68.6%. An overview of the summary statistics demonstrated that no one dosing algorithm could be considered optimal. The larger validation cohort from the prospective trial produced more consistent statistics across the six dosing algorithms. The study found that all the regression models performed worse in the validation cohort when compared to the derivation cohort. Further, there was little difference between regression models that contained pharmacogenetic coefficients and algorithms containing just non-pharmacogenetic coefficients. The inconsistency of results between the validation cohorts suggests that unaccounted population specific factors cause variability in dosing algorithm performance. Better methods for dosing that take into account inter- and intra-individual variability, at the initiation and maintenance phases of warfarin treatment, are needed.

Genetic variants associated with warfarin dose in African-American individuals: a genome-wide association study

OpenAIRE

Perera, Minoli A; Cavallari, Larisa H; Limdi, Nita A; Gamazon, Eric R; Konkashbaev, Anuar; Daneshjou, Roxana; Pluzhnikov, Anna; Crawford, Dana C; Wang, Jelai; Liu, Nianjun; Tatonetti, Nicholas; Bourgeois, Stephane; Takahashi, Harumi; Bradford, Yukiko; Burkley, Benjamin M

2013-01-01

Summary BackgroundVKORC1 and CYP2C9 are important contributors to warfarin dose variability, but explain less variability for individuals of African descent than for those of European or Asian descent. We aimed to identify additional variants contributing to warfarin dose requirements in African Americans. MethodsWe did a genome-wide association study of discovery and replication cohorts. Samples from African-American adults (aged ≥18 years) who were taking a stable maintenance dose of warfar...

Lipase-supported metal-organic framework bioreactor catalyzes warfarin synthesis.

Science.gov (United States)

Liu, Wan-Ling; Yang, Ni-Shin; Chen, Ya-Ting; Lirio, Stephen; Wu, Cheng-You; Lin, Chia-Her; Huang, Hsi-Ya

2015-01-02

A green and sustainable strategy synthesizes clinical medicine warfarin anticoagulant by using lipase-supported metal-organic framework (MOF) bioreactors (see scheme). These findings may be beneficial for future studies in the industrial production of chemical, pharmaceutical, and agrochemical precursors. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Fluorescence Determination of Warfarin Using TGA-capped CdTe Quantum Dots in Human Plasma Samples.

Science.gov (United States)

Dehbozorgi, A; Tashkhourian, J; Zare, S

2015-11-01

In this study, some effort has been performed to provide low temperature, less time consuming and facile routes for the synthesis of CdTe quantum dots using ultrasound and water soluble capping agent thioglycolic acid. TGA-capped CdTe quantum dots were characterized through x-ray diffraction, transmission electron microscopy, Fourier transform infrared, ultraviolet-visible and fluorescence spectroscopy. The prepared quantum dots were used for warfarin determination based on the quenching of the fluorescence intensity in aqueous solution. Under the optimized conditions, the linear range of quantum dots fluorescence intensity versus the concentration of warfarin was 0.1-160.0 μM, with the correlation coefficient of 0.9996 and a limit of detection of 77.5 nM. There was no interference to coexisting foreign substances. The selectivity of the sensor was also tested and the results show that the developed method possesses a high selectivity for warfarin.

Serious Bleeding Events due to Warfarin and Antibiotic Co-prescription In a Cohort of Veterans

Science.gov (United States)

Lane, Michael A.; Zeringue, Angelique; McDonald, Jay R.

2014-01-01

Background Antibiotics may interact with warfarin, increasing the risk for significant bleeding events. Methods Retrospective cohort study of veterans prescribed warfarin for ≥ 30 days without interruption through the VA between October 1, 2002 and September 1, 2008. Antibiotics considered to be high-risk for interaction with warfarin include: trimethoprim/sulfamethoxazole (TMP/SMX), ciprofloxacin, levofloxacin, metronidazole, fluiconazole, azithromycin, and clarithromycin. Low-risk antibiotics include: clindamycin and cephalexin. Risk of bleeding event within 30 days of antibiotic exposure was measured using Cox proportional hazards regression, adjusted for demographic characteristics, comorbid conditions and receipt of other medications interacting with warfarin. Results A total of 22,272 patients met inclusion criteria with 14,078 and 8,194 receiving high- and low-risk antibiotics, respectively. There were 93 and 36 bleeding events in the high- and low-risk groups, respectively. Receipt of a high-risk antibiotic (HR 1.48, 95% CI 1.00-2.19) and azithromycin (HR 1.93, 95% CI 1.13-3.30) were associated with increased risk of bleeding as a primary diagnosis. TMP/SMX (HR 2.09, 95% CI 1.45-3.02), ciprofloxacin (HR 1.87, 95% CI 1.42-2.50), levofloxacin (HR 1.77, 95% CI 1.22-2.50), azithromycin (HR 1.64, 95% CI 1.16-2.33), and clarithromycin (HR 2.40, 95% CI 1.16-4.94) were associated with serious bleeding as a primary or secondary diagnosis. INR alterations were common; 9.7% of patients prescribed fluconazole had INR value >6. Patients who had INR performed 3-14 days of co-prescription were at a decrease risk of serious bleeding (HR 0.61, 95% CI 0.42-0.88). Conclusions Warfarin users who are prescribed high-risk antibiotics are at higher risk for serious bleeding events. Early INR evaluation may mitigate this risk. PMID:24657899

Increased short-term risk of thrombo-embolism or death after interruption of warfarin treatment in patients with atrial fibrillation

DEFF Research Database (Denmark)

Raunsø, Jakob; Selmer, Christian; Olesen, Jonas Bjerring

2012-01-01

AimsIt is presently unknown whether patients with atrial fibrillation (AF) are at increased risk of thrombo-embolic adverse events after interruption of warfarin treatment. The purpose of this study was to assess the risk and timing of thrombo-embolism after warfarin treatment interruption.Method...

Safety and efficacy of rivaroxaban compared with warfarin in patients undergoing peripheral arterial procedures.

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Talukdar, Anjan; Wang, S Keisin; Czosnowski, Lauren; Mokraoui, Nassim; Gupta, Alok; Fajardo, Andres; Dalsing, Michael; Motaganahalli, Raghu

2017-10-01

Rivaroxaban is a United States Food and Drug Administration-approved oral anticoagulant for venous thromboembolic disease; however, there is no information regarding the safety and its efficacy to support its use in patients after open or endovascular arterial interventions. We report the safety and efficacy of rivaroxaban vs warfarin in patients undergoing peripheral arterial interventions. This single-institution retrospective study analyzed all sequential patients from December 2012 to August 2014 (21 months) who were prescribed rivaroxaban or warfarin after a peripheral arterial procedure. Our study population was then compared using American College of Chest Physicians guidelines with patients then stratified as low, medium, or high risk for bleeding complications. Statistical analyses were performed using the Student t-test and χ 2 test to compare demographics, readmissions because of bleeding, and the need for secondary interventions. Logistic regression models were used for analysis of variables associated with bleeding complications and secondary interventions. The Fisher exact test was used for power analysis. There were 44 patients in the rivaroxaban group and 50 patients in the warfarin group. Differences between demographics and risk factors for bleeding between groups or reintervention rate were not statistically significant (P = .297). However, subgroup evaluation of the safety profile suggests that patients who were aged ≤65 years and on warfarin had an overall higher incidence of major bleeding (P = .020). Patients who were aged >65 years, undergoing open operation, had a significant risk for reintervention (P = .047) when they received rivaroxaban. Real-world experience using rivaroxaban and warfarin in patients after peripheral arterial procedures suggests a comparable safety and efficacy profile. Subgroup analysis of those requiring an open operation demonstrated a decreased bleeding risk when rivaroxaban was used (in those aged <65�

Venous thromboembolic prophylaxis after simultaneous bilateral total knee arthroplasty: aspirin versus warfarin.

Science.gov (United States)

Goel, R; Fleischman, A N; Tan, T; Sterbis, E; Huang, R; Higuera, C; Parvizi, J; Rothman, R H

2018-01-01

The aims of this study were to compare the efficacy of two agents, aspirin and warfarin, for the prevention of venous thromboembolism (VTE) after simultaneous bilateral total knee arthroplasty (SBTKA), and to elucidate the risk of VTE conferred by this procedure compared with unilateral TKA (UTKA). A retrospective, multi-institutional study was conducted on 18 951 patients, 3685 who underwent SBTKA and 15 266 who underwent UTKA, using aspirin or warfarin as VTE prophylaxis. Each patient was assigned an individualised baseline VTE risk score based on a system using the Nationwide Inpatient Sample. Symptomatic VTE, including pulmonary embolism (PE) and deep vein thrombosis (DVT), were identified in the first 90 days post-operatively. Statistical analyses were performed with logistic regression accounting for baseline VTE risk. The adjusted incidence of PE following SBTKA was 1.0% (95% confidence interval (CI) 0.86 to 1.2) with aspirin and 2.2% (95% CI 2.0 to 2.4) with warfarin. Similarly, the adjusted incidence of VTE following SBTKA was 1.6% (95% CI 1.1 to 2.3) with aspirin and 2.5% (95% CI 1.9 to 3.3) with warfarin. The risk of PE and VTE were reduced by 66% (odds ratio (OR) 0.44, 95% CI 0.25 to 0.78) and 38% (OR 0.62, 95% CI 0.38 to 1.0), respectively, using aspirin. In addition, the risk of PE was 204% higher for patients undergoing SBTKA relative to those undergoing UTKA. For each ten-point increase in baseline VTE risk, the risk of PE increased by 25.5% for patients undergoing SBTKA compared with 10.5% for those undergoing UTKA. Patients with a history of myocardial infarction or peripheral vascular disease had the greatest increase in risk from undergoing SBTKA instead of UTKA. Aspirin is more effective than warfarin for the prevention of VTE following SBTKA, and serves as the more appropriate agent for VTE prophylaxis for patients in all risk categories. Furthermore, patients undergoing SBTKA are at a substantially increased risk of VTE, even more so for

Influence of fatty acids on the binding of warfarin and phenprocoumon to human serum albumin with relation to anticoagulant therapy

DEFF Research Database (Denmark)

Vorum, H; Honoré, B

1996-01-01

of palmitic, stearic, oleic or linoleic acids with energetic couplings for co-binding of one molecule of each of the fatty acids and one molecule of warfarin of 0.9, 1.1, 0.7 and 0.6 kJ mol-1, respectively. The affinity of phenprocoumon was only increased slightly on addition of palmitate with an energetic...... of warfarin but not of phenprocoumon was correlated to the increasing plasma fatty acid concentration. Anticoagulant therapy with phenprocoumon may thus be less sensitive than warfarin to changes in the fatty acid concentration of plasma. Udgivelsesdato: 1996-Aug...

Abacavir and warfarin modulate allosterically kinetics of NO dissociation from ferrous nitrosylated human serum heme-albumin

International Nuclear Information System (INIS)

Ascenzi, Paolo; Imperi, Francesco; Coletta, Massimo; Fasano, Mauro

2008-01-01

Human serum albumin (HSA) participates to heme scavenging, in turn HSA-heme binds gaseous diatomic ligands at the heme-Fe-atom. Here, the effect of abacavir and warfarin on denitrosylation kinetics of HSA-heme-Fe(II)-NO (i.e., k off ) is reported. In the absence of drugs, the value of k off is (1.3 ± 0.2) x 10 -4 s -1 . Abacavir and warfarin facilitate NO dissociation from HSA-heme-Fe(II)-NO, the k off value increases to (8.6 ± 0.9) x 10 -4 s -1 . From the dependence of k off on the drug concentration, values of the dissociation equilibrium constant for the abacavir and warfarin binding to HSA-heme-Fe(II)-NO (i.e., K = (1.2 ± 0.2) x 10 -3 M and (6.2 ± 0.7) x 10 -5 M, respectively) were determined. The increase of k off values reflects the stabilization of the basic form of HSA-heme-Fe by ligands (e.g., abacavir and warfarin) that bind to Sudlow's site I. This event parallels the stabilization of the six-coordinate derivative of the HSA-heme-Fe(II)-NO atom. Present data highlight the allosteric modulation of HSA-heme-Fe(II) reactivity by heterotropic effectors

Comparative effectiveness of rivaroxaban versus warfarin or dabigatran for the treatment of patients with non-valvular atrial fibrillation.

Science.gov (United States)

Norby, Faye L; Bengtson, Lindsay G S; Lutsey, Pamela L; Chen, Lin Y; MacLehose, Richard F; Chamberlain, Alanna M; Rapson, Ian; Alonso, Alvaro

2017-09-06

Rivaroxaban is an oral anticoagulant approved in the US for prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation (NVAF). We determined the effectiveness and associated risks of rivaroxaban versus other oral anticoagulants in a large real-world population. We selected NVAF patients initiating oral anticoagulant use in 2010-2014 enrolled in MarketScan databases. Rivaroxaban users were matched with warfarin and dabigatran users by age, sex, enrolment date, anticoagulant initiation date, and high-dimensional propensity score. Study endpoints, including ischemic stroke, intracranial bleeding (ICB), myocardial infarction (MI), and gastrointestinal (GI) bleeding, were identified from inpatient diagnostic codes. Multivariable Cox models were used to assess associations between type of anticoagulant and outcomes. The analysis included 44,340 rivaroxaban users matched to 89,400 warfarin and 16,957 dabigatran users (38% female, mean age 70) with 12 months of mean follow-up. Anticoagulant-naïve rivaroxaban initiators, but not those switching from warfarin, had lower risk of ischemic stroke [hazard ratio (HR) (95% confidence interval (CI)): 0.75 (0.62, 0.91)] and ICB [HR (95%CI): 0.55, (0.39, 0.78)] than warfarin users. In contrast, anticoagulant-experienced rivaroxaban initiators had higher risk of GI bleeding than warfarin users [HR (95%CI): 1.55 (1.32, 1.83)]. Endpoint rates were similar when comparing anticoagulant-naïve rivaroxaban and dabigatran initiators, with the exception of higher GI bleeding risk in rivaroxaban users [HR (95%CI) 1.28 (1.06, 1.54)]. There were no significant differences in the risk of MI among the comparison groups. In this large real-world sample of NVAF patients, effectiveness and risks of rivaroxaban versus warfarin differed by prior anticoagulant status, while effectiveness of rivaroxaban versus dabigatran differed in GI bleeding risk.

Elevated prothrombin time/international normalized ratio associated with concurrent administration of regorafenib and warfarin in a patient with advanced colorectal cancer.

Science.gov (United States)

Kitade, Hironori; Hiromasa-Yamasaki, Azusa; Hokkoku, Kengo; Mori, Mitsue; Watanabe, Michio; Nakai, Masuo; Yano, Seiji

2016-01-01

Regorafenib and its metabolites may inhibit the activities of several CYP or UDP-glucuronosyltransferase isoforms, including that of CYP2C9. Therefore, pharmacological agents that are CYP2C9 substrates may show elevated circulating levels and enhanced drug efficacy when concurrently used with regorafenib. Previous studies showed that the area under the plasma concentration-time curve of warfarin, which is the substrate for CYP2C9, increased upon co-administration of regorafenib. However, there are no reports indicating that the anticoagulant effects of warfarin increased upon co-administration of regorafenib. We report a case of a 76-year-old man with liver metastasis of colon cancer. He was treated with regorafenib at a dosage of 120 mg daily on days 1 to 21 every 4 weeks as a third-line therapy. He had a history of acute myocardial infarction and had taken 2 mg warfarin daily. Three weeks after the treatment began, PT/INR values markedly increased, although there was no hemorrhage. Administration of regorafenib and warfarin was discontinued, and then PT/INR rapidly decreased. Warfarin administration was restarted (0.5 mg daily) and the dose was increased up to 1.5 mg daily. The patient's PT/INR values exhibited a tendency to increase when concurrently used with regorafenib, the dose of which was reduced to 80 mg daily on days 1 to 14 every 3 weeks at a physician's discretion. The clinical course of this patient suggested that PT/INR might increase during concurrent use of warfarin and regorafenib. Therefore, PT/INR should be periodically monitored during the concurrent use of warfarin and regorafenib.

Influence of NR3C1 and VDR polymorphisms on stable warfarin dose in patients with mechanical cardiac valves.

Science.gov (United States)

Lee, Kyung Eun; Chung, Jee Eun; Yi, Boram; Cho, Yoon Jeong; Kim, Hyun Jeong; Lee, Gwan Yung; Kim, Joo Hee; Chang, Byung Chul; Gwak, Hye Sun

2017-06-01

The aim of this study was to evaluate the associations between polymorphisms of VKORC1, CYP2C9, CYP4F2, NR3C1 and VDR genes and stable warfarin doses in Korean patients with mechanical heart valves. Seventeen single-nucleotide polymorphisms (SNPs) in 204 patients with stable warfarin dose were analyzed: VKORC1 (rs9934438), CYP2C9 (rs1057910), CYP4F2 (rs2108622), NR3C1 (rs41423247, rs1800445, rs56149945, rs10052957, rs6198, rs33388, rs6196, and rs244465), and VDR (rs1544410, rs11568820, rs731236, rs757343, rs7975232, and rs2228570). Statistical analyses were conducted to evaluate the associations of gene variations with stable warfarin dose. Number needed to genotype was obtained by calculating the percentage of patients whose predicted dose was at least 20% higher or lower than the actual stable dose. The combined genotypes of rs7975232 and rs2228570 of the VDR gene revealed a significant association with stable warfarin dose, along with VKORC1, CYP2C9, and CYP4F2 polymorphisms. Patients with the genotype combination GT,TT/CT,CC of VDR rs7975232/rs2228570 required significantly higher stable warfarin dose (5.79±2.02mg) than those with the other genotypic combinations (5.19±1.78mg, p=0.034). Multivariate analysis showed that VDR rs7975232/rs2228570 explained 2.0% of the 47.5% variability in overall warfarin dose. Adding VDR SNP combinations to the base model including non-genetic variables (age, sex, and body weight) and genetic variables (VKORC1 rs9934438, CYP2C9 rs1057910, and CYP4F2 rs2108622) gave a number needed to genotype of 41. This study showed that stable warfarin dose is associated with VDR SNPs along with VKORC1, CYP2C9, and CYP4F2 SNPs. Copyright © 2017 Elsevier B.V. All rights reserved.

Consequence of patient substitution of nattokinase for warfarin after aortic valve replacement with a mechanical prosthesis

OpenAIRE

Elahi, Maqsood M.; Choi, Charles H.; Konda, Subbareddy; Shake, Jay G.

2015-01-01

This report describes a patient's self-substitution of nattokinase for the vitamin K antagonist warfarin after aortic valve replacement with a mechanical prosthesis. Nattokinase is an enzyme derived from a popular fermented soybean preparation in Japan (natto), which has fibrinolytic properties and is gaining popularity in nontraditional health journals and nonmedical health websites as an over-the-counter thrombolytic. After nearly a year of use of nattokinase without warfarin, the patient d...

Impact of Computer-Aided Warfarin Dosing in a Saudi Arabian ...

African Journals Online (AJOL)

Purpose: To compare the efficacy of computer-aided dosing using Coagclinic (a web-based software) with physician dosing in patients receiving warfarin for various cardiac indications. Methods: In order to calculate the effectiveness of physician managed anticoagulation dosing, we calculated the “percentage of time ...

Poor anticoagulation control in patients taking warfarin at a tertiary and districtlevel prothrombin clinic in Cape Town South Africa

Directory of Open Access Journals (Sweden)

I Ebrahim

2018-05-01

Full Text Available Background. Warfarin is the most commonly used anticoagulant for both primary and secondary prevention of thromboembolism. For anticoagulation efficacy, the international normalised ratio (INR needs to be within the therapeutic range for at least 65% of time on warfarin.Objectives. To describe INR control in patients on long-term warfarin and identified predictors of good INR control at two dedicated warfarin follow-up clinics in Cape Town, South Africa (SA.Methods. We reviewed clinical records of patients in care at the INR clinics at Mitchell’s Plain Community Health Centre and Groote Schuur Hospital. We included patients who had been on warfarin therapy for at least 27 months and excluded patients with <6 months of INR monitoring data or a >70-day gap between INR tests in the calculation period, and if >25% of follow-up time was at an alternative site. The time in therapeutic range (TTR over 180 days using the Rosendaal method was calculated, and we categorised INR control as good if the TTR was ≥65%. We constructed a multivariate logistic regression model to identify associations with good INR control.Results. We included 363 patients, with a median age of 55 years (interquartile range (IQR 44 - 64, of whom 65.6% were women. The most common indications for warfarin were valvular heart disease (45.7% and atrial fibrillation (25.1%. The mean TTR was 47%, with only 91/363 patients having good INR control. In a multivariate model adjusted for age, sex, clinic and target INR, patients aged ≥55 years were more likely to have good INR control than younger patients (adjusted odds ratio 1.69, 95% confidence interval 1.03 - 2.79. Poorly controlled patients had more frequent INR monitoring than those with good INR control, with a median of 8 INRs (IQR 6 - 10 v. 6 INRs (IQR 5 - 8 in the 180-day period (p<0.0001.Conclusions. Only 25.1% of patients in our study achieved good INR control, despite regular INR monitoring. There is an

Methodological challenges in assessment of current use of warfarin among patients with atrial fibrillation using dispensation data from administrative health care databases.

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Sinyavskaya, Liliya; Matteau, Alexis; Johnson, Sarasa; Durand, Madeleine

2018-06-05

Algorithms to define current exposure to warfarin using administrative data may be imprecise. Study objectives were to characterize dispensation patterns, to measure gaps between expected and observed refill dates for warfarin and direct oral anticoagulants (DOACs). Retrospective cohort study using administrative health care databases of the Régie de l'assurance-maladie du Québec. We identified every dispensation of warfarin, dabigatran, rivaroxaban, or apixaban for patients with AF initiating oral anticoagulants between 2010 and 2015. For each dispensation, we extracted date and duration. Refill gaps were calculated as difference between expected and observed dates of successive dispensation. Refill gaps were summarized using descriptive statistics. To account for repeated observations nested within patients and to assess the components of variance of refill gaps, we used unconditional multilevel linear models. We identified 61 516 new users. Majority were prescribed warfarin (60.3%), followed by rivaroxaban (16.4%), dabigatran (14.5%), apixaban (8.8%). Most frequent recorded duration of dispensation was 7 days, suggesting use of pharmacist-prepared weekly pillboxes. The average refill gap from multilevel model was higher for warfarin (9.28 days, 95%CI:8.97-9.59) compared with DOACs (apixaban 3.08 days, 95%CI: 2.96-3.20, dabigatran 3.70, 95%CI: 3.56-3.84, rivaroxaban 3.15, 95%CI: 3.03-3.27). The variance of refill gaps was greater among warfarin users than among DOAC users. Greater refill gaps for warfarin may reflect inadequate capture of the period covered by the number of dispensed pills recorded in administrative data. A time-dependent definition of exposure using dispensation data would lead to greater misclassification of warfarin than DOACs use. Copyright © 2018 John Wiley & Sons, Ltd.

One-year adherence to warfarin treatment for venous thromboembolism in high-risk patients and its association with long-term risk of recurrent events.

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Chen, Shih-Yin; Wu, Ning; Gulseth, Michael; LaMori, Joyce; Bookhart, Brahim K; Boulanger, Luke; Fields, Larry; Schein, Jeff

2013-05-01

Warfarin is the predominant oral anticoagulant used for the prevention of recurrent venous thromboembolism (VTE) events. However, its long-term use is complicated by the need to manage the drug within a narrow therapeutic range and by possible food and drug interactions. To examine the association between 1-year adherence, measured through compliance with and persistence on warfarin treatment for VTE, and long-term risk of recurrent events among patients at high risk. Medical and pharmacy claims for patients with commercial or Medicare supplemental insurance in the Thomson Reuters MarketScan database were analyzed. Adult patients with medical claims with an associated VTE diagnosis between January 1, 2006, and March 31, 2008, were identified. The index date was defined as the date of the first observed VTE claim or the date of discharge if the index event was a hospital stay. High-risk patients (patients with cancer, or noncancer patients who did not have reversible risk factors during the 3-month period prior to the index date) who filled a warfarin prescription within 2 weeks of the index date were included. Persistence was evaluated in terms of discontinuation, defined as a 90-day gap in warfarin supply during a 1-year assessment period following the index date. Compliance was measured by the proportion of days covered (PDC) over the 1-year assessment period, with PDC less than 0.8 defined as noncompliance. Recurrent VTE events were identified as hospitalizations where VTE was the primary diagnosis after the 1-year assessment period and until patients were lost to follow-up. The association between adherence to warfarin therapy and VTE recurrence was evaluated descriptively via Kaplan-Meier curves and a Cox proportional hazards model, adjusted for patient demographic and clinical characteristics. A similar analysis using the medication possession ratio (MPR) as a measure of compliance was also performed in a subset of patients who had filled at least 2 warfarin

Resource consumption and management associated with monitoring of warfarin treatment in primary health care in Sweden

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Nilsson Gunnar H

2006-11-01

Full Text Available Abstract Background Warfarin is used for the prevention and treatment of various thromboembolic complications. It is an efficacious anticoagulant, but it has a narrow therapeutic range, and regular monitoring is required to ensure therapeutic efficacy and at the same time avoid life-threatening adverse events. The objective was to assess management and resource consumption associated with patient monitoring episodes during warfarin treatment in primary health care in Sweden. Methods Delphi technique was used to systematically explore attitudes, demands and priorities, and to collect informed judgements related to monitoring of warfarin treatment. Two separate Delphi-panels were performed in three and two rounds, respectively, one concerning tests taken in primary health care centres, involving 34 GPs and 10 registered nurses, and one concerning tests taken in patients' homes, involving 49 district nurses. Results In the primary health care panel 10 of the 34 GPs regularly collaborated with a registered nurse. Average time for one monitoring episode was estimated to 10.1 minutes for a GP and 21.4 minutes for a nurse, when a nurse assisted a doctor. The average time for monitoring was 17.6 minutes for a GP when not assisted by a nurse. Considering all the monitoring episodes, 11.6% of patient blood samples were taken in the individual patient's home. Average time for such a monitoring episode was estimated to 88.2 minutes. Of all the visits, 8.2% were performed in vain and took on average 44.6 minutes. In both studies, approximately 20 different elements of work concerning management of patients during warfarin treatment were identified. Conclusion Monitoring of patients during treatment with warfarin in primary health care in Sweden involves many elements of work, and demands large resources, especially when tests are taken in the patient's home.

Evaluation of SAMe-TT2R2 Score on Predicting Success With Extended-Interval Warfarin Monitoring.

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Hwang, Andrew Y; Carris, Nicholas W; Dietrich, Eric A; Gums, John G; Smith, Steven M

2018-06-01

In patients with stable international normalized ratios, 12-week extended-interval warfarin monitoring can be considered; however, predictors of success with this strategy are unknown. The previously validated SAMe-TT 2 R 2 score (considering sex, age, medical history, treatment, tobacco, and race) predicts anticoagulation control during standard follow-up (every 4 weeks), with lower scores associated with greater time in therapeutic range. To evaluate the ability of the SAMe-TT 2 R 2 score in predicting success with extended-interval warfarin follow-up in patients with previously stable warfarin doses. In this post hoc analysis of a single-arm feasibility study, baseline SAMe-TT 2 R 2 scores were calculated for patients with ≥1 extended-interval follow-up visit. The primary analysis assessed achieved weeks of extended-interval follow-up according to baseline SAMe-TT 2 R 2 scores. A total of 47 patients receiving chronic anticoagulation completed a median of 36 weeks of extended-interval follow-up. The median baseline SAMe-TT 2 R 2 score was 1 (range 0-5). Lower SAMe-TT 2 R 2 scores appeared to be associated with greater duration of extended-interval follow-up achieved, though the differences between scores were not statistically significant. No individual variable of the SAMe-TT 2 R 2 score was associated with achieved weeks of extended-interval follow-up. Analysis of additional patient factors found that longer duration (≥24 weeks) of prior stable treatment was significantly associated with greater weeks of extended-interval follow-up completed ( P = 0.04). Conclusion and Relevance: This pilot study provides limited evidence that the SAMe-TT 2 R 2 score predicts success with extended-interval warfarin follow-up but requires confirmation in a larger study. Further research is also necessary to establish additional predictors of successful extended-interval warfarin follow-up.

Computational investigation of potential dosing schedules for a switch of medication from warfarin to rivaroxaban-an oral, direct Factor Xa inhibitor.

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Burghaus, Rolf; Coboeken, Katrin; Gaub, Thomas; Niederalt, Christoph; Sensse, Anke; Siegmund, Hans-Ulrich; Weiss, Wolfgang; Mueck, Wolfgang; Tanigawa, Takahiko; Lippert, Jörg

2014-01-01

The long-lasting anticoagulant effect of vitamin K antagonists can be problematic in cases of adverse drug reactions or when patients are switched to another anticoagulant therapy. The objective of this study was to examine in silico the anticoagulant effect of rivaroxaban, an oral, direct Factor Xa inhibitor, combined with the residual effect of discontinued warfarin. Our simulations were based on the recommended anticoagulant dosing regimen for stroke prevention in patients with atrial fibrillation. The effects of the combination of discontinued warfarin plus rivaroxaban were simulated using an extended version of a previously validated blood coagulation computer model. A strong synergistic effect of the two distinct mechanisms of action was observed in the first 2-3 days after warfarin discontinuation; thereafter, the effect was close to additive. Nomograms for the introduction of rivaroxaban therapy after warfarin discontinuation were derived for Caucasian and Japanese patients using safety and efficacy criteria described previously, together with the coagulation model. The findings of our study provide a mechanistic pharmacologic rationale for dosing schedules during the therapy switch from warfarin to rivaroxaban and support the switching strategies as outlined in the Summary of Product Characteristics and Prescribing Information for rivaroxaban.

Computational investigation of potential dosing schedules for a switch of medication from warfarin to rivaroxaban—an oral, direct Factor Xa inhibitor

Science.gov (United States)

Burghaus, Rolf; Coboeken, Katrin; Gaub, Thomas; Niederalt, Christoph; Sensse, Anke; Siegmund, Hans-Ulrich; Weiss, Wolfgang; Mueck, Wolfgang; Tanigawa, Takahiko; Lippert, Jörg

2014-01-01

The long-lasting anticoagulant effect of vitamin K antagonists can be problematic in cases of adverse drug reactions or when patients are switched to another anticoagulant therapy. The objective of this study was to examine in silico the anticoagulant effect of rivaroxaban, an oral, direct Factor Xa inhibitor, combined with the residual effect of discontinued warfarin. Our simulations were based on the recommended anticoagulant dosing regimen for stroke prevention in patients with atrial fibrillation. The effects of the combination of discontinued warfarin plus rivaroxaban were simulated using an extended version of a previously validated blood coagulation computer model. A strong synergistic effect of the two distinct mechanisms of action was observed in the first 2–3 days after warfarin discontinuation; thereafter, the effect was close to additive. Nomograms for the introduction of rivaroxaban therapy after warfarin discontinuation were derived for Caucasian and Japanese patients using safety and efficacy criteria described previously, together with the coagulation model. The findings of our study provide a mechanistic pharmacologic rationale for dosing schedules during the therapy switch from warfarin to rivaroxaban and support the switching strategies as outlined in the Summary of Product Characteristics and Prescribing Information for rivaroxaban. PMID:25426077

Influence of warfarin and low-dose aspirin on the outcomes of geriatric patients with traumatic intracranial hemorrhage resulting from ground-level fall.

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Inamasu, Joji; Nakatsukasa, Masashi; Miyatake, Satoru; Hirose, Yuichi

2012-10-01

Ground-level fall is the most common cause of traumatic intracranial hemorrhage (TICH) in the elderly, and is a major cause of morbidity and mortality in that population. A retrospective study was carried out to evaluate whether the use of warfarin/low-dose aspirin (LDA) is predictive of unfavorable outcomes in geriatric patients who sustain a fall-induced TICH. Charts of 76 geriatric patients (≥ 65 years-of-age) with fall-induced TICH were reviewed. The number of patients taking warfarin and LDA was 12 and 21, respectively, whereas the other 43 took neither medication (non-user group). The frequency of patients with unfavorable outcomes (Glasgow Outcome Scale score of 1-3) at discharge was calculated. Furthermore, variables predictive of unfavorable outcomes were identified by logistic regression analysis. The frequency of patients with unfavorable outcomes was 75% in the warfarin group, 33% in the LDA group and 27% in the non-user group, respectively. The risk of having unfavorable outcomes was significantly higher in the warfarin group compared with the LDA group (P = 0.03) and non-user group (P fall-induced TICH. The risk of TICH should be communicated properly to elderly taking warfarin. The information might be important not only to trauma surgeons who take care of injured elderly, but also to geriatric physicians who prescribe warfarin/LDA to them. © 2012 Japan Geriatrics Society.

Influence of Genotype on Warfarin Maintenance Dose Predictions Produced Using a Bayesian Dose Individualization Tool.

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Saffian, Shamin M; Duffull, Stephen B; Roberts, Rebecca L; Tait, Robert C; Black, Leanne; Lund, Kirstin A; Thomson, Alison H; Wright, Daniel F B

2016-12-01

A previously established Bayesian dosing tool for warfarin was found to produce biased maintenance dose predictions. In this study, we aimed (1) to determine whether the biased warfarin dose predictions previously observed could be replicated in a new cohort of patients from 2 different clinical settings, (2) to explore the influence of CYP2C9 and VKORC1 genotype on predictive performance of the Bayesian dosing tool, and (3) to determine whether the previous population used to develop the kinetic-pharmacodynamic model underpinning the Bayesian dosing tool was sufficiently different from the test (posterior) population to account for the biased dose predictions. The warfarin maintenance doses for 140 patients were predicted using the dosing tool and compared with the observed maintenance dose. The impact of genotype was assessed by predicting maintenance doses with prior parameter values known to be altered by genetic variability (eg, EC50 for VKORC1 genotype). The prior population was evaluated by fitting the published kinetic-pharmacodynamic model, which underpins the Bayesian tool, to the observed data using NONMEM and comparing the model parameter estimates with published values. The Bayesian tool produced positively biased dose predictions in the new cohort of patients (mean prediction error [95% confidence interval]; 0.32 mg/d [0.14-0.5]). The bias was only observed in patients requiring ≥7 mg/d. The direction and magnitude of the observed bias was not influenced by genotype. The prior model provided a good fit to our data, which suggests that the bias was not caused by different prior and posterior populations. Maintenance doses for patients requiring ≥7 mg/d were overpredicted. The bias was not due to the influence of genotype nor was it related to differences between the prior and posterior populations. There is a need for a more mechanistic model that captures warfarin dose-response relationship at higher warfarin doses.

Effect of Genotype-Guided Warfarin Dosing on Clinical Events and Anticoagulation Control Among Patients Undergoing Hip or Knee Arthroplasty: The GIFT Randomized Clinical Trial.

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Gage, Brian F; Bass, Anne R; Lin, Hannah; Woller, Scott C; Stevens, Scott M; Al-Hammadi, Noor; Li, Juan; Rodríguez, Tomás; Miller, J Philip; McMillin, Gwendolyn A; Pendleton, Robert C; Jaffer, Amir K; King, Cristi R; Whipple, Brandi DeVore; Porche-Sorbet, Rhonda; Napoli, Lynnae; Merritt, Kerri; Thompson, Anna M; Hyun, Gina; Anderson, Jeffrey L; Hollomon, Wesley; Barrack, Robert L; Nunley, Ryan M; Moskowitz, Gerard; Dávila-Román, Victor; Eby, Charles S

2017-09-26

Warfarin use accounts for more medication-related emergency department visits among older patients than any other drug. Whether genotype-guided warfarin dosing can prevent these adverse events is unknown. To determine whether genotype-guided dosing improves the safety of warfarin initiation. The randomized clinical Genetic Informatics Trial (GIFT) of Warfarin to Prevent Deep Vein Thrombosis included patients aged 65 years or older initiating warfarin for elective hip or knee arthroplasty and was conducted at 6 US medical centers. Enrollment began in April 2011 and follow-up concluded in October 2016. Patients were genotyped for the following polymorphisms: VKORC1-1639G>A, CYP2C9*2, CYP2C9*3, and CYP4F2 V433M. In a 2 × 2 factorial design, patients were randomized to genotype-guided (n = 831) or clinically guided (n = 819) warfarin dosing on days 1 through 11 of therapy and to a target international normalized ratio (INR) of either 1.8 or 2.5. The recommended doses of warfarin were open label, but the patients and clinicians were blinded to study group assignment. The primary end point was the composite of major bleeding, INR of 4 or greater, venous thromboembolism, or death. Patients underwent a screening lower-extremity duplex ultrasound approximately 1 month after arthroplasty. Among 1650 randomized patients (mean age, 72.1 years [SD, 5.4 years]; 63.6% women; 91.0% white), 1597 (96.8%) received at least 1 dose of warfarin therapy and completed the trial (n = 808 in genotype-guided group vs n = 789 in clinically guided group). A total of 87 patients (10.8%) in the genotype-guided group vs 116 patients (14.7%) in the clinically guided warfarin dosing group met at least 1 of the end points (absolute difference, 3.9% [95% CI, 0.7%-7.2%], P = .02; relative rate [RR], 0.73 [95% CI, 0.56-0.95]). The numbers of individual events in the genotype-guided group vs the clinically guided group were 2 vs 8 for major bleeding (RR, 0.24; 95% CI, 0

A Novel Admixture-Based Pharmacogenetic Approach to Refine Warfarin Dosing in Caribbean Hispanics

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Claudio-Campos, Karla; Rivera-Miranda, Giselle; Bermúdez-Bosch, Luis; Renta, Jessicca Y.; Cadilla, Carmen L.; Cruz, Iadelisse; Feliu, Juan F.; Vergara, Cunegundo; Ruaño, Gualberto

2016-01-01

Aim This study is aimed at developing a novel admixture-adjusted pharmacogenomic approach to individually refine warfarin dosing in Caribbean Hispanic patients. Patients & Methods A multiple linear regression analysis of effective warfarin doses versus relevant genotypes, admixture, clinical and demographic factors was performed in 255 patients and further validated externally in another cohort of 55 individuals. Results The admixture-adjusted, genotype-guided warfarin dosing refinement algorithm developed in Caribbean Hispanics showed better predictability (R2 = 0.70, MAE = 0.72mg/day) than a clinical algorithm that excluded genotypes and admixture (R2 = 0.60, MAE = 0.99mg/day), and outperformed two prior pharmacogenetic algorithms in predicting effective dose in this population. For patients at the highest risk of adverse events, 45.5% of the dose predictions using the developed pharmacogenetic model resulted in ideal dose as compared with only 29% when using the clinical non-genetic algorithm (pwarfarin dose variance when externally validated in 55 individuals from an independent validation cohort (MAE = 0.89 mg/day, 24% mean bias). Conclusions Results supported our rationale to incorporate individual’s genotypes and unique admixture metrics into pharmacogenetic refinement models in order to increase predictability when expanding them to admixed populations like Caribbean Hispanics. Trial Registration ClinicalTrials.gov NCT01318057 PMID:26745506

A new warfarin dosing algorithm including VKORC1 3730 G > A polymorphism: comparison with results obtained by other published algorithms.

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Cini, Michela; Legnani, Cristina; Cosmi, Benilde; Guazzaloca, Giuliana; Valdrè, Lelia; Frascaro, Mirella; Palareti, Gualtiero

2012-08-01

Warfarin dosing is affected by clinical and genetic variants, but the contribution of the genotype associated with warfarin resistance in pharmacogenetic algorithms has not been well assessed yet. We developed a new dosing algorithm including polymorphisms associated both with warfarin sensitivity and resistance in the Italian population, and its performance was compared with those of eight previously published algorithms. Clinical and genetic data (CYP2C9*2, CYP2C9*3, VKORC1 -1639 G > A, and VKORC1 3730 G > A) were used to elaborate the new algorithm. Derivation and validation groups comprised 55 (58.2% men, mean age 69 years) and 40 (57.5% men, mean age 70 years) patients, respectively, who were on stable anticoagulation therapy for at least 3 months with different oral anticoagulation therapy (OAT) indications. Performance of the new algorithm, evaluated with mean absolute error (MAE) defined as the absolute value of the difference between observed daily maintenance dose and predicted daily dose, correlation with the observed dose and R(2) value, was comparable with or slightly lower than that obtained using the other algorithms. The new algorithm could correctly assign 53.3%, 50.0%, and 57.1% of patients to the low (≤25 mg/week), intermediate (26-44 mg/week) and high (≥ 45 mg/week) dosing range, respectively. Our data showed a significant increase in predictive accuracy among patients requiring high warfarin dose compared with the other algorithms (ranging from 0% to 28.6%). The algorithm including VKORC1 3730 G > A, associated with warfarin resistance, allowed a more accurate identification of resistant patients who require higher warfarin dosage.

Prospective randomized evaluation of the watchman left atrial appendage closure device in patients with atrial fibrillation versus long-term warfarin therapy: The PREVAIL trial.

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Belgaid, Djouhar Roufeida; Khan, Zara; Zaidi, Mariam; Hobbs, Adrian

2016-09-15

Assessing the safety and effectiveness of left atrial appendage (LAA) (pouch found in the upper chambers of the heart) occlusion, using the Watchman device compared to long term warfarin therapy (drug that reduces clot formation), in preventing the risk of stroke in patients with atrial fibrillation (most common type of irregular heart beat). 90% of strokes in atrial fibrillation arise from clots forming in this pouch. By mechanically blocking it using the device less clots are suggested to be formed. This is an alternative to taking warfarin especially in patients who cannot take it. 50 sites in the United States enrolled 407 participants. After being randomly allocated, the device group had 269 participants and warfarin group (comparator)had 138 participants. Patients with atrial fibrillation and at high risk of stroke were randomly allocated a group after they were deemed eligible. Patients in the device group had to take warfarin and aspirin for 45days till the complete closure of the LAA. The oral anticoagulant was followed by dual antiplatelet therapy until 6months and then ASA. Patients in the warfarin group have to take it for life and were continually monitored. The study ran for 26months. The trial assessed the rate of adverse events using three endpoints: The PREVAIL trial was not designed to show superiority, but non-inferiority. It met the safety endpoint and one efficacy endpoint for the watchman device compared to long term warfarin for overall efficacy of the device. The results established that LAA occlusion is not worse than warfarin intake for the prevention of stroke more than 1week after randomization. Compared to previous trials, the safety of the device has also improved. LAA occlusion is a reasonable alternative to chronic warfarin therapy in stroke prevention for patients with atrial fibrillation. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Effect of vitamin K2 on the anticoagulant activity of warfarin during the perioperative period of catheter ablation: Population analysis of retrospective clinical data.

Science.gov (United States)

Zhou, Zhi; Yano, Ikuko; Odaka, Sumiko; Morita, Yosuke; Shizuta, Satoshi; Hayano, Mamoru; Kimura, Takeshi; Akaike, Akinori; Inui, Ken-Ichi; Matsubara, Kazuo

2016-01-01

Catheter ablation is a non-medication therapy for atrial fibrillation, and during the procedure, warfarin is withdrawn in the preoperative period to prevent the risk of bleeding. In case of emergency, vitamin K2 can be intravenously administered to antagonize the anticoagulant activity of warfarin. The aims of this study were to conduct population pharmacokinetic/pharmacodynamic modeling for retrospective clinical data and to investigate the effect of vitamin K2 on the anticoagulant activity of warfarin in the perioperative period of catheter ablation. A total of 579 international normalized ratio (INR) values of prothrombin time from 100 patients were analyzed using the nonlinear mixed-effects modeling program NONMEM. A 1-compartment model was adapted to the pharmacokinetics of warfarin and vitamin K2, and the indirect response model was used to investigate the relationship between plasma concentration and the pharmacodynamic response of warfarin and vitamin K2. Since no plasma concentration data for warfarin and vitamin K2 were available, 3 literally available pharmacokinetic parameters were used to simultaneously estimate 1 pharmacokinetic parameter and 5 pharmacodynamic parameters. The population parameters obtained not only successfully explained the observed INR values, but also indicated an increase in sensitivity to warfarin in patients with reduced renal function. Simulations using these parameters indicated that vitamin K2 administration of more than 20 mg caused a slight dose-dependent decrease in INR on the day of catheter ablation and a delayed INR elevation after warfarin re-initiation. A pharmacokinetic/pharmacodynamic model was successfully built to explain the retrospective INR data during catheter ablation. Simulation studies suggest that vitamin K2 should be administered with care and that more than 20 mg is unnecessary in the preoperative period of catheter ablation.

Warfarin for venous thromboembolism prophylaxis after elective hip or knee arthroplasty: exploring the evidence, guidelines, and challenges remaining.

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Dager, William E

2012-01-01

Guidelines for the prevention of venous thromboembolism (VTE) after elective total hip or knee arthroplasty (THA/TKA) have been developed separately by the American Academy of Orthopaedic Surgeons (AAOS) and the American College of Chest Physicians (ACCP). Differences exist in approaches to preventing postoperative VTE through prophylaxis. To compare trials using vitamin K antagonists (VKAs) and differences in guidelines to determine the benefits and drawbacks of warfarin for VTE prophylaxis following THA/TKA. Guidelines from the AAOS published in 2009 and revised in 2011 and from the ACCP published in 2008 were compared for recommendations on the use of VKAs. A MEDLINE search from 1960 to November 2009 was conducted to identify pertinent articles on the use of warfarin or VKAs for VTE prophylaxis following THA/TKA. Search terms included warfarin, vitamin K antagonist, total hip or total knee replacement, and total hip or total knee arthroplasty. Only clinical trials in which warfarin was the primary agent for prophylaxis compared to other anticoagulants were included. Data on differences between guideline recommendations for the use of VKAs and the importance of a deep vein thrombosis or asymptomatic events were extracted. Thirteen comparative trials using VKAs for VTE prophylaxis and international normalized ratio (INR) targets were assessed. Overall, the incidence of bleeding tended to be lower with the use of VKAs, but thrombosis when including asymptomatic events was numerically higher when comparing INR targets. However, INR targets varied, with no comparative trials assessing the AAOS 2009 recommended INR target of 1.5-2.0. The AAOS guidelines initially recommended a longer duration of therapy and expressed stronger support for the use of aspirin for prophylaxis; however, in 2011, its guidelines were revised, with no specific recommendations as to agent, dose, or INR target goal. Warfarin is an effective agent to prevent VTE after elective THA/TKA. The most

Extensive small bowel intramural haematoma secondary to warfarin

OpenAIRE

Limmer, Alexandra M.; Clement, Zackariah

2017-01-01

Abstract Intramural haematoma is a rare complication of oral anticoagulant therapy, occurring in? 1 in 2500 patients treated with warfarin. This report describes a 71-year-old gentleman who presented with tachycardia, vomiting and abdominal distension on a background of anticoagulation for a metallic aortic valve. He was found to have a supratherapeutic international normalized ratio (INR) of 9.9 with an extensive small bowel intramural haematoma and secondary small bowel obstruction. He was ...

Natural history of bleeding and characteristics of early bleeders among warfarin initiators – a cohort study in Finland

Directory of Open Access Journals (Sweden)

Rikala M

2016-02-01

Full Text Available Maria Rikala,1 Helena Kastarinen,1,2 Pekka Tiittanen,1 Risto Huupponen,1,3 Maarit Jaana Korhonen1,4,5 1Department of Pharmacology, Drug Development and Therapeutics, University of Turku, Turku, 2Social Insurance Institution, Regional Office for Eastern and Northern Finland, Kuopio, 3Unit of Clinical Pharmacology, Turku University Hospital, 4Department of Public Health, University of Turku, Turku, Finland; 5Division of Pharmaceutical Outcomes and Policy, UNC Eshelman School of Pharmacy, The University of North Carolina at Chapel Hill, NC, USA Aims: The demand for oral anticoagulant therapy will continue to increase in the future along with the aging of the population. This study aimed to determine the rate of bleeding requiring hospitalization and to characterize early bleeders among persons initiating warfarin therapy. Characterization of those most susceptible to early bleeding is important in order to increase the safety of warfarin initiation. Patients and methods: Using data from nationwide health registers, we identified persons initiating warfarin therapy between January 1, 2009 and June 30, 2012, n=101,588, and followed them until hospitalization for bleeding, death, or administrative end of the study (December 31, 2012. We defined early bleeders as persons with a bleeding requiring hospitalization within 30 days since warfarin initiation. Results: The rate of hospitalization for bleeding during a median follow-up of 1.9 years was 2.6% per person-year (95% confidence interval [CI] 2.5%–2.7%, with a peak within the first 30 days of warfarin initiation (6.5% per person-year, 95% CI 6.0%–7.1%. In a multivariable Cox proportional hazards regression analysis, early bleeders were characterized by prior bleeding (<180 days before initiation, hazard ratio [HR] =13.7, 95% CI 10.9–17.1; during 180 days–7 years before initiation, HR =1.48, 95% CI 1.15–1.90, male sex (HR =1.32, 95% CI 1.10–1.57, older age (HR =1.13, 95% CI 1.04–1

Bleeding risk of apixaban, dabigatran, and low-dose rivaroxaban compared with warfarin in Japanese patients with non-valvular atrial fibrillation: a propensity matched analysis of administrative claims data.

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Kohsaka, Shun; Murata, Tatsunori; Izumi, Naoko; Katada, Jun; Wang, Feng; Terayama, Yasuo

2017-11-01

There is scarce evidence comparing novel oral anticoagulants (NOACs) with warfarin in real-world settings in Japan. This study compared the risk of bleeding events among patients with non-valvular atrial fibrillation (NVAF) initiating treatment with NOACs versus warfarin. A retrospective cohort study was conducted using a de-identified electronic health record based database of health claims and Diagnosis Procedure Combination data from 275 consenting hospitals in Japan. NVAF patients newly initiated on oral anticoagulants were eligible. Based on the first prescription, patients were assigned to 5/2.5 mg BID apixaban, 150/110 mg BID dabigatran, 15/10 mg QD rivaroxaban (approved dose lower in Japan compared to Western countries [20/15 mg QD]) or warfarin groups. One-to-one propensity score matching (PSM) was used to balance patient characteristics between warfarin and each NOAC. Patients were followed up to 1 year post-first prescription. Among 38,662 eligible patients, a total of 5977, 5090, and 6726 matched pairs were identified for warfarin versus apixaban, warfarin versus dabigatran, and warfarin versus rivaroxaban, respectively after PSM. Compared to warfarin, apixaban (hazard ratio [HR] 0.586; 95% CI 0.421-0.815), dabigatran (HR 0.617; 0.425-0.895) and rivaroxaban (HR 0.693; 0.514-0.933) were associated with a significantly lower risk of major bleeding. The risk of any bleeding was significantly lower for apixaban (HR 0.782; 0.682-0.896), but not for dabigatran (HR 0.988; 0.860-1.135) or rivaroxaban (HR 0.938; 0.832-1.057) when comparing to warfarin. Among Japanese patients with NVAF, treatment with apixaban 5/2.5 mg BID was associated with a significantly lower risk of major bleeding and any bleeding when compared to warfarin. Treatment with dabigatran 150/110 mg BID or rivaroxaban 15/10 mg QD was associated with a significantly lower risk of major bleeding, but not any bleeding, than warfarin. The potential benefit of individual NOACs in real

A cellular system for quantitation of vitamin K cycle activity: structure-activity effects on vitamin K antagonism by warfarin metabolites

Science.gov (United States)

Haque, Jamil A.; McDonald, Matthew G.; Kulman, John D.

2014-01-01

Warfarin and other 4-hydroxycoumarins inhibit vitamin K epoxide reductase (VKOR) by depleting reduced vitamin K that is required for posttranslational modification of vitamin K–dependent clotting factors. In vitro prediction of the in vivo potency of vitamin K antagonists is complicated by the complex multicomponent nature of the vitamin K cycle. Here we describe a sensitive assay that enables quantitative analysis of γ-glutamyl carboxylation and its antagonism in live cells. We engineered a human embryonic kidney (HEK) 293–derived cell line (HEK 293-C3) to express a chimeric protein (F9CH) comprising the Gla domain of factor IX fused to the transmembrane and cytoplasmic regions of proline-rich Gla protein 2. Maximal γ-glutamyl carboxylation of F9CH required vitamin K supplementation, and was dose-dependently inhibited by racemic warfarin at a physiologically relevant concentration. Cellular γ-glutamyl carboxylation also exhibited differential VKOR inhibition by warfarin enantiomers (S > R) consistent with their in vivo potencies. We further analyzed the structure-activity relationship for inhibition of γ-glutamyl carboxylation by warfarin metabolites, observing tolerance to phenolic substitution at the C-5 and especially C-6, but not C-7 or C-8, positions on the 4-hydroxycoumarin nucleus. After correction for in vivo concentration and protein binding, 10-hydroxywarfarin and warfarin alcohols were predicted to be the most potent inhibitory metabolites in vivo. PMID:24297869

The Clinical Pharmacokinetics and Pharmacodynamics of Warfarin When Combined with Compound Danshen: A Case Study for Combined Treatment of Coronary Heart Diseases with Atrial Fibrillation

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Chunxiao Lv

2017-11-01

Full Text Available Warfarin is used as anticoagulant and Compound Danshen prescription (CDP is able to promote blood circulation. The combination might produce a synergic effect for patients of coronary heart diseases (CHDs with atrial fibrillation (AF. Whether the combination increases the bleeding risk of warfarin is unclear, so the effects of Compound Danshen dripping pill (CDDP on the pharmacokinetics (PK and pharmacodynamics (PD profiles of warfarin was investigated in patients. The dose and blood concentrations of warfarin, the four indicators of blood coagulation, prothrombin time, activated partial thromboplatin time, thrombin time, fibrinogen, and international normalized ratio value were compared when with and without CDDP treatment. The population PK (PPK and PPK-PD models were established to assess patient demographics, genetic polymorphisms and CDDP as covariates. And the Seattle Angina Questionnaire was used to evaluate clinical efficacy, and the bleeding risk of combination was analyzed. The results indicated that CDDP had little influence on PK and PD profiles of warfarin in most patients and the combination of CCDP and warfarin would be a promising alternative regime for CHD with AF patients. The study was registered on China Clinical Trial Registry with number ChiCTR-ONRC-13003523.

Design and rationale for the WARFA trial: a randomized controlled cross-over trial testing the therapeutic equivalence of branded and generic warfarin in atrial fibrillation patients in Brazil.

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Freitas, Carolina Gomes; Walsh, Michael; Atallah, Álvaro Nagib

2017-06-07

Warfarin is a commonly used anticoagulant. Whether a given dose of the different formulations of Brazilian warfarin will result in the same effect on the international normalized ratio (INR) is uncertain. The aim of the WARFA trial is to determine whether the branded and two generic warfarins available in Brazil differ in their effect on the INR. WARFA is a cross-over RCT comparing three warfarins. The formulations tested are the branded Marevan® (Uniao Quimica/Farmoquimica) and two generic warfarin (manufactured respectively by Uniao Quimica Farmaceutica Nacional and Laboratorio Teuto Brasileiro). All of them were manufactured in Brazil, are available in all settings of the Brazilian healthcare system and were purchased from retail drugstores. Eligible participants had atrial fibrillation or flutter, had been using warfarin for at least 2 months with a therapeutic range of 2.0-3.0 and had low variability in INR results during the 1st period of the trial. Our primary outcome, for which we have an equality hypothesis, is the difference between warfarins in the mean absolute difference between two INR results, obtained after three and 4 weeks with each drug. Our secondary outcomes, that will be tested for inequality (except for the mean INR, which will be tested for equality), include the difference in the warfarin dose, and time in therapeutic range. Clinical events and adherence were also recorded and will be reported. To our knowledge, WARFA will be the first comparison of the more readily applicable INR results between branded and generic warfarins in Brazil. WARFA is important because warfarins are commonly switched between in the course of a chronic treatment in Brazil. Final results of WARFA are expected in May 2017. ClinicalTrials.gov NCT02017197 . Registered 11 December 2013.

Monotherapy of aspirin or warfarin for prevention of ischemic stroke in low-risk atrial fibrillation: A Easter Asian population-based study.

Science.gov (United States)

Liu, Chieh-Yu; Chen, Hui-Chun

2018-05-02

This study aimed to investigate the effectiveness of monotherapy aspirin and warfarin for stroke prevention in low-risk atrial fibrillation (AF) by using a population-based cohort study in Taiwan. A newly diagnosed low-risk AF patient cohort were identified by using National Health Insurance Research Database (NHIRD) in Taiwan in 2008. The study cohort was observed with a follow-up of 2 years to examine the onset of ischemic stroke (IS) (to 2010). The longitudinal data were analyzed by using generalized estimation equations (GEE). A total of 8,065 newly-diagnosed low-risk AF patients were identified in 2008. 7.4% were prescribed with aspirin and 4.6% were prescribed with warfarin. The GEE results showed that low-risk AF patients with hypertension who received warfarin were associated with a statistically significant 58.4% reduction of IS risk (OR = 0.416, p = 0.024, 95% CI 0.194-0.891). Additionally, low-risk AF patients with hyperlipidemia who received warfarin were associated with a 69.3% reduction of IS risk (OR = 0.307, p = 0.044, 95% CI 0.097-0.969). Warfarin is suggested to be prescribed in preventing ischemic stroke for low-stroke-risk atrial fibrillation patients with hypertension and hyperlipidemia.

An electrochemical sensor for warfarin determination based on covalent immobilization of quantum dots onto carboxylated multiwalled carbon nanotubes and chitosan composite film modified electrode

International Nuclear Information System (INIS)

Gholivand, Mohammad Bagher; Mohammadi-Behzad, Leila

2015-01-01

A method is described for the construction of a novel electrochemical warfarin sensor based on covalent immobilization of CdS-quantum dots (CdS-QDs) onto carboxylated multiwalled carbon nanotubes/chitosan (CS) composite film on the surface of a glassy carbon electrode. The CdS-QDs/CS/MWCNTs were characterized by field-emission scanning electron microscopy (FE-SEM), transmission electron microscopy (TEM), Fourier transform infra-red (FTIR) spectroscopy, XRD analysis and electrochemical impedance spectroscopy (EIS). The sensor showed optimum anodic stripping response within 90 s at an accumulation potential of 0.75 V. The modified electrode was used to detect the concentration of warfarin with a wide linear range of 0.05–80 μM and a detection limit (S/N = 3) of 8.5 nM. The proposed sensor has good storage stability, repeatability and reproducibility and was successfully applied for the determination of warfarin in real samples such as urine, serum and milk. - Highlights: • A new sensitive sensor for warfarin determination was developed. • The sensor was constructed based on covalent immobilization of CdS-QDs on the chitosan/MWCNTs/GCE. • The parameters affecting the stripping analysis of warfarin were optimized. • The proposed sensor is used for trace determination of warfarin in urine, serum and milk

An electrochemical sensor for warfarin determination based on covalent immobilization of quantum dots onto carboxylated multiwalled carbon nanotubes and chitosan composite film modified electrode

Energy Technology Data Exchange (ETDEWEB)

Gholivand, Mohammad Bagher, E-mail: mbgholivand2013@gmail.com; Mohammadi-Behzad, Leila

2015-12-01

A method is described for the construction of a novel electrochemical warfarin sensor based on covalent immobilization of CdS-quantum dots (CdS-QDs) onto carboxylated multiwalled carbon nanotubes/chitosan (CS) composite film on the surface of a glassy carbon electrode. The CdS-QDs/CS/MWCNTs were characterized by field-emission scanning electron microscopy (FE-SEM), transmission electron microscopy (TEM), Fourier transform infra-red (FTIR) spectroscopy, XRD analysis and electrochemical impedance spectroscopy (EIS). The sensor showed optimum anodic stripping response within 90 s at an accumulation potential of 0.75 V. The modified electrode was used to detect the concentration of warfarin with a wide linear range of 0.05–80 μM and a detection limit (S/N = 3) of 8.5 nM. The proposed sensor has good storage stability, repeatability and reproducibility and was successfully applied for the determination of warfarin in real samples such as urine, serum and milk. - Highlights: • A new sensitive sensor for warfarin determination was developed. • The sensor was constructed based on covalent immobilization of CdS-QDs on the chitosan/MWCNTs/GCE. • The parameters affecting the stripping analysis of warfarin were optimized. • The proposed sensor is used for trace determination of warfarin in urine, serum and milk.

A Green, Enantioselective Synthesis of Warfarin for the Undergraduate Organic Laboratory

Science.gov (United States)

Wong, Terence C.; Sultana, Camille M.; Vosburg, David A.

2010-01-01

The enantioselective synthesis of drugs is of fundamental importance in the pharmaceutical industry. In this experiment, students synthesize either enantiomer of warfarin, a widely used anticoagulant, in a single step from inexpensive starting materials. Stereoselectivity is induced by a commercial organocatalyst, ("R","R")- or…

Clinical Pharmacogenetics Implementation Consortium Guidelines for CYP2C9 and VKORC1 Genotypes and Warfarin Dosing

Science.gov (United States)

Johnson, JA; Gong, L; Whirl-Carrillo, M; Gage, BF; Scott, SA; Stein, CM; Anderson, JL; Kimmel, SE; Lee, MTM; Pirmohamed, M; Wadelius, M; Klein, TE; Altman, RB

2011-01-01

Warfarin is a widely used anticoagulant with a narrow therapeutic index and large interpatient variability in the dose required to achieve target anticoagulation. Common genetic variants in the cytochrome P450-2C9 (CYP2C9) and vitamin K–epoxide reductase complex (VKORC1) enzymes, in addition to known nongenetic factors, account for ~50% of warfarin dose variability. The purpose of this article is to assist in the interpretation and use of CYP2C9 and VKORC1 geno-type data for estimating therapeutic warfarin dose to achieve an INR of 2–3, should genotype results be available to the clinician. The Clinical Pharmacogenetics Implementation Consortium (CPIC) of the National Institutes of Health Pharmacogenomics Research Network develops peer-reviewed gene–drug guidelines that are published and updated periodically on http://www.pharmgkb.org based on new developments in the field.1 PMID:21900891

Cost-Effectiveness Analysis of Apixaban, Dabigatran, Rivaroxaban, and Warfarin for Stroke Prevention in Atrial Fibrillation in Taiwan.

Science.gov (United States)

Liu, Chieh-Yu; Chen, Hui-Chun

2017-03-01

The aim of this study was to evaluate the cost effectiveness of novel oral anticoagulants (NOACs) for stroke prevention among atrial fibrillation (AF) patients by incorporating Taiwanese demographic information derived from a population-based database, the National Health Insurance Research Database (NHIRD), into cost-effectiveness analysis. From 1 January to 31 December 2012, 98,213 AF patients were selected from the NHIRD database. A Markov model was constructed that combined published secondary data with the Taiwan NHIRD to compare the cost and incremental cost effectiveness of apixaban 5 mg twice daily, dabigatran 110 or 150 mg twice daily, rivaroxaban 20 mg once daily, and warfarin. The lifetime costs of warfarin, dabigatran 110 mg, dabigatran 150 mg, rivaroxaban 20 mg, and apixaban 5 mg were US$10,660, US$13,693, US$13,426, US$13,455, US$15,965, respectively. Apixaban resulted in an incremental cost effectiveness of US$39,351, US$27,039, US$41,298, and US$48,896 per quality-adjusted life-year (QALY) compared with warfarin, dabigatran 110 mg, dabigatran 150 mg, and rivaroxaban 20 mg, respectively. In Monte-Carlo analyses, apixaban 5 mg, rivaroxaban 20 mg, warfarin, and dabigatran 110 mg were cost effective in 83, 10.4, 7, and 0.8%, respectively, of the simulations using a willingness-to-pay (WTP) threshold of US$50,000 per QALY. Apixaban was more cost effective than warfarin, dabigatran, and rivaroxaban for stroke prevention in patients with AF. Among the anticoagulant therapies, the WTP threshold of apixaban was about US$50,000 per QALY gained. These cost-effectiveness estimations provide useful information to aid clinical decision making in stroke prevention for AF patients.

Is warfarin usage a risk factor for osteoporotic fractures? A cohort study in the emergency department

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Genady Drozdinsky

2017-04-01

Full Text Available Background Several studies have examined the association between warfarin sodium use and risk of osteoporotic fractures with conflicting results. Our study addresses this question, for the first time regarding patients attending emergency department (ED. Aims The aim of this study was to retrospectively detect whether there is higher rate of usage of warfarin sodium in patients with osteoporotic fractures attending an ED. Methods This is a retrospective study from patients' computerized charts. All individuals >65 years old who had an osteoporotic fracture and attended an ED in a tertiary hospital were compared with a similar group of elderly individuals >65 years old without an osteoporotic fracture who attended the ED for a cause other than an osteoporotic fracture. Results This study included 328 patients who were evaluated in the years 2005–2016. Overall, 164 individuals with a typical osteoporotic fracture (hip -66 patients (40 per cent, spine- 92 patients (56 per cent, humerus -4 patients (2 per cent, radius -13 patients (8 per cent were identified and compared with a matched group of elderly individuals who were evaluated in the ED for other complaints. Warfarin sodium was used in 61 individuals (19 per cent in the entire cohort, 34 in the fracture group and 27 in the non-fracture group (p=0.324. Conclusion In elderly patients, attending an ED, warfarin sodium use does not seem to be a risk factor for an osteoporotic fracture

Warfarin Safety: A Cross-Sectional Study of the Factors Associated with the Consumption of Medicinal Plants in a Brazilian Anticoagulation Clinic.

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Leite, Paula Mendonça; de Freitas, Aline A; Mourão, Aline de O Magalhães; Martins, Maria A P; Castilho, Rachel O

2018-06-01

The aim of this study was to analyze factors associated with the consumption of medicinal plants by patients being treated with warfarin in a Brazilian anticoagulation clinic and to study the safety of medicinal plant use in patients on warfarin therapy. The study was performed as an observational cross-sectional analysis. Study participants were outpatients on long-term warfarin therapy for at least 2 months for atrial fibrillation or prosthetic cardiac valves. Interviews were carried out concerning information about the habits of medicinal herb consumption, and logistic regression analysis was performed to identify factors associated with the consumption of herbs. The scientific names of the medicinal plants were identified to search for information on the effects on the hemostasis of the interactions between the medicinal herbs reported and warfarin. The mean age of the 273 patients included was 60.8 years; 58.7% were women. Medicinal plants were used by 67% of the participants. No association between demographic and clinical data and the use of medicinal plants was identified. Patients reported a total of 64 different plants, primarily consumed in the form of tea. The plants were mainly used to treat respiratory tract and central nervous system disorders. About 40% of the plants cited have been reported to potentially interfere with the anticoagulation therapy, principally by potentiating the effects of warfarin, which could, increase the risk of bleeding. The use of medicinal plants was highly common and widespread in patients receiving warfarin as an anticoagulation therapy. Univariate analysis of variables associated with the consumption of herbs showed no statistically significant difference in the consumption of medicinal plants for any of the sociodemographic and clinical data. The medicinal plants that were reportedly consumed by the patients could affect hemostasis. This study reinforces the need for further studies evaluating the habits of patients

COST-EFFECTIVENESS OF APIXABAN AS COMPARED WITH WARFARIN AND ACETYLSALICYLIC ACID IN PATIENTS WITH NON-VALVULAR ATRIAL FIBRILLATION IN THE RUSSIAN FEDERATION

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A. V. Rudakova

2015-09-01

Full Text Available Background. For prevention of thromboembolic events in patients with non-valvular atrial fibrillation (NVAF the following types of antithrombotic therapy are used: anticoagulant therapy with vitamin K antagonists (such as warfarin, antiplatelet therapy (such as acetylsalicylic acid and novel oral anticoagulants such as apixaban, rivaroxaban and dabigatran. Administration of vitamin K antagonists (VKA is complicated by the need for individual dose adjustment and frequent monitoring of international normalized ratio (INR. Both warfarin and acetylsalicylic acid are widely used for thrombosis prevention in patients with NVAF in the Russian Federation.Aim. To evaluate the cost-effectiveness ratio of apixaban compared with warfarin and acetylsalicylic acid in patients with NVAF from the Russian Federation national health care system perspective.Material and methods. This analysis used a Markov model that allowed estimation of the incremental cost-effectiveness ratio (ICER for apixaban as compared with warfarin and acetylsalicylic acid over lifetime horizon in VKA suitable and VKA unsuitable patients with NVAF respectively. The model enclosed cardiovascular event rates based on the results of the randomized clinical trials comparing clinical effectiveness and safety of apixaban with warfarin (ARISTOTLE and acetylsalicylic acid (AVERROES. The following cardiovascular events were taken into consideration: ischemic and hemorrhagic stroke, systemic embolism, intracranial hemorrhage, other major bleeds, clinically relevant non-major bleeds and myocardial infarction. Direct medical costs were determined based on the rates of the compulsory national medical insurance system. The price of the antithrombotic drugs was taken as a weighted average tender price for the year 2013. In the model both costs and benefits (quality-adjusted life years and life-years were discounted at 3.5%. Cost-effectiveness threshold was set at 1.4 million rubles per quality

COST-EFFECTIVENESS OF APIXABAN AS COMPARED WITH WARFARIN AND ACETYLSALICYLIC ACID IN PATIENTS WITH NON-VALVULAR ATRIAL FIBRILLATION IN THE RUSSIAN FEDERATION

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A. V. Rudakova

2014-01-01

Full Text Available Background. For prevention of thromboembolic events in patients with non-valvular atrial fibrillation (NVAF the following types of antithrombotic therapy are used: anticoagulant therapy with vitamin K antagonists (such as warfarin, antiplatelet therapy (such as acetylsalicylic acid and novel oral anticoagulants such as apixaban, rivaroxaban and dabigatran. Administration of vitamin K antagonists (VKA is complicated by the need for individual dose adjustment and frequent monitoring of international normalized ratio (INR. Both warfarin and acetylsalicylic acid are widely used for thrombosis prevention in patients with NVAF in the Russian Federation.Aim. To evaluate the cost-effectiveness ratio of apixaban compared with warfarin and acetylsalicylic acid in patients with NVAF from the Russian Federation national health care system perspective.Material and methods. This analysis used a Markov model that allowed estimation of the incremental cost-effectiveness ratio (ICER for apixaban as compared with warfarin and acetylsalicylic acid over lifetime horizon in VKA suitable and VKA unsuitable patients with NVAF respectively. The model enclosed cardiovascular event rates based on the results of the randomized clinical trials comparing clinical effectiveness and safety of apixaban with warfarin (ARISTOTLE and acetylsalicylic acid (AVERROES. The following cardiovascular events were taken into consideration: ischemic and hemorrhagic stroke, systemic embolism, intracranial hemorrhage, other major bleeds, clinically relevant non-major bleeds and myocardial infarction. Direct medical costs were determined based on the rates of the compulsory national medical insurance system. The price of the antithrombotic drugs was taken as a weighted average tender price for the year 2013. In the model both costs and benefits (quality-adjusted life years and life-years were discounted at 3.5%. Cost-effectiveness threshold was set at 1.4 million rubles per quality

A systematic review of the pharmacokinetic and pharmacodynamic interactions of herbal medicine with warfarin.

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Songie Choi

Full Text Available The aim of this study was to systematically review data regarding pharmacokinetic (PK-pharmacodynamic (PD parameters from randomized controlled trials relating to interactions between herbal medicines and warfarin.Three electronic databases were searched to identify relevant trials. Two reviewers independently performed the study selection and data extraction. The risk of bias and reporting quality were also assessed independently by two reviewers using the Cochrane risk of bias tool and the consolidated standards of reporting trials (CONSORT. Outcomes were measured for all reported PK-PD parameters and adverse events.Nine randomized controlled trials met our inclusion criteria. Most of the included studies were unclear regarding the risk of bias and had a low quality of methodology. Using CONSORT, the reporting percentages for the articles ranged from 36.5% to 61.5% and the mean percentage for all articles was 45.6%. St John's wort and echinacea affected the PK parameters of warfarin. Ginseng, ginger, garlic, and cranberry had no significant effect on the PK parameters. American ginseng altered the PD parameters of warfarin. St John's wort, ginseng, Korea red ginseng, ginkgo, ginger, garlic, aged garlic, and echincea did not significantly alter the PD parameters. Studies of ginkgo and cranberry showed conflicting results on the PK parameters and PD parameters, respectively. The incidence of adverse events in all trials was low and no major adverse events were reported.It was difficult to determine whether ten herbal medicines had significant effects on the PK-PD parameters of warfarin. Low quality of evidence, different compounds within and different compositions of the herbs, and methodological limitations of the crossover study, which is a clinical study in which subjects receive a sequence of different interventions, made it difficult to form conclusions. Additional studies that remedy these vulnerabilities are necessary to verify these

Clinical factors influencing normalization of prothrombin time after stopping warfarin: a retrospective cohort study

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Zondag Michelle

2008-10-01

Full Text Available Abstract Background Anticoagulation with warfarin should be stopped 4–6 days before invasive procedures to avoid bleeding complications. Despite this routine, some patients still have high International Normalized Ratio (INR values on the day of surgery and the procedure may be cancelled. We sought to identify easily available clinical characteristics that may influence the rate of normalization of prothrombin time when warfarin is stopped before surgery or invasive procedures. Methods Clinical data were collected retrospectively from consecutive cases from two cohorts, who stopped warfarin 6 days before surgery. An INR value of 1.6 or higher on the day of surgery or requirement for reversal with vitamin K the day before surgery were criteria for slow return (S to normal INR. Results Of 202 patients, 14 (7% were classified as S. Eight of the S-patients required reversal with vitamin K one day before surgery and in another case surgery was cancelled due to high INR. Baseline INR was the only variable significantly associated with classification as S in stepwise logistic regression analysis (p = 0.003. The odds ratio for being in the normal group was 0.27 (95% confidence interval 0.12–0.62 for each unit baseline INR increased. The positive predictive value of baseline INR with a cut off at > 3.0 was only 15% and for INR > 3.5 it was 33%. Conclusion Baseline INR, but not the size of the maintenance dose, is associated with the rate of normalization of prothrombin time after stopping warfarin, but it has limited utility as predictor in clinical practice. Whenever normal hemostasis is considered crucial for the safety, the INR should be checked again before the invasive procedure.

Safety and efficacy of direct oral anticoagulants compared to warfarin for extended treatment of venous thromboembolism -a systematic review and meta-analysis

DEFF Research Database (Denmark)

Sindet-Pedersen, Caroline; Pallisgaard, Jannik Langtved; Olesen, Jonas Bjerring

2015-01-01

OBJECTIVE: To examine and compare the safety and efficacy of extended treatment with dabigatran, apixaban, rivaroxaban and warfarin in patients with unprovoked venous thromboembolism. METHODS: PubMed and Embase were searched for randomized clinical trials reporting on the use of direct oral...... anticoagulants (DOACs) and warfarin for the extended treatment of VTE. Meta-analysis was performed on studies reporting similar study design and comparator. RESULTS: A total of 729 articles were identified and 5 studies covering 6 randomized clinical trials met the eligibility criteria and were included...... in the study. 5 studies were included in the meta-analysis. Results from the meta-analysis showed that the extended use of DOACs and warfarin significantly decreased the risk of recurrent VTE with 83 % when compared placebo. Warfarin (RR: 0.03, CI: 0.00-0.49) and dabigatran (RR: 0.08, CI: 0.03-0.27) showed...

Determinants of the over-anticoagulation response during warfarin initiation therapy in Asian patients based on population pharmacokinetic-pharmacodynamic analyses.

Science.gov (United States)

Ohara, Minami; Takahashi, Harumi; Lee, Ming Ta Michael; Wen, Ming-Shien; Lee, Tsong-Hai; Chuang, Hui-Ping; Luo, Chen-Hui; Arima, Aki; Onozuka, Akiko; Nagai, Rui; Shiomi, Mari; Mihara, Kiyoshi; Morita, Takashi; Chen, Yuan-Tsong

2014-01-01

To clarify pharmacokinetic-pharmacodynamic (PK-PD) factors associated with the over-anticoagulation response in Asians during warfarin induction therapy, population PK-PD analyses were conducted in an attempt to predict the time-courses of the plasma S-warfarin concentration, Cp(S), and coagulation and anti-coagulation (INR) responses. In 99 Chinese patients we analyzed the relationships between dose and Cp(S) to estimate the clearance of S-warfarin, CL(S), and that between Cp(S) and the normal prothrombin concentration (NPT) as a coagulation marker for estimation of IC50. We also analyzed the non-linear relationship between NPT inhibition and the increase in INR to derive the non-linear index λ. Population analyses accurately predicted the time-courses of Cp(S), NPT and INR. Multivariate analysis showed that CYP2C9*3 mutation and body surface area were predictors of CL(S), that VKORC1 and CYP4F2 polymorphisms were predictors of IC50, and that baseline NPT was a predictor of λ. CL(S) and λ were significantly lower in patients with INR≥4 than in those with INR<4 (190 mL/h vs 265 mL/h, P<0.01 and 3.2 vs 3.7, P<0.01, respectively). Finally, logistic regression analysis revealed that CL(S), ALT and hypertension contributed significantly to INR≥4. All these results indicate that factors associated with the reduced metabolic activity of warfarin represented by CL(S), might be critical determinants of the over-anticoagulation response during warfarin initiation in Asians. ClinicalTrials.gov NCT02065388.

Determinants of the over-anticoagulation response during warfarin initiation therapy in Asian patients based on population pharmacokinetic-pharmacodynamic analyses.

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Minami Ohara

Full Text Available To clarify pharmacokinetic-pharmacodynamic (PK-PD factors associated with the over-anticoagulation response in Asians during warfarin induction therapy, population PK-PD analyses were conducted in an attempt to predict the time-courses of the plasma S-warfarin concentration, Cp(S, and coagulation and anti-coagulation (INR responses. In 99 Chinese patients we analyzed the relationships between dose and Cp(S to estimate the clearance of S-warfarin, CL(S, and that between Cp(S and the normal prothrombin concentration (NPT as a coagulation marker for estimation of IC50. We also analyzed the non-linear relationship between NPT inhibition and the increase in INR to derive the non-linear index λ. Population analyses accurately predicted the time-courses of Cp(S, NPT and INR. Multivariate analysis showed that CYP2C9*3 mutation and body surface area were predictors of CL(S, that VKORC1 and CYP4F2 polymorphisms were predictors of IC50, and that baseline NPT was a predictor of λ. CL(S and λ were significantly lower in patients with INR≥4 than in those with INR<4 (190 mL/h vs 265 mL/h, P<0.01 and 3.2 vs 3.7, P<0.01, respectively. Finally, logistic regression analysis revealed that CL(S, ALT and hypertension contributed significantly to INR≥4. All these results indicate that factors associated with the reduced metabolic activity of warfarin represented by CL(S, might be critical determinants of the over-anticoagulation response during warfarin initiation in Asians.ClinicalTrials.gov NCT02065388.

Risk of stroke/systemic embolism, major bleeding and associated costs in non-valvular atrial fibrillation patients who initiated apixaban, dabigatran or rivaroxaban compared with warfarin in the United States Medicare population.

Science.gov (United States)

Amin, Alpesh; Keshishian, Allison; Trocio, Jeffrey; Dina, Oluwaseyi; Le, Hannah; Rosenblatt, Lisa; Liu, Xianchen; Mardekian, Jack; Zhang, Qisu; Baser, Onur; Vo, Lien

2017-09-01

To compare the risk and cost of stroke/systemic embolism (SE) and major bleeding between each direct oral anticoagulant (DOAC) and warfarin among non-valvular atrial fibrillation (NVAF) patients. Patients (≥65 years) initiating warfarin or DOACs (apixaban, rivaroxaban, and dabigatran) were selected from the Medicare database from 1 January 2013 to 31 December 2014. Patients initiating each DOAC were matched 1:1 to warfarin patients using propensity score matching to balance demographics and clinical characteristics. Cox proportional hazards models were used to estimate the risks of stroke/SE and major bleeding of each DOAC vs. warfarin. Two-part models were used to compare the stroke/SE- and major-bleeding-related medical costs between matched cohorts. Of the 186,132 eligible patients, 20,803 apixaban-warfarin pairs, 52,476 rivaroxaban-warfarin pairs, and 16,731 dabigatran-warfarin pairs were matched. Apixaban (hazard ratio [HR] = 0.40; 95% confidence interval [CI] 0.31, 0.53) and rivaroxaban (HR = 0.72; 95% CI 0.63, 0.83) were significantly associated with lower risk of stroke/SE compared to warfarin. Apixaban (HR = 0.51; 95% CI 0.44, 0.58) and dabigatran (HR = 0.79; 95% CI 0.69, 0.91) were significantly associated with lower risk of major bleeding; rivaroxaban (HR = 1.17; 95% CI 1.10, 1.26) was significantly associated with higher risk of major bleeding compared to warfarin. Compared to warfarin, apixaban ($63 vs. $131) and rivaroxaban ($93 vs. $139) had significantly lower stroke/SE-related medical costs; apixaban ($292 vs. $529) and dabigatran ($369 vs. $450) had significantly lower major bleeding-related medical costs. Among the DOACs in the study, only apixaban is associated with a significantly lower risk of stroke/SE and major bleeding and lower related medical costs compared to warfarin.

Utility of abdominal computed tomography in geriatric patients on warfarin with a fall from standing

Directory of Open Access Journals (Sweden)

Amit Bahl

2018-01-01

Full Text Available Context: Geriatric head trauma resulting from falls has been extensively studied both in the presence and absence of blood thinners. In this population, however, the prevalence and extent of abdominal injury resulting from falls are much less defined. Aim: We aim to evaluate the utility of abdominal computed tomography (CT imaging in geriatric patients on Warfarin with a recent history of fall. Setting and Design: A retrospective analysis was completed of consecutive geriatric patients who presented to a Level 1 Trauma Center emergency department after fall from standing while taking Warfarin. Methods: Inclusion criteria included age 65 years or older and fall while taking Warfarin. Incomplete medical records were excluded from the study. Data collection included the type of anticoagulant medications, demographics, physical examination, laboratories, CT/X-ray findings if ordered, and final diagnosis on admission. Categorical variables were examined using Pearson's Chi-square where appropriate (expected frequency >5, or Fisher's Exact test. Continuous variables were examined using nonparametric Wilcoxon rank tests. Results: Eight hundred and sixty-three charts were reviewed. One hundred and thirty-one subjects met inclusion criteria. Mean age was 83 years. Nearly 39.6% of patients were male. A total of 48 patients had abdominal CT imaging. Seven of the 131 patients (5.3% had an abdominal injury. Abdominal tenderness was predictive of injury, with 4 of 7 cases with abdominal injury demonstrating abdominal tenderness versus only 10 of 124 cases without abdominal injury demonstrating tenderness (P = 0.003. Abdominal CTs were ordered in 11 of 19 cases of patients that exhibited head trauma yet none of these patients were shown to have sustained abdominal trauma (P = 0.08. There was no association between international normalized ratio level and presence of abdominal injury (P = 0.99. Conclusions: A small percentage of elderly fall patients on

International normalized ratio stabilization in newly initiated warfarin patients with nonvalvular atrial fibrillation.

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Nelson, Winnie W; Desai, Sunita; Damaraju, C V; Lu, Lang; Fields, Larry E; Wildgoose, Peter; Schein, Jeff R

2014-12-01

Warfarin is effective for stroke prevention in patients with atrial fibrillation (AF), but international normalized ratio (INR) levels fluctuate and frequent monitoring is necessary. This study used data from a large anticoagulation management service database to analyze the relationship between INR stabilization and warfarin utilization for >1 year in patients with nonvalvular AF (NVAF). Anticoagulation records from a large US electronic database collected from 2006 to 2010 were analyzed. Patients with NVAF and ≥ 3 INR values in the dataset were identified (n = 15,276). INR stabilization was defined as the first three consecutive INR values between 2.0 and 3.0 after warfarin initiation. One quarter of patients (n = 3809) failed to reach INR stabilization. After initial stabilization, 30% of subsequent INR values were out of range. The mean (± standard deviation [SD]) follow-up time from stabilization to the end of study for these patients was 494.2 ± 418.1 days. Age ≥ 75 years (odds ratio [OR] = 1.17, 95% confidence interval [CI] = 1.08-1.27), hypertension (OR = 1.19, 95% CI = 1.10-1.29), or prior stroke (OR = 1.29, 95% CI = 1.04-1.61) were positively associated with achieving stabilization; heart failure was negatively associated with stabilization (OR = 0.78, 95% CI = 0.70-0.87). Male gender (p < 0.0001) and hypertension were associated with earlier stabilization (p = 0.0013); heart failure was associated with later stabilization (p = 0.0098). Patients who achieved INR stabilization within 1 year were 10 times more likely to remain on warfarin than patients who did not achieve it. Observational data may contain incomplete records. Data on adherence, concurrent medications, vitamin K intake, genotype, reasons for discontinuation of monitoring, and patient outcomes were not available in the dataset. The study findings were generalizable only to patients with AF who were managed by anticoagulation clinics. Given the importance of stroke prevention among

Warfarin affects acute inflammatory response induced by subcutaneous polyvinyl sponge implantation in rats.

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Mirkov, Ivana; Popov Aleksandrov, Aleksandra; Demenesku, Jelena; Ninkov, Marina; Mileusnic, Dina; Kataranovski, Dragan; Kataranovski, Milena

2017-09-01

Warfarin (WF) is an anticoagulant which also affects physiological processes other than hemostasis. Our previous investigations showed the effect of WF which gained access to the organism via skin on resting peripheral blood granulocytes. Based on these data, the aim of the present study was to examine whether WF could modulate the inflammatory processes as well. To this aim the effect of WF on the inflammatory response induced by subcutaneous sponge implantation in rats was examined. Warfarin-soaked polyvinyl sponges (WF-sponges) were implanted subcutaneously and cell infiltration into sponges, the levels of nitric oxide (NO) and inflammatory cytokines tumor necrosis factor (TNF) and interleukin-6 (IL-6) production by sponge cells were measured as parameters of inflammation. T cell infiltration and cytokine interferon-γ (IFN-γ), interleukin-17 (IL-17) and interleukin-10 (IL-10) were measured at day 7 post implantation. Warfarin exerted both stimulatory and suppressive effects depending on the parameter examined. Flow cytometry of cells recovered from sponges showed higher numbers of granulocytes (HIS48 + cells) at days 1 and 3 post implantation and CD11b + cells at day 1 compared to control sponges. Cells from WF-sponges had an increased NO production (Griess reaction) at days 1 and 7. In contrast, lower levels of TNF (measured by ELISA) production by cells recovered from WF-soaked sponges were found in the early (day one) phase of reaction with unchanged levels at other time points. While IL-6 production by cells recovered from WF-soaked sponges was decreased at day 1, it was increased at day 7. Higher T cell numbers were noted in WF sponges at day 7 post implantation, and recovered cells produced more IFN-γ and IL-17, while IL-10 production remained unchanged. Warfarin affects some of the parameters of inflammatory reaction induced by subcutaneous polyvinyl sponge implantation. Differential (both stimulatory as well as inhibitory) effects of WF on

Effect of Semaglutide on the Pharmacokinetics of Metformin, Warfarin, Atorvastatin and Digoxin in Healthy Subjects.

Science.gov (United States)

Hausner, Helene; Derving Karsbøl, Julie; Holst, Anders G; Jacobsen, Jacob B; Wagner, Frank-Dietrich; Golor, Georg; Anderson, Thomas W

2017-11-01

Semaglutide is a glucagon-like peptide-1 analogue in development for the once-weekly treatment of type 2 diabetes mellitus. Its effect on the rate and extent of absorption of concomitant oral medications (metformin, warfarin, atorvastatin and digoxin) was evaluated in healthy subjects. Subjects received metformin (500 mg twice daily for 3.5 days), warfarin (25 mg, single dose), atorvastatin (40 mg, single dose) or digoxin (0.5 mg, single dose) before and with subcutaneous semaglutide treatment at steady state (1.0 mg). Lack of drug-drug interaction was concluded if the 90% confidence intervals for the area under the plasma concentration-time curve ratio before and with semaglutide were within a pre-specified interval (0.80-1.25). Overall, metformin, warfarin, atorvastatin and digoxin pharmacokinetics were not affected to a clinically relevant degree with semaglutide co-administration. Estimated area under the plasma concentration-time curve ratios for all concomitant medications before and with semaglutide treatment were within the pre-specified interval. In addition, semaglutide did not affect maximum plasma concentration of concomitant medications to a relevant degree. Furthermore, no clinically relevant change in international normalised ratio response to warfarin was observed with semaglutide co-administration. Most adverse events with semaglutide treatment were mild or moderate. Adverse events with semaglutide and co-administered medication were comparable to those reported during treatment with semaglutide alone, and were mostly gastrointestinal related. No clinically significant pharmacokinetic or pharmacodynamic interactions were identified and no new safety issues observed with combined treatment with semaglutide. This suggests that no dose adjustments should be required when semaglutide is administered concomitantly with these medications.

Pharmacokinetic Evaluation of the Interactions of Amenamevir (ASP2151) with Ketoconazole, Rifampicin, Midazolam, and Warfarin in Healthy Adults.

Science.gov (United States)

Kusawake, Tomohiro; den Adel, Martin; Groenendaal-van de Meent, Dorien; Garcia-Hernandez, Alberto; Takada, Akitsugu; Kato, Kota; Ohtsu, Yoshiaki; Katashima, Masataka

2017-11-01

Amenamevir is a nonnucleoside antiherpes virus compound available for treating herpes zoster infections. Four studies aimed to determine any potential interactions between amenamevir and ketoconazole, rifampicin, midazolam, or warfarin in healthy male participants. Two studies were open-label studies that evaluated the effects of multiple doses of ketoconazole (400 mg) and rifampicin (600 mg) on the pharmacokinetics of a single oral dose of amenamevir. The other two studies were randomized, double-blind, parallel-group studies that evaluated the effects of multiple doses of amenamevir on the pharmacokinetics of a single dose of midazolam (7.5 mg) and warfarin (25 mg). A drug interaction was considered to occur if the 90% confidence interval (CI) of the least squares geometric mean ratio (GMR) of amenamevir to the comparator was outside the prespecified interval of 0.80-1.25. Interactions were observed between amenamevir and ketoconazole, rifampicin, and midazolam, but not between amenamevir and warfarin. After a single 400-mg dose of amenamevir, the GMRs of amenamevir plus ketoconazole or rifampicin versus amenamevir alone for C max and the area under the plasma concentration-time curve from time zero to infinity (AUC inf ) were 1.30 (90% CI 1.17-1.45) and 2.58 (90% CI 2.32-2.87), respectively, for ketoconazole and 0.42 (90% CI 0.37-0.49) and 0.17 (90% CI 0.15-0.19), respectively, for rifampicin. Following multiple doses of amenamevir (400 mg), the GMRs of midazolam plus amenamevir versus midazolam alone for AUC inf and C max were 0.53 (90% CI 0.47-0.61) and 0.63 (90% CI 0.50-0.80), respectively. After a single dose of warfarin, the (S)-warfarin and (R)-warfarin mean C max increased and mean AUC inf decreased in the presence of amenamevir; however, the 90% CIs of the GMRs for these parameters remained within the predefined limits. These findings confirm that amenamevir (as a cytochrome P450 3A4 substrate) can interact with ketoconazole or rifampicin, and (as a

The Role of Warfarin Alone or in Combination with Certain Natural Products Against Blood Disorders Induced by Gamma Radiation in Experimental Animals

International Nuclear Information System (INIS)

Fahim, M.G.; Radwan, R.R.; Shaaban, E.A.; El-Denshary, E.S.

2016-01-01

The effect of warfarin against blood disorder induced by radiation and possible effect of certain natural products in modifying anticoagulant effect of warfarin in irradiated rats was investigated. Prothrombin time (PT), international normalized ratio (INR), partial thromboplastin time (PTT), thrombin time (TT), fibrinogen level and platelet count were evaluated. Furthermore, plasma level of malondialdehyde (MDA), reduced glutathione (GSH) and nitric oxide (NO) were determined. The obtained data showed that irradiation elevated Pt, INR, PTT, TT and fibrinogen level. Moreover, irradiation increased MDA and NO levels while, reduced GSH level. It was found that administration of garlic, fenugreek or green tea with warfarin for one week before irradiation resulted in elevation in PT and INR. Results suggest that patients on warfarin and exposed to radiation are specifically advised to avoid taking herbal medicines or to have their PT and INR measured within two weeks of starting the drug, to be on a safer side

Pharmacogenetics-Based Warfarin Dosing in Patients With Cardiac Valve Replacement: The Effects of CYP2C9 and VKORC1 Gene Polymorphisms.

Science.gov (United States)

Farzamikia, Negin; Sakhinia, Ebrahim; Afrasiabirad, Abbas

2017-12-22

Many lines of evidence suggest that warfarin dosing variability is significantly associated with cytochrome P450 2C9 (CYP2C9) and vitamin K epoxide reductase complex subunit 1 (VKORC1) variant alleles. Therefore, we investigated the influence of CYP2C9*2 (430C/T), *3 (1075A/C) and VKORC1 (-1639G/A) polymorphisms on warfarin dose requirements in patients who underwent cardiac valve surgery during the postoperative period.A total of 100 patients with heart valve replacement who had a prescribed target international normalized ratio (INR) range of 2-3 were enrolled in the study. Genotyping of CYP2C9 and VKORC1 was carried out using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) technique. The demographic and clinical data were collected using a precodified questionnaire and clinical examination and then were analyzed.Our findings revealed that the prevalence of CYP2C9 *2, *3 and VKORC1 -1639A alleles in patients were 10.5%, 39%, and 48%, respectively. We also found that patients with CYP2C9 *1 and VKORC1 -1639G alleles required the highest dosages of warfarin, while the carriers of CYP2C9 variant *2 and *3 alleles and VKORC1 -1639A required less warfarin. Univariate regression analysis showed that age and presence of CYP2C9 *2 allele significantly influenced the daily warfarin dose requirement. Our findings provide additional evidence to support the hypothesis that CYP2C9*2 (430C/T), *3 (1075A/C) and VKORC1 (-1639G/A) polymorphisms explain a considerable proportion of interindividual variability in warfarin dose. Therefore, testing for these variants might be helpful for adjusting patient warfarin dosage to an effective and safe level. © American Society for Clinical Pathology 2017. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Low-level overexpression of p53 promotes warfarin-induced calcification of porcine aortic valve interstitial cells by activating Slug gene transcription.

Science.gov (United States)

Gao, Li; Ji, Yue; Lu, Yan; Qiu, Ming; Shen, Yejiao; Wang, Yaqing; Kong, Xiangqing; Shao, Yongfeng; Sheng, Yanhui; Sun, Wei

2018-03-09

The most frequently used oral anti-coagulant warfarin has been implicated in inducing calcification of aortic valve interstitial cells (AVICs), whereas the mechanism is not fully understood. The low-level activation of p53 is found to be involved in osteogenic transdifferentiation and calcification of AVICs. Whether p53 participates in warfarin-induced AVIC calcification remains unknown. In this study, we investigated the role of low-level p53 overexpression in warfarin-induced porcine AVIC (pAVIC) calcification. Immunostaining, quantitative PCR, and Western blotting revealed that p53 was expressed in human and pAVICs and that p53 expression was slightly increased in calcific human aortic valves compared with non-calcific valves. Terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling staining indicated that apoptosis slightly increased in calcific aortic valves than in non-calcific valves. Warfarin treatment led to a low-level increase of p53 mRNA and protein in both pAVICs and mouse aortic valves. Low-level overexpression of p53 in pAVICs via an adenovirus vector did not affect pAVIC apoptosis but promoted warfarin-induced calcium deposition and expression of osteogenic markers. shRNA-mediated p53 knockdown attenuated the pAVIC calcium deposition and osteogenic marker expression. Moreover, ChIP and luciferase assays showed that p53 was recruited to the slug promoter and activated slug expression in calcific pAVICs. Of note, overexpression of Slug increased osteogenic marker Runx2 expression, but not pAVIC calcium deposition, and Slug knockdown attenuated pAVIC calcification and p53-mediated pAVIC calcium deposition and expression of osteogenic markers. In conclusion, we found that p53 plays an important role in warfarin induced pAVIC calcification, and increased slug transcription by p53 is required for p53-mediated pAVIC calcification. © 2018 by The American Society for Biochemistry and Molecular Biology, Inc.

Anxiety, Depression, and Adverse Clinical Outcomes in Patients With Atrial Fibrillation Starting Warfarin: Cardiovascular Research Network WAVE Study.

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Baumgartner, Christine; Fan, Dongjie; Fang, Margaret C; Singer, Daniel E; Witt, Daniel M; Schmelzer, John R; Williams, Marc S; Gurwitz, Jerry H; Sung, Sue Hee; Go, Alan S

2018-04-14

Anxiety and depression are associated with worse outcomes in several cardiovascular conditions, but it is unclear whether they affect outcomes in atrial fibrillation (AF). In a large diverse population of adults with AF, we evaluated the association of diagnosed anxiety and/or depression with stroke and bleeding outcomes. The Cardiovascular Research Network WAVE (Community-Based Control and Persistence of Warfarin Therapy and Associated Rates and Predictors of Adverse Clinical Events in Atrial Fibrillation and Venous Thromboembolism) Study included adults with AF newly starting warfarin between 2004 and 2007 within 5 health delivery systems in the United States. Diagnosed anxiety and depression and other patient characteristics were identified from electronic health records. We identified stroke and bleeding outcomes from hospitalization databases using validated International Classification of Diseases, Ninth Revision ( ICD-9 ), codes. We used multivariable Cox regression to assess the relation between anxiety and/or depression with outcomes after adjustment for stroke and bleeding risk factors. In 25 570 adults with AF initiating warfarin, 490 had an ischemic stroke or intracranial hemorrhage (1.52 events per 100 person-years). In multivariable analyses, diagnosed anxiety was associated with a higher adjusted rate of combined ischemic stroke and intracranial hemorrhage (hazard ratio, 1.52; 95% confidence interval, 1.01-2.28). Results were not materially changed after additional adjustment for patient-level percentage of time in therapeutic anticoagulation range on warfarin (hazard ratio, 1.56; 95% confidence interval, 1.03-2.36). In contrast, neither isolated depression nor combined depression and anxiety were significantly associated with outcomes. Diagnosed anxiety was independently associated with increased risk of combined ischemic stroke and intracranial hemorrhage in adults with AF initiating warfarin that was not explained by differences in risk factors

Effect of CYP2C9, VKORC1, CYP4F2 and GGCX genetic variants on warfarin maintenance dose and explicating a new pharmacogenetic algorithm in South Indian population.

Science.gov (United States)

Krishna Kumar, Dhakchinamoorthi; Shewade, Deepak Gopal; Loriot, Marie-Anne; Beaune, Philippe; Balachander, Jayaraman; Sai Chandran, B V; Adithan, Chandrasekaran

2014-01-01

To determine the influence of genetic polymorphisms on warfarin maintenance dose and to explicate an algorithm using the pharmacogenetic and clinical factors to determine the maintenance and/or starting dose of warfarin in South Indian patients receiving warfarin therapy. Patients receiving stabilized warfarin therapy (n=257) were included in the study. Single nucleotide polymorphisms (SNPs) of CYP2C9 (rs1799853 and rs1057910), VKORC1 (rs9923231, rs7196161, rs2884737, rs9934438, rs8050894, rs2359612 and rs7294), CYP4F2 (rs2108622) and GGCX (rs11676382) were genotyped by the quantitative real time-PCR method. The mean daily maintenance dose of warfarin was found to be 4.7 ± 2.1 mg/day. Patients with the CYP2C9*1/*2, *1/*3 and *2/*3 variant genotypes required a 51.0 (2.8 mg), 60.9 (2.3 mg) and 62.2 % (2.2 mg) lower daily maintenance dose of warfarin, respectively, than those patients with the CYP2C9*1/*1 wild-type genotype (5.2 mg) (pmaintenance dose. Genetic polymorphisms of CYP2C9, VKORC1, CYP4F2 and GGCX are important predictive factors of warfarin maintenance dose, and the developed algorithm will be useful to predict the required maintenance and/or starting warfarin dose in South Indian populations.

R-warfarin clearances from plasma associated with polymorphic cytochrome P450 2C19 and simulated by individual physiologically based pharmacokinetic models for 11 cynomolgus monkeys.

Science.gov (United States)

Utoh, Masahiro; Kusama, Takashi; Miura, Tomonori; Mitsui, Marina; Kawano, Mirai; Hirano, Takahiro; Shimizu, Makiko; Uno, Yasuhiro; Yamazaki, Hiroshi

2018-02-01

1. Cynomolgus monkey cytochrome P450 2C19 (formerly known as P450 2C75), homologous to human P450 2C19, has been identified as R-warfarin 7-hydroxylase. In this study, simulations of R-warfarin clearance in individual cynomolgus monkeys genotyped for P450 2C19 p.[(Phe100Asn; Ala103Val; Ile112Leu)] were performed using individual simplified physiologically based pharmacokinetic (PBPK) modeling. 2. Pharmacokinetic parameters and absorption rate constants, volumes of the systemic circulation, and hepatic intrinsic clearances for individual PBPK models were estimated for eleven cynomolgus monkeys. 3. One-way ANOVA revealed significant effects of the genotype (p warfarin among the homozygous mutant, heterozygous mutant, and wild-type groups. R-Warfarin clearances in individual cynomolgus monkeys genotyped for P450 2C19 were simulated by simplified PBPK modeling. The modeled hepatic intrinsic clearances were significantly associated with the P450 2C19 genotypes. The liver microsomal elimination rates of R-warfarin for individual animals after in vivo administration showed significant reductions associated with the genotype (p warfarin and related medicines associated with polymorphic P450 2C19 in individual cynomolgus monkeys, thereby facilitating calculation of the fraction of hepatic clearance.

Direct Oral Anticoagulant- or Warfarin-Related Major Bleeding: Characteristics, Reversal Strategies, and Outcomes From a Multicenter Observational Study.

Science.gov (United States)

Xu, Yan; Schulman, Sam; Dowlatshahi, Dar; Holbrook, Anne M; Simpson, Christopher S; Shepherd, Lois E; Wells, Philip S; Giulivi, Antonio; Gomes, Tara; Mamdani, Muhammad; Khuu, Wayne; Frymire, Eliot; Johnson, Ana P

2017-07-01

Direct oral anticoagulants (DOACs) have expanded the armamentarium for antithrombotic therapy. Although DOAC-related major bleeding was associated with favorable outcomes compared with warfarin in clinical trials, warfarin effects were reversed in bleeding events. Red blood cell transfusions occurred more often in DOAC bleeding events than in warfarin events (52.0% vs 39.5%; adjusted relative risk [aRR], 1.32; 95% CI, 1.19-2.47). However, units of blood products transfused were not different between the two groups. Thirty-four DOAC cases (7.4%) received activated prothrombin complex concentrates or recombinant factor VIIa. In-hospital mortality was lower following DOAC bleeding events (9.8% vs 15.2%; aRR, 0.66; 95% CI, 0.49-0.89), although differences in 30-day mortality did not reach statistical significance (12.6% vs 16.3%; aRR, 0.79; 95% CI, 0.61-1.03). In this unselected cohort of patients with oral anticoagulant-related hemorrhage with high rates of warfarin reversal, in-hospital mortality was lower among DOAC-associated bleeding events. These findings support the safety of DOACs in routine care and present useful baseline measures for evaluations of DOAC-specific reversal agents. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

Effect of Apixaban Versus Warfarin Use on Health Care Resource Utilization and Costs Among Elderly Patients with Nonvalvular Atrial Fibrillation.

Science.gov (United States)

Deitelzweig, Steven; Luo, Xuemei; Gupta, Kiran; Trocio, Jeffrey; Mardekian, Jack; Curtice, Tammy; Lingohr-Smith, Melissa; Menges, Brandy; Lin, Jay

2017-11-01

The clinical trial ARISTOTLE showed that apixaban was superior to warfarin in reducing the risks of stroke and bleeding among patients with nonvalvular atrial fibrillation (NVAF). Further study of the effect of apixaban versus warfarin use on health care resource utilization (HCRU) and associated costs in the real-world setting is warranted, especially among elderly patients who are at higher risk of stroke and bleeding. To compare HCRU and costs among elderly NVAF patients treated with apixaban versus warfarin in the United States. Elderly patients (aged ≥ 65 years) with Medicare coverage who initiated apixaban or warfarin were identified from the Humana research database during January 1, 2013-September 30, 2015. Patients were required to have 12 months of continuous insurance coverage before drug initiation (baseline period) and an atrial fibrillation diagnosis during the baseline period or on the date of drug initiation. NVAF patients were grouped into cohorts depending on the drug initiated. Propensity score matching (PSM) was conducted to control for differences in demographics and clinical characteristics of study cohorts. Patients were followed after the index date for a variable length of follow-up. All-cause and disease-specific HCRU and costs during the follow-up were evaluated before and after PSM and reported as per patient per year. Of the overall (unmatched) population, 8,250 patients (mean age: 78.0 years) initiated apixaban and 14,051 patients (mean age: 78.2 years) initiated warfarin. Among NVAF patients who initiated apixaban versus those who initiated warfarin, mean Charlson Comorbidity Index (CCI) scores (3.0 vs. 3.4, P the baseline period for patients treated with apixaban versus warfarin ($17,077 vs. $20,236, P the baseline period. During the follow-up among matched cohorts, apixaban versus warfarin treatment was associated with higher annual pharmacy costs ($5,159 vs. $2,867, P the real-world setting apixaban versus warfarin use was

Strokes attributable to underuse of warfarin and antiplatelets

DEFF Research Database (Denmark)

Olsen, Tom Skyhøj; Rasmussen, Berit Hammershaimb; Kammersgaard, Lars Peter

2007-01-01

atrial fibrillation, prior myocardial infarction, angina, or prior stroke transient ischemic attack (TIA). Sufficient information on cardiovascular risk factors before stroke was available in 404 patients. A total of 54 patients had atrial fibrillation known before the stroke. Of these, 16 had...... fibrillation could have been prevented if warfarin or antiplatelets had been given before stroke. A total of 147 patients had known stroke/TIA and/or myocardial infarction/angina before stroke (41 patients had not received antiplatelets on admission). If antiplatelet therapy had been given before stroke, 10...

COMPARISON OF DIRECT COSTS OF DABIGATRAN AND WARFARIN THERAPY IN PATIENTS WITH NON-VALVULAR ATRIAL FIBRILLATION DURING PREPARATION FOR ELECTIVE CARDIOVERSION IN THE REAL CLINICAL PRACTICE

Directory of Open Access Journals (Sweden)

L. E. Kuvshinova

2015-09-01

Full Text Available Aim. To compare direct medical costs of dabigatran and warfarin therapy in patients with non-valvular atrial fibrillation (NVAF during preparation for elective cardioversion. Material and methods. An open non-randomized study was conducted to evaluate direct medical costs (cost of drug, cost of the international normalized ratio (INR adjust- ment in outpatient clinic, cost of visits to cardiologist. Patients (n=62 with persistent NVAF (AF paroxysm duration > 48 hours were enrolled. All of them requested medical as- sistance and were decided to perform an elective cardioversion. The patients received warfarin (n=32 or dabigatran (n=30. The patients of the both groups were similar in the main clinical characteristics and thromboembolic risk levels according to CHA2DS2-VASc scale.Results. Treatment duration before elective cardioversion was 21±2 and 30.5±4.5 days for dabigatran and warfarin groups, respectively (p<0.05. Average costs of visits to cardiologists were 3,720 and 744 RUB in warfarin and dabigatran groups, respectively (p<0.05, and drug costs were 53.63 and 1,172.01 RUB, respectively (p<0.05. The costs of laboratory INR monitoring were 3,058 RUB in warfarin group. Total costs per patient were 6,831.63 and 1,916.01 RUB in warfarin and dabigatran groups, respectively (p<0.05. Conclusion. In the real clinical practice in patients with NVAF dabigatran antithromboembolic therapy substantially reduces direct medical costs in comparison with warfarin ther- apy during preparation for elective cardioversion. Dabigatran therapy reduces time from the decision of elective cardioversion and antithromboembolic therapy start to car- dioversion performance.

COMPARISON OF DIRECT COSTS OF DABIGATRAN AND WARFARIN THERAPY IN PATIENTS WITH NON-VALVULAR ATRIAL FIBRILLATION DURING PREPARATION FOR ELECTIVE CARDIOVERSION IN THE REAL CLINICAL PRACTICE

Directory of Open Access Journals (Sweden)

L. E. Kuvshinova

2013-01-01

Full Text Available Aim. To compare direct medical costs of dabigatran and warfarin therapy in patients with non-valvular atrial fibrillation (NVAF during preparation for elective cardioversion. Material and methods. An open non-randomized study was conducted to evaluate direct medical costs (cost of drug, cost of the international normalized ratio (INR adjust- ment in outpatient clinic, cost of visits to cardiologist. Patients (n=62 with persistent NVAF (AF paroxysm duration > 48 hours were enrolled. All of them requested medical as- sistance and were decided to perform an elective cardioversion. The patients received warfarin (n=32 or dabigatran (n=30. The patients of the both groups were similar in the main clinical characteristics and thromboembolic risk levels according to CHA2DS2-VASc scale.Results. Treatment duration before elective cardioversion was 21±2 and 30.5±4.5 days for dabigatran and warfarin groups, respectively (p<0.05. Average costs of visits to cardiologists were 3,720 and 744 RUB in warfarin and dabigatran groups, respectively (p<0.05, and drug costs were 53.63 and 1,172.01 RUB, respectively (p<0.05. The costs of laboratory INR monitoring were 3,058 RUB in warfarin group. Total costs per patient were 6,831.63 and 1,916.01 RUB in warfarin and dabigatran groups, respectively (p<0.05. Conclusion. In the real clinical practice in patients with NVAF dabigatran antithromboembolic therapy substantially reduces direct medical costs in comparison with warfarin ther- apy during preparation for elective cardioversion. Dabigatran therapy reduces time from the decision of elective cardioversion and antithromboembolic therapy start to car- dioversion performance.

Efficacy and Safety of Uninterrupted Low-Intensity Warfarin for Radiofrequency Catheter Ablation of Atrial Fibrillation in the Elderly.

Science.gov (United States)

Xing, Yangbo; Xu, Buyun; Xu, Chao; Peng, Fang; Yang, Biao; Qiu, Yufang; Sun, Yong; Wang, Shengkai; Guo, Hangyuan

2017-09-01

No previous studies exist investigating the optimal intensity of uninterrupted anticoagulation with warfarin during radiofrequency catheter ablation (RFCA) for atrial fibrillation (AF) in the elderly. Evaluate the efficacy and safety of continuous low-intensity warfarin therapy throughout the periprocedural period of RFCA for AF in the elderly. This is a prospective randomized study. We enrolled AF patients (age ≥ 70 years) who underwent first-time RFCA for AF. Enrolled patients were randomized to group A and group B. The international normalized ratios before ablation were maintained at 1.5 to 2.0 and 2.0 to 2.5 in group A and B, respectively. Primary end points were periprocedural thromboembolic complications and major bleeding. Secondary end points included periprocedural asymptomatic cerebral emboli (ACE) and minor bleeding. A total of 101 patients were enrolled in our study (group A: 52; group B: 49). Baseline characteristics were well balanced between the 2 groups. Only 1 patient suffered from stroke in group B. No major bleeding events occurred in either group. The incidence of new ACE lesions was comparable between the 2 groups (11.5% vs 8.2%, P = 0.82). Minor bleeding occurred in 1 of 52 (1.9%) patients in group A and in 5 of 49 (10.2%) patients in group B ( P = 0.10). Uninterrupted low-intensity warfarin for RFCA of AF might be as effective as standard-intensity warfarin in preventing periprocedural thromboembolic complications and might be associated with fewer bleeding events in the elderly.

Assessment of Pharmacokinetic Interactions Between Obeticholic Acid and Caffeine, Midazolam, Warfarin, Dextromethorphan, Omeprazole, Rosuvastatin, and Digoxin in Phase 1 Studies in Healthy Subjects.

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Edwards, Jeffrey E; Eliot, Lise; Parkinson, Andrew; Karan, Sharon; MacConell, Leigh

2017-09-01

Obeticholic acid (OCA), a potent and selective farnesoid X receptor agonist, is indicated for the treatment of primary biliary cholangitis (PBC). We investigated the potential drug-drug interaction effect of OCA on metabolic CYP450 enzymes and drug transporters. Five phase 1 single-center, open-label, fixed-sequence, inpatient studies were conducted in healthy adult subjects to evaluate the effect of oral daily doses of 10 or 25 mg OCA on single-dose plasma pharmacokinetics of specific probe substrates for enzymes CYP1A2 (caffeine, R-warfarin), CYP3A (midazolam, R-warfarin), CYP2C9 (S-warfarin), CYP2D6 (dextromethorphan), CYP2C19 (omeprazole), and drug transporters, BCRP/OATP1B1/OATP1B3 (rosuvastatin), and P-gp (digoxin). OCA showed no substantial suppression/inhibition of S-warfarin, digoxin, and dextromethorphan and weak interactions with caffeine, omeprazole, rosuvastatin, and midazolam. The maximal pharmacodynamic responses (E max ) to warfarin-based INR, PT, and aPTT were reduced by 11%, 11%, and 1%, respectively, for the 10-mg dose group and by 7%, 7% and 0%, respectively, for the 25-mg dose group. Overall, drugs dosed in combination with OCA were well tolerated, and most adverse events were mild in severity. No clinically important trends were noted in laboratory evaluations, vital signs, or 12-lead ECGs. In these studies, OCA showed weak to no suppression/inhibition of metabolic enzymes and drug transporters at the highest recommended therapeutic dose in patients with PBC. On the basis on these analyses, monitoring and maintenance of target INR range are required during coadministration of OCA with drugs that are metabolized by CYP1A2 (R-warfarin). Intercept Pharmaceuticals, Inc.

Effectiveness and safety of rivaroxaban versus warfarin for treatment and prevention of recurrence of venous thromboembolism.

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Coleman, Craig I; Bunz, Thomas J; Turpie, Alexander G G

2017-10-05

The efficacy and safety or rivaroxaban versus enoxaparin/vitamin K antagonist for treatment and prevention recurrence of venous thromboembolism (VTE) was demonstrated in the randomised EINSTEIN trials. We assessed the effectiveness and safety of rivaroxaban versus warfarin in VTE patients managed in routine practice. Using US MarketScan claims from 1/2012-6/2015, we included adults with a primary diagnosis of deep vein thrombosis (DVT) or pulmonary embolism (PE) during a hospitalisation/emergency department visit, newly-initiated on rivaroxaban or warfarin within 30-days after the VTE and with ≥180-days of continuous medical/prescription benefits prior to the VTE (baseline). Patients with a claim for anticoagulation at baseline were excluded. Recurrent VTE, major bleeding, intracranial haemorrhage (ICH) and gastrointestinal bleeding (GIB) were assessed. Differences in baseline characteristics between cohorts were adjusted for using inverse probability of treatment weights based on propensity-scores. Patients had a maximum of 12-months period of follow-up post-VTE or until endpoint occurrence, switch/discontinuation of index anticoagulation, insurance disenrollment or end-of-follow-up. Cox regression was performed and reported as hazard ratios (HRs) with 95 % confidence intervals (CIs). In total, 13,609 rivaroxaban and 32,244 warfarin users experiencing VTE were included. Rivaroxaban was associated with an 19 % (95 %CI=10-27 %) reduction in recurrent VTE and a 21 % (95 %CI=4-35 %) reduction in major bleeding hazard versus warfarin. Rivaroxaban was also associated with significantly decreased hazards of ICH (HR=0.40) and GIB (HR=0.72). Rivaroxaban appears to reduce patients' hazard of both recurrent VTE and major bleeding in routine practice. These results appear consistent with EINSTEIN and post-marketing registry studies.

Non-vitamin K oral anticoagulants are non-inferior for stroke prevention but cause fewer major bleedings than well-managed warfarin: A retrospective register study.

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Vilhelm Sjögren

Full Text Available For patients with atrial fibrillation, non-vitamin K oral anticoagulants, or NOACs (dabigatran, rivaroxaban, edoxaban, and apixaban have been proven non-inferior or superior to warfarin in preventing stroke and systemic embolism, and in risk of haemorrhage. In the pivotal NOAC studies, quality of warfarin treatment was poor with mean time in therapeutic range (TTR 55-65%, compared with ≥70% in Swedish clinical practice.We compared NOACs (as a group to warfarin in non-valvular atrial fibrillation, studying all 12,694 patients starting NOAC treatment within the Swedish clinical register and dosing system Auricula, from July 1, 2011 to December 31, 2014, and matching them to 36,317 patients starting warfarin using propensity scoring. Endpoints were thromboembolic events and major bleedings that were fatal or required hospital care. Outcome data were collected from validated Swedish hospital administrative and clinical registers.Mean age was 72.2 vs 72.3 years, proportion of males 58.2% vs 57.0%, and mean follow-up time 299 vs 283 days for NOACs and warfarin. Distribution of NOACs was: dabigatran 40.3%, rivaroxaban 31.2%, and apixaban 28.5%. Mean TTR was 70%. There were no significant differences in rates of thromboembolic/thrombotic events or gastrointestinal bleeding. NOAC treated patients had lower rates of major bleeding overall, hazard ratio 0.78 (95% confidence interval 0.67-0.92, intracranial bleeding 0.59 (0.40-0.87, haemorrhagic stroke 0.49 (0.28-0.86, and other major bleeding 0.71 (0.57-0.89.For patients with atrial fibrillation, NOACs are as effective for stroke prevention as well-managed warfarin but cause fewer major bleedings.

Safety and Efficacy of Bridging With Low-Molecular-Weight Heparin During Temporary Interruptions of Warfarin: A Register-Based Cohort Study.

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Sjögren, Vilhelm; Grzymala-Lubanski, Bartosz; Renlund, Henrik; Svensson, Peter J; Själander, Anders

2017-11-01

Low-molecular-weight heparin (LMWH) is often recommended as a bridging therapy during temporary interruptions in warfarin treatment, despite lack of evidence. The aim of this study was to see whether we could find benefit from LMWH bridging. We studied all planned interruptions of warfarin within the Swedish anticoagulation register Auricula during 2006 to 2011. Low-molecular-weight heparin bridging was compared to nonbridging (control) after propensity score matching. Complications were identified in national clinical registers for 30 days following warfarin cessation, and defined as all-cause mortality, bleeding (intracranial, gastrointestinal, or other), or thrombosis (ischemic stroke or systemic embolism, venous thromboembolism, or myocardial infarction) that was fatal or required hospital care. Of the 14 556 identified warfarin interruptions, 12 659 with a known medical background had a mean age of 69 years, 61% were males, mean CHADS 2 (1 point for each of congestive heart failure, hypertension, age ≥75 years, diabetes, and 2 points for stroke or transient ischemic attack) score was 1.7, and CHA 2 DS 2 -VASc score was 3.4. The total number of LMWH bridgings was 7021. Major indications for anticoagulation were mechanical heart valve prostheses 4331, atrial fibrillation 1097, and venous thromboembolism 1331. Bridging patients had a higher rate of thrombotic events overall. Total risk of any complication did not differ significantly between bridging (1.5%) and nonbridging (1.2%). Regardless of indication for warfarin treatment, we found no benefit from bridging. The type of procedure prompting bridging was not known, and the likely reason for the observed higher risk of thrombosis with LMWH bridging is that low-risk procedures more often meant no bridging. Results from randomized trials are needed, especially for patients with mechanical heart valves.

Hospital length of stay in patients initiated on direct oral anticoagulants versus warfarin for venous thromboembolism: a real-world single-center study.

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Badreldin, Hisham

2018-07-01

This study was conducted to describe the real-world hospital length of stay in patients treated with all of the U.S. Food and Drug Administration approved direct oral anticoagulants (DOACs) versus warfarin for new-onset venous thromboembolism (VTE) at a large, tertiary, academic medical center. A retrospective cohort analysis of all adult patients diagnosed with acute onset VTE was conducted. Of the 441 patients included, 261 (57%) patients received DOACs versus 180 (41%) patients received warfarin. In the DOAC group, a total of 92 (35%) patients received rivaroxaban, followed by 83 (32%) patients received apixaban, 50 (19%) patients received dabigatran, and 36 (14%) patients received edoxaban. Patients initiated on DOACs had a statistically significant shorter hospital length of stay compared to patients initiated on warfarin (median 3 days, [IQR 0-5] vs. 8 days [IQR 5-11], P < 0.05). Despite the shorter hospital length of stay in patients receiving DOACs, the overall reported differences between the DOACs group and the warfarin group in terms of recurrent VTE, major bleeding, intracranial bleeding, and gastrointestinal bleeding at 3 and 6 months were deemed to be statistically insignificant.

A prospective randomized trial of aspirin-clopidogrel combination therapy and dose-adjusted warfarin on indices of thrombogenesis and platelet activation in atrial fibrillation.

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Kamath, Sridhar; Blann, Andrew D; Chin, Bernard S P; Lip, Gregory Y H

2002-08-07

This study was designed to investigate whether or not combination aspirin-clopidogrel therapy would reduce markers of thrombogenesis and platelet activation in atrial fibrillation (AF), in a manner similar to warfarin. Dose-adjusted warfarin is beneficial as thromboprophylaxis in AF, but potentially serious side effects and regular monitoring leave room for alternative therapies. METHODS; We randomized 70 patients with nonvalvular AF who were not on any antithrombotic therapy to either dose-adjusted warfarin (international normalized ratio 2 to 3) (Group I) or combination therapy with aspirin 75 mg and clopidogrel 75 mg (Group II). Plasma indices of thrombogenesis (fibrin D-dimer, prothrombin fragment 1+2) and platelet activation (beta-thromboglobulin [TG] and soluble P-selectin) were quantified, along with platelet aggregation responses to standard agonists, at baseline (pretreatment) and at six weeks posttreatment. RESULTS; Pretreatment levels of fibrin D-dimer (p = 0.001), beta-TG (p = 0.01) and soluble P-selectin (p = 0.03) were raised in patients with AF, whereas plasma prothrombin fragment 1+2 levels and platelet aggregation were not significantly different compared with controls. Dose-adjusted warfarin reduced plasma levels of fibrin D-dimer, prothrombin fragment 1+2 and beta-thromboglobulin levels at six weeks (all p failed to reduce plasma indices of thrombogenesis and platelet activation in AF, although some aspects of ex vivo platelet aggregation were altered. Anticoagulation with warfarin may be superior to combination aspirin-clopidogrel therapy as thromboprophylaxis in AF.

Can We Predict Individual Combined Benefit and Harm of Therapy? Warfarin Therapy for Atrial Fibrillation as a Test Case.

Directory of Open Access Journals (Sweden)

Guowei Li

Full Text Available To construct and validate a prediction model for individual combined benefit and harm outcomes (stroke with no major bleeding, major bleeding with no stroke, neither event, or both in patients with atrial fibrillation (AF with and without warfarin therapy.Using the Kaiser Permanente Colorado databases, we included patients newly diagnosed with AF between January 1, 2005 and December 31, 2012 for model construction and validation. The primary outcome was a prediction model of composite of stroke or major bleeding using polytomous logistic regression (PLR modelling. The secondary outcome was a prediction model of all-cause mortality using the Cox regression modelling.We included 9074 patients with 4537 and 4537 warfarin users and non-users, respectively. In the derivation cohort (n = 4632, there were 136 strokes (2.94%, 280 major bleedings (6.04% and 1194 deaths (25.78% occurred. In the prediction models, warfarin use was not significantly associated with risk of stroke, but increased the risk of major bleeding and decreased the risk of death. Both the PLR and Cox models were robust, internally and externally validated, and with acceptable model performances.In this study, we introduce a new methodology for predicting individual combined benefit and harm outcomes associated with warfarin therapy for patients with AF. Should this approach be validated in other patient populations, it has potential advantages over existing risk stratification approaches as a patient-physician aid for shared decision-making.

Effectiveness and safety of apixaban versus warfarin in non-valvular atrial fibrillation patients in "real-world" clinical practice. A propensity-matched analysis of 76,940 patients.

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Li, Xiaoyan Shawn; Deitelzweig, Steve; Keshishian, Allison; Hamilton, Melissa; Horblyuk, Ruslan; Gupta, Kiran; Luo, Xuemei; Mardekian, Jack; Friend, Keith; Nadkarni, Anagha; Pan, Xianying; Lip, Gregory Y H

2017-06-02

The ARISTOTLE trial showed a risk reduction of stroke/systemic embolism (SE) and major bleeding in non-valvular atrial fibrillation (NVAF) patients treated with apixaban compared to warfarin. This retrospective study used four large US claims databases (MarketScan, PharMetrics, Optum, and Humana) of NVAF patients newly initiating apixaban or warfarin from January 1, 2013 to September 30, 2015. After 1:1 warfarin-apixaban propensity score matching (PSM) within each database, the resulting patient records were pooled. Kaplan-Meier curves and Cox proportional hazards models were used to estimate the cumulative incidence and hazard ratios (HRs) of stroke/SE and major bleeding (identified using the first listed diagnosis of inpatient claims) within one year of therapy initiation. The study included a total of 76,940 (38,470 warfarin and 38,470 apixaban) patients. Among the 38,470 matched pairs, 14,563 were from MarketScan, 7,683 were from PharMetrics, 7,894 were from Optum, and 8,330 were from Humana. Baseline characteristics were balanced between the two cohorts with a mean (standard deviation [SD]) age of 71 (12) years and a mean (SD) CHA 2 DS 2 -VASc score of 3.2 (1.7). Apixaban initiators had a significantly lower risk of stroke/SE (HR: 0.67, 95 % CI: 0.59-0.76) and major bleeding (HR: 0.60, 95 % CI: 0.54-0.65) than warfarin initiators. Different types of stroke/SE and major bleeding - including ischaemic stroke, haemorrhagic stroke, SE, intracranial haemorrhage, gastrointestinal bleeding, and other major bleeding - were all significantly lower for apixaban compared to warfarin treatment. Subgroup analyses (apixaban dosage, age strata, CHA 2 DS 2 -VASc or HAS-BLED score strata, or dataset source) all show consistently lower risks of stroke/SE and major bleeding associated with apixaban as compared to warfarin treatment. This is the largest "real-world" study on apixaban effectiveness and safety to date, showing that apixaban initiation was associated with

Valvular Heart Disease Patients on Edoxaban or Warfarin in the ENGAGE AF-TIMI 48 Trial.

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De Caterina, Raffaele; Renda, Giulia; Carnicelli, Anthony P; Nordio, Francesco; Trevisan, Marco; Mercuri, Michele F; Ruff, Christian T; Antman, Elliott M; Braunwald, Eugene; Giugliano, Robert P

2017-03-21

The use of non-vitamin K antagonist oral anticoagulants (NOACs) instead of vitamin K antagonists (VKAs) in patients with atrial fibrillation (AF) and coexisting valvular heart disease (VHD) is of substantial interest. This study explored outcomes in patients with AF with and without VHD in the ENGAGE AF-TIMI 48 (Effective Anticoagulation with factor Xa Next Generation in Atrial Fibrillation-Thrombolysis In Myocardial Infarction 48) trial, comparing edoxaban with warfarin. Valvular heart disease was defined as history or baseline echocardiography evidence of at least moderate aortic/mitral regurgitation, aortic stenosis, or prior valve surgery (bioprosthesis replacement, valve repair, valvuloplasty). Patients with moderate to severe mitral stenosis or mechanical heart valves were excluded from the trial. Comparisons were made of rates of stroke/systemic embolic event (SSEE), major bleeding, additional efficacy and safety outcomes, as well as net clinical outcomes, in patients with or without VHD treated with edoxaban or warfarin, using adjusted Cox proportional hazards. After adjustment for multiple baseline characteristics, compared with no-VHD patients (n = 18,222), VHD patients (n = 2,824) had a similar rate of SSEE but higher rates of death (hazard ratio [HR]: 1.40; 95% confidence interval [CI]:1.26 to 1.56; p <0.001), major adverse cardiovascular events (HR: 1.29; 95% CI: 1.16 to 1.43; p <0.001), and major bleeding (HR: 1.21; 95% CI: 1.03 to 1.42; p = 0.02). Higher-dose edoxaban regimen had efficacy similar to warfarin in the presence of VHD (for SSEE, HR: 0.69; 95% CI: 0.44 to 1.07, in patients with VHD, and HR: 0.91; 95% CI: 0.77 to 1.07, in patients without VHD; p interaction [p int ] = 0.26; and for less major bleeding, HR: 0.74; 95% CI: 0.53 to 1.02 in patients with VHD, and HR: 0.82; 95% CI: 0.71 to 0.94, in patients with no VHD; p int  = 0.57). The presence of VHD increased the risk of death, major adverse cardiovascular events, and major

Avoidance of Vitamin K-Rich Foods Is Common among Warfarin Users and Translates into Lower Usual Vitamin K Intakes.

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Leblanc, Cristina; Dubé, Marie-Pierre; Presse, Nancy; Dumas, Stéphanie; Nguyen, Mimosa; Rouleau-Mailloux, Étienne; Perreault, Sylvie; Ferland, Guylaine

2016-06-01

Warfarin users should aim for stable daily vitamin K intakes. However, some studies report that patients are often advised to avoid eating green vegetables. Whether this advice impacts vitamin K intakes is unknown. Our aim was to describe the nature and sources of vitamin K-related dietary recommendations that patients received at the initiation of warfarin therapy, assess their adherence to these recommendations, and examine whether usual vitamin K intakes vary according to these recommendations. We conducted a retrospective cohort study with patients enrolled in the Québec Warfarin Cohort Study. Patients were asked to report dietary recommendations they had received at warfarin initiation and their adherence to these recommendations. Usual vitamin K intakes were assessed using a validated semi-quantitative food frequency questionnaire. Three hundred seventeen patients aged 36 to 97 years who initiated warfarin between 2011 and 2012 and were treated for 12 months or longer with a target international normalized ratio range of 2.0 to 3.0 or 2.5 to 3.5. Patients were classified according to vitamin K-related recommendations reported: limit or avoid vitamin K-rich foods; aim for stable consumption of vitamin K-rich foods; or no vitamin K-related advice. A one-way analysis of covariance was used to compare mean usual vitamin K intakes between patients after adjustment for covariates. Most patients (68%) reported being advised to limit or avoid vitamin K-rich foods, particularly green vegetables, 10% reported being advised to aim for stable consumption of vitamin K-rich foods, and 22% did not recall receiving any vitamin K-related recommendation. Mean usual vitamin K intakes of patients adhering to the recommendation to limit or avoid vitamin K-rich foods was 35% to 46% lower than those of other patients (Pvitamin K-rich foods, which translated into lower usual vitamin K intakes. Copyright © 2016 Academy of Nutrition and Dietetics. Published by Elsevier Inc. All

Out-of-range international normalized ratio values and healthcare cost among new warfarin patients with non-valvular atrial fibrillation.

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Nelson, Winnie W; Wang, Li; Baser, Onur; Damaraju, C V; Schein, Jeffrey R

2015-05-01

Patients with out-of-range international normalized ratio (INR) values 3.0 have been associated with increased risk of thromboembolic and bleeding events. INR monitoring is costly, because of associated physician and nurse time, laboratory resource use, and dose adjustments. This study assessed the healthcare cost burden associated with out-of-range INR among warfarin initiator patients diagnosed with non-valvular atrial fibrillation (NVAF) in the US Veterans Health Administration (VHA) population. Adult NVAF patients (≥18 years) initiating warfarin were selected from the VHA dataset for the study period October 1, 2007-September 30, 2012. Only valid INR measurements (0.5 ≤ INR ≤ 20) were examined for the follow-up period, from the index date (warfarin initiation date) until the end of warfarin exposure or death. All-cause healthcare costs within 30 days were measured starting from the second month (31 days post-index date) to the end of the study period. Costs for inpatient stays, emergency room, outpatient facility, physician office visits, and other services were computed separately. Multiple regression was performed using the generalized linear model for overall cost analysis. In total, 29,463 patients were included in the study sample. Mean costs for out-of-range INR ranged from $3419 to $5126. Inpatient, outpatient, outpatient pharmacy, and total costs were significantly higher after patients experienced out-of-range results (INR  3), compared with in-range INR (2 ≤ INR ≤ 3). When exposed to out-of-range INR, patients also incurred higher mean total costs within 2-6 months ($3840-$5820) than after the first 6 months ($2789-$3503) of warfarin therapy. In the VHA population, INR measures outside of the 2-3 range were associated with significantly higher healthcare costs. Increased costs were especially apparent when INR values were below 2, although INR measures above 3 were also associated with higher costs relative to in

Efficacy and safety of dabigatran compared with warfarin at different levels of international normalised ratio control for stroke prevention in atrial fibrillation: an analysis of the RE-LY trial.

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Wallentin, Lars; Yusuf, Salim; Ezekowitz, Michael D; Alings, Marco; Flather, Marcus; Franzosi, Maria Grazia; Pais, Prem; Dans, Antonio; Eikelboom, John; Oldgren, Jonas; Pogue, Janice; Reilly, Paul A; Yang, Sean; Connolly, Stuart J

2010-09-18

Effectiveness and safety of warfarin is associated with the time in therapeutic range (TTR) with an international normalised ratio (INR) of 2·0-3·0. In the Randomised Evaluation of Long-term Anticoagulation Therapy (RE-LY) trial, dabigatran versus warfarin reduced both stroke and haemorrhage. We aimed to investigate the primary and secondary outcomes of the RE-LY trial in relation to each centre's mean TTR (cTTR) in the warfarin population. In the RE-LY trial, 18 113 patients at 951 sites were randomly assigned to 110 mg or 150 mg dabigatran twice daily versus warfarin dose adjusted to INR 2·0-3·0. Median follow-up was 2·0 years. For 18 024 patients at 906 sites, the cTTR was estimated by averaging TTR for individual warfarin-treated patients calculated by the Rosendaal method. We compared the outcomes of RE-LY across the three treatment groups within four groups defined by the quartiles of cTTR. RE-LY is registered with ClinicalTrials.gov, number NCT00262600. The quartiles of cTTR for patients in the warfarin group were: less than 57·1%, 57·1-65·5%, 65·5-72·6%, and greater than 72·6%. There were no significant interactions between cTTR and prevention of stroke and systemic embolism with either 110 mg dabigatran (interaction p=0·89) or 150 mg dabigatran (interaction p=0·20) versus warfarin. Neither were any significant interactions recorded with cTTR with regards to intracranial bleeding with 110 mg dabigatran (interaction p=0·71) or 150 mg dabigatran (interaction p=0·89) versus warfarin. There was a significant interaction between cTTR and major bleeding when comparing 150 mg dabigatran with warfarin (interaction p=0·03), with less bleeding events at lower cTTR but similar events at higher cTTR, whereas rates of major bleeding were lower with 110 mg dabigatran than with warfarin irrespective of cTTR. There were significant interactions between cTTR and effects of both 110 mg and 150 mg dabigatran versus warfarin on the composite of all

Warfarin dose requirement in Turkish patients: the influences of patient characteristics and polymorphisms in CYP2C9, VKORC1 and factor VII.

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Yildirim, E; Erol, K; Birdane, A

2014-01-01

To determine the contribution of cytochrome P4502C9 (CYP2C9), vitamin K epoxide reductase (VKORC1) and factor VII genotypes, age, body mass index (BMI), international normalized ratio (INR) and other individual patient characteristics on warfarin dose requirements in an adult Turkish population. Blood samples were collected from 101 Turkish patients. Genetic analyses for CYP2C9*2 and *3, VKORC1 -1639 G>A and factor VII -401 G>T polymorphisms were performed. Age, INR, BMI values and other individual patient characteristics were also recorded. The mean daily warfarin dosage was significantly higher in patients with the CYP2C9*1/*1 genotype than in the CYP2C9*2/*2 and CYP2C9*1/*3 groups (p ≤ 0.05). With respect to the VKORC1 -1639 G>A polymorphism, the mean warfarin daily dose requirement was higher in the wild type group compared to the heterozygous group (p≤0.001). The mean daily dose requirement for patients with the GG form of factor VII was significantly higher than that of patients with the TT genotype (p ≤ 0.05). Age, gender, BMI, INR had no statistically significant correlation with warfarin dose (p ≥ 0.05). Polymorphisms in CYP2C9, VKORC1 and factor VII did partially affect daily warfarin dose requirements, while age, gender, BMI and INR do not. However, further case-control studies with a larger study size and different genetic loci are needed to confirm our study.

Safety and effectiveness of rivaroxaban and warfarin in moderate-to-advanced CKD: real world data.

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Di Lullo, Luca; Tripepi, Giovanni; Ronco, Claudio; De Pascalis, Antonio; Barbera, Vincenzo; Granata, Antonio; Russo, Domenico; Di Iorio, Biagio Raffaele; Paoletti, Ernesto; Ravera, Maura; Fusaro, Maria; Bellasi, Antonio

2018-06-07

In recent years, novel anticoagulant drugs have been introduced in the clinical armamentarium and have progressively gained momentum. Although their use is increasing among CKD patients, some skepticism about their risk-benefit ratio still persists. We sought to investigate the safety and effectiveness of rivaroxaban in a cohort of moderate-to-advanced CKD patients. This observational, retrospective, longitudinal study involved 347 consecutive CKD stage 3b-4 (according to NKF-KDOQI guidelines) patients enrolled from 8 cardiac outpatient clinics between March 2015 and October 2017. All patients received anticoagulation (100 warfarin vs. 247 rivaroxaban) as part of their non-valvular atrial fibrillation management at the attending physician's discretion. Clinical effectiveness (defined as the occurrence of ischemic stroke, venous thromboembolism, or transient ischemic attack) and safety (intracranial hemorrhage, gastrointestinal or other bleeding) were assessed separately. Over a mean follow-up period of 16 ± 0.3 months, 25 stroke episodes (15 hemorrhagic, and 10 ischemic) occurred in 24 warfarin treated patients vs. none in the rivaroxaban arm. There were 5 vs. 0 episodes of deep venous thrombosis and 8 vs. 2 major episodes of bleeding in the warfarin and rivaroxaban groups, respectively. In contrast, the proportion of minor episodes of bleeding was similar between groups. Rivaroxaban seems a safe and effective therapeutic option in CKD stage 3b-4 patients. However, future randomized controlled trials are needed to definitively establish the role of rivaroxaban in CKD patients.

THE CONTROL OF INTERNATIONAL NORMALISED RATIO IN PATIENTS WITH ATRIAL FIBRILLATION TREATED WITH WARFARIN IN OUTPATIENT AND HOSPITAL SETTINGS: DATA FROM RECVASA REGISTRIES

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M. M. Loukianov

2018-01-01

Full Text Available Am. To study in the RECVASA registers the availability of data about the international normalized ratio (INR indicator and achievement of its target values in outpatient and hospital practice in patients with atrial fibrillation (AF receiving anticoagulant therapy with warfarin.Material and methods. Data about the INR control and the frequency of achievement of its target values at the outpatient and hospital stages were analyzed in RECVASA (Ryazan and RECVASA FP – Yaroslavl outpatient registries, as well as in the hospital registers RECVASA FP (Moscow, Kursk, Tula in 817 patients (46.9% of men, age 68.5±9.6 years with AF and the prescribed anticoagulant therapy with warfarin.Results. INR was determined in 689 (84.3% of 817 patients. The values of INR were monitored during therapy with warfarin in RECVASA (Ryazan and RECVASA FP –Yaroslavl outpatient registries in 73.7% and 77.7% of patients, respectively, and in RECVASA FP hospital registers: 95.8% (Moscow; 81.3% (Tula and 93.5% (Kursk. The target level of INR (2.0-3.0 was achieved in a minority of patients with AF during treatment with warfarin: inRyazan – in 26.3% of cases;Yaroslavl – 38.3%;Kursk – 34.8%;Moscow – 39.5%; Tule – 26.3%. Control of INR in hospital registries during warfarin therapy in patients with AF significantly more often (p<0.05 was performed at the hospital stage, compared with prehospital (in Kursk –2.3 times more often in Moscow – 2.6 times, in Tula – in 1,8 times. The target level of INR in the hospital was achieved significantly more often (p<0.05 than before hospitalization (Moscow andKursk, but no significant differences were found in the RECVASA FP –Tula register (p=0.08. The INR was monitored by 94.9% of the patients; however, the target values of this indicator were achieved only in 33% of cases in the sample study in the RECVASA FP –Moscow registry according to a survey of 39 patients with AF who continued to receive warfarin after 2.6±0

Decreasing warfarin sensitivity during the first three months after heart valve surgery : Implications for dosing

NARCIS (Netherlands)

Meijer, K.; Kim, Y. -K.; Schulman, S.

Introduction: Vitamin K antagonists are prescribed to prevent thromboembolic complications after heart valve surgery. In our experience, patients often show a progressive decrease in sensitivity to warfarin after surgery making it difficult to reach and maintain a therapeutic International

Comparison of outcomes among patients randomized to warfarin therapy according to anticoagulant control: results from SPORTIF III and V

DEFF Research Database (Denmark)

White, Harvey D; Gruber, Michael; Feyzi, Jan

2007-01-01

BACKGROUND: Warfarin sodium reduces stroke risk in patients with atrial fibrillation, but international normalized ratio (INR) monitoring is required. Target INRs are frequently not achieved, and the risk of death, bleeding, myocardial infarction (MI), and stroke or systemic embolism event (SEE......) may be related to INR control. METHODS: We analyzed the relationship between INR control and the rates of death, bleeding, MI, and stroke or SEE among 3587 patients with atrial fibrillation randomized to receive warfarin treatment in the SPORTIF (Stroke Prevention Using an Oral Thrombin Inhibitor...... control group (1.69% and 1.58%, respectively) (Pwarfarin, the risks of death...

Cost-effectiveness of pharmacogenetic-guided dosing of warfarin in the United Kingdom and Sweden

NARCIS (Netherlands)

Verhoef, T. I.; Redekop, W. K.; Langenskiold, S.; Kamali, F.; Wadelius, M.; Burnside, G.; Maitland-van der Zee, A.-H.; Hughes, D. A.; Pirmohamed, M.

2016-01-01

We aimed to assess the cost-effectiveness of pharmacogenetic-guided dosing of warfarin in patients with atrial fibrillation (AF) in the United Kingdom and Sweden. Data from EU-PACT, a randomized controlled trial in newly diagnosed AF patients, were used to model the incremental costs per

Gene polymorphisms and the risk of warfarin-induced bleeding complications at therapeutic international normalized ratio (INR)

Energy Technology Data Exchange (ETDEWEB)

Pourgholi, Leyla [Department of Pathology and Laboratory Medicine, Tehran Heart Center, Tehran University of Medical Sciences, P.O. Box 1411713138, Tehran (Iran, Islamic Republic of); Department of Pharmacology & Toxicology, School of Pharmacy, Kerman University of Medical Sciences, P.O. Box 7616911319, Kerman (Iran, Islamic Republic of); Goodarzynejad, Hamidreza [Department of Cardiac Research, Tehran Heart Center, Tehran University of Medical Sciences, P.O. Box 1411713138, Tehran (Iran, Islamic Republic of); Mandegary, Ali [Department of Pharmacology & Toxicology, School of Pharmacy, Kerman University of Medical Sciences, P.O. Box 7616911319, Kerman (Iran, Islamic Republic of); Gastroenterology and Hepatology Research Center, Afzalipour' s Hospital, Imam Highway, P.O. Box 7616913911, Kerman (Iran, Islamic Republic of); Ziaee, Shayan [Department of Pathology and Laboratory Medicine, Tehran Heart Center, Tehran University of Medical Sciences, P.O. Box 1411713138, Tehran (Iran, Islamic Republic of); Talasaz, Azita Hajhosseini [Department of Cardiac Research, Tehran Heart Center, Tehran University of Medical Sciences, P.O. Box 1411713138, Tehran (Iran, Islamic Republic of); Department of Clinical Pharmacy, School of Pharmacy, Tehran University of Medical Sciences (Iran, Islamic Republic of); Jalali, Arash [Department of Cardiac Research, Tehran Heart Center, Tehran University of Medical Sciences, P.O. Box 1411713138, Tehran (Iran, Islamic Republic of); Boroumand, Mohammadali, E-mail: maboroumand@yahoo.com [Department of Pathology and Laboratory Medicine, Tehran Heart Center, Tehran University of Medical Sciences, P.O. Box 1411713138, Tehran (Iran, Islamic Republic of)

2016-10-15

Background: Bleeding episodes commonly occur in patients on warfarin treatment even in those within therapeutic range of international normalized ratio (INR). The objective of this study was to investigate the effects of the 8 examined polymorphisms on the risk of bleeding complications in a sample of Iranian patients. Methods: A total of 552 warfarin treated patients who maintained on a target INR level of 2.0–3.5 for at least three consecutive intervals were enrolled from those attended our anticoagulation clinics. Ninety-two bleeding events were observed in 87 patients. The presences of the examined polymorphisms were analyzed using polymerase chain reaction-based restriction fragment length polymorphism (PCR-RFLP). Results: Patients with the T allele in NQO1*2 (CT or TT genotypes) had a higher risk of bleeding than patients with the CC genotype (adjusted OR: 2.25, 95% CI: 1.37 to 3.70, P = 0.001). Those who were carriers of CYP2C9 one-variant haplotypes (*1/*2 or *1/*3) were also found to be associated with the higher risk of bleeding events. Compared to reference group (*1/*1), the odds of bleeding increased for carriers of one variant allele (*1/*2 or *1/*3) (adjusted OR: 1.75, 95% CI: 1.03 to 2.97, P = 0.039). Variant VKORC1, Factor VII, and EPHX1 genotypes were not significantly associated with the risk of bleeding events. Conclusion: The SNP C609T within NQO1 and haplotypes of CYP2C9 (1*2 or 1*3) are independently associated to bleeding complications of warfarin at normal INR. Further studies are required to confirm such associations in diverse racial and ethnic populations. - Highlights: • NQO1 C609T variant is associated with warfarin induced bleeding at therapeutic INR. • Haplotypes of CYP2C9 (1*2 or 1*3) are also associated with bleeding events. • VKORC1, Factor VII, and EPHX1 genotypes were not associated with bleeding risk.

Gene polymorphisms and the risk of warfarin-induced bleeding complications at therapeutic international normalized ratio (INR)

International Nuclear Information System (INIS)

Pourgholi, Leyla; Goodarzynejad, Hamidreza; Mandegary, Ali; Ziaee, Shayan; Talasaz, Azita Hajhosseini; Jalali, Arash; Boroumand, Mohammadali

2016-01-01

Background: Bleeding episodes commonly occur in patients on warfarin treatment even in those within therapeutic range of international normalized ratio (INR). The objective of this study was to investigate the effects of the 8 examined polymorphisms on the risk of bleeding complications in a sample of Iranian patients. Methods: A total of 552 warfarin treated patients who maintained on a target INR level of 2.0–3.5 for at least three consecutive intervals were enrolled from those attended our anticoagulation clinics. Ninety-two bleeding events were observed in 87 patients. The presences of the examined polymorphisms were analyzed using polymerase chain reaction-based restriction fragment length polymorphism (PCR-RFLP). Results: Patients with the T allele in NQO1*2 (CT or TT genotypes) had a higher risk of bleeding than patients with the CC genotype (adjusted OR: 2.25, 95% CI: 1.37 to 3.70, P = 0.001). Those who were carriers of CYP2C9 one-variant haplotypes (*1/*2 or *1/*3) were also found to be associated with the higher risk of bleeding events. Compared to reference group (*1/*1), the odds of bleeding increased for carriers of one variant allele (*1/*2 or *1/*3) (adjusted OR: 1.75, 95% CI: 1.03 to 2.97, P = 0.039). Variant VKORC1, Factor VII, and EPHX1 genotypes were not significantly associated with the risk of bleeding events. Conclusion: The SNP C609T within NQO1 and haplotypes of CYP2C9 (1*2 or 1*3) are independently associated to bleeding complications of warfarin at normal INR. Further studies are required to confirm such associations in diverse racial and ethnic populations. - Highlights: • NQO1 C609T variant is associated with warfarin induced bleeding at therapeutic INR. • Haplotypes of CYP2C9 (1*2 or 1*3) are also associated with bleeding events. • VKORC1, Factor VII, and EPHX1 genotypes were not associated with bleeding risk.

The effect of broad-spectrum antibiotics on warfarin excretion and metabolism in the rat

International Nuclear Information System (INIS)

Remmel, R.P.; Elmer, G.W.

1981-01-01

The excretion and metabolism of 14 C-warfarin in rats was examined in a crossover experiment, the first phase consisting of treatment with normal saline, the second phase using the same animals given neomycin, bacitracin, and tetracycline orally. Urine and feces were collected every 24 hours for 72 hours and examined for warfarin and its metabolites, both unconjugated and conjugated. Significantly more radioactivity was eliminated in th feces of antibiotic-treated rats. The feces of antibiotic-treated rats contained only trace amounts of beta-glucuronidase activity. Urine contained a similar ratio of unconjugated to conjugated radioactivity in both treatment groups, but the antibiotic-treated animals had significantly larger amount of conjugates in their feces. Examination of metabolic profiles of conjugated and unconjugated fractions revealed significantly fewer hydroxylated metabolites in antibiotic-treated rats, especially in the feces. The lower amount of hydroxylative metabolism in attributed to a reduction in gut flora-medicated interohepatic recycling caused by the antibiotics

Rivaroxaban in antiphospholipid syndrome (RAPS) protocol: a prospective, randomized controlled phase II/III clinical trial of rivaroxaban versus warfarin in patients with thrombotic antiphospholipid syndrome, with or without SLE.

Science.gov (United States)

Cohen, H; Doré, C J; Clawson, S; Hunt, B J; Isenberg, D; Khamashta, M; Muirhead, N

2015-09-01

The current mainstay of the treatment of thrombotic antiphospholipid syndrome (APS) is long-term anticoagulation with vitamin K antagonists (VKAs) such as warfarin. Non-VKA oral anticoagulants (NOACs), which include rivaroxaban, have been shown to be effective and safe compared with warfarin for the treatment of venous thromboembolism (VTE) in major phase III prospective, randomized controlled trials (RCTs), but the results may not be directly generalizable to patients with APS. The primary aim is to demonstrate, in patients with APS and previous VTE, with or without systemic lupus erythematosus (SLE), that the intensity of anticoagulation achieved with rivaroxaban is not inferior to that of warfarin. Secondary aims are to compare rates of recurrent thrombosis, bleeding and the quality of life in patients on rivaroxaban with those on warfarin. Rivaroxaban in antiphospholipid syndrome (RAPS) is a phase II/III prospective non-inferiority RCT in which eligible patients with APS, with or without SLE, who are on warfarin, target international normalized ratio (INR) 2.5 for previous VTE, will be randomized either to continue warfarin (standard of care) or to switch to rivaroxaban. Intensity of anticoagulation will be assessed using thrombin generation (TG) testing, with the primary outcome the percentage change in endogenous thrombin potential (ETP) from randomization to day 42. Other TG parameters, markers of in vivo coagulation activation, prothrombin fragment 1.2, thrombin antithrombin complex and D-dimer, will also be assessed. If RAPS demonstrates i) that the anticoagulant effect of rivaroxaban is not inferior to that of warfarin and ii) the absence of any adverse effects that cause concern with regard to the use of rivaroxaban, this would provide sufficient supporting evidence to make rivaroxaban a standard of care for the treatment of APS patients with previous VTE, requiring a target INR of 2.5. © The Author(s) 2015.

Apixaban 5 and 2.5 mg twice-daily versus warfarin for stroke prevention in nonvalvular atrial fibrillation patients: Comparative effectiveness and safety evaluated using a propensity-score-matched approach.

Science.gov (United States)

Li, Xiaoyan; Keshishian, Allison; Hamilton, Melissa; Horblyuk, Ruslan; Gupta, Kiran; Luo, Xuemei; Mardekian, Jack; Friend, Keith; Nadkarni, Anagha; Pan, Xianying; Lip, Gregory Y H; Deitelzweig, Steve

2018-01-01

Prior real-world studies have shown that apixaban is associated with a reduced risk of stroke/systemic embolism (stroke/SE) and major bleeding versus warfarin. However, few studies evaluated the effectiveness and safety of apixaban according to its dosage, and most studies contained limited numbers of patients prescribed 2.5 mg twice-daily (BID) apixaban. Using pooled data from 4 American claims database sources, baseline characteristics and outcomes for patients prescribed 5 mg BID and 2.5 mg BID apixaban versus warfarin were compared. After 1:1 propensity-score matching, 31,827 5 mg BID apixaban-matched warfarin patients and 6600 2.5 mg BID apixaban-matched warfarin patients were identified. Patients prescribed 2.5 mg BID apixaban were older, had clinically more severe comorbidities, and were more likely to have a history of stroke and bleeding compared with 5 mg BID apixaban patients. Compared with warfarin, 5 mg BID apixaban was associated with a lower risk of stroke/SE (hazard ratio [HR]: 0.70, 95% confidence interval [CI]: 0.60-0.81) and major bleeding (HR: 0.59, 95% CI: 0.53-0.66). Compared with warfarin, 2.5 mg BID apixaban was also associated with a lower risk of stroke/SE (HR: 0.63, 95% CI: 0.49-0.81) and major bleeding (HR: 0.59, 95% CI: 0.49-0.71). In this real-world study, both apixaban doses were assessed in 2 patient groups differing in age and clinical characteristics. Each apixaban dose was associated with a lower risk of stroke/SE and major bleeding compared with warfarin in the distinct population for which it is being prescribed in United States clinical practice. Clinicaltrials.Gov Identifier: NCT03087487.

Low-molecular-weight heparinoid compared with warfarin for prophylaxis of deep-vein thrombosis in patients who are operated on for fracture of the hip. A prospective, randomized trial

International Nuclear Information System (INIS)

Gerhart, T.N.; Yett, H.S.; Robertson, L.K.; Lee, M.A.; Smith, M.; Salzman, E.W.

1991-01-01

In a randomized, prospective trial, a low-molecular-weight heparinoid (Org 10172 [Lomoparan]) was compared with warfarin for efficacy and safety in preventing deep-vein thrombosis in 263 patients who had an operatively treated fracture of the hip. One group of patients received Org 10172 in a dose of 750 units subcutaneously every twelve hours until the ninth postoperative day; on the seventh postoperative day, warfarin was added to the regimen. The other group received only warfarin. Both drugs were begun preoperatively, immediately after the admission evaluation. In the patients who received warfarin, the desired prothrombin time was one and one-half times the control level. Deep-vein thrombosis was detected by 125 I-fibrinogen scanning and impedance plethysmography and was confirmed by phlebography and compression ultrasonography. Deep-vein thrombosis was found in nine (7 per cent) of the 132 patients who received Org 10172 and in twenty-eight (21 per cent) of the 131 patients who received warfarin (p less than 0.001). Adverse reactions were not significantly different in the two groups. Major bleeding complications occurred in eight patients in the Org-10172 group, only four of whom were receiving the drug at the time of bleeding, and in five patients who were receiving warfarin (not significant). There was no difference in intraoperative loss of blood or in requirements for transfusion. We concluded that the low-molecular-weight heparinoid Org 10172 is a safe, convenient, effective antithrombotic agent for the prevention of venous thrombosis after an operation for fracture of the hip

[Gene polymorphism of CYP450 2C9 and VKORC1 in Chinese population and their relationships to the maintaining dosage of warfarin].

Science.gov (United States)

Zhang, Ya-nan; Cui, Wei; Han, Mei; Zheng, Bin; Liu, Fan; Xie, Rui-qin; Yang, Xiao-hong; Gu, Guo-qiang; Zheng, Hong-mei; Wen, Jin-kun

2010-02-01

To investigate the distribution of gene polymorphism of CYP450 2C9 and VKORC1-1639A/G in the Chinese population as well as the difference of genetic polymorphism between Chinese Han population and other ethnic populations. Contribution of CYP2C9 and VKORC1 genotype to the maintenance doses on warfarin was also studied. The genotype and allele frequencies were calculated and compared with those in other populations. One hundred and one patients with stable anticoagulation with warfarin under a target international normalized ratio (INR) of 2.0 to 3.0 were enrolled for studying the relationship between the CYP2C9 and VKORC1 gene polymorphism and the warfarin maintaining dosage. CYP450 2C9*3 + 1075C/A allele frequencies were:AA in 449 cases (92.2%), AC in 36 cases (7.4%) and CC in 2 cases (0.4%), respectively. VKORC1 -1639A/G allele frequencies were AA in 415 cases (85.2%), GA in 72 cases (14.8%), but GG in no case (0.0%), respectively. When linear stepwise regression analysis was used to identify factors contributing to warfarin stable dose, the final equation was: ln (D) = 0.346 + 0.017 (weight) - 0.376 (CYP450 2C9*3 + 1075C/A) + 0.148 (VKORC1-1639A/G) - 0.002 (age) (r = 0.827, P = 0.02). There existed significant gene polymorphism CYP450 2C9*3 + 1075C/A and VKORC1-1639A/G in the Chinese Han population. Both Gene polymorphisms of CYP450 2C9*3 + 1075C/A and VKORC1-1639A/G were significantly affecting the maintaining dose of warfarin in the Chinese population.

Clinical presentation and course of bleeding events in patients with venous thromboembolism, treated with apixaban or enoxaparin and warfarin. Results from the AMPLIFY trial.

Science.gov (United States)

Bleker, Suzanne M; Cohen, Alexander T; Büller, Harry R; Agnelli, Giancarlo; Gallus, Alexander S; Raskob, Gary E; Weitz, Jeffrey I; Curto, Madelyn; Sisson, Melanie; Middeldorp, Saskia

2016-11-30

Apixaban, a direct acting oral anticoagulant (DOAC), was found to be non-inferior to and safer as enoxaparin followed by warfarin for treatment of venous thromboembolism (VTE) in the AMPLIFY trial. Information is needed on how bleeding events with DOACs present and develop. In this post-hoc analysis, the clinical presentation and course of all major and clinically relevant non major (CRNM) bleeding events in the AMPLIFY trial were blindly classified by three investigators, using pre-designed classification schemes containing four categories. Odds ratios (OR) for classifying as category three or four (representing a more severe clinical presentation and course) were calculated between apixaban and enoxaparin/warfarin. In total, 63 major and 311 CRNM bleeding events were classified. Of the major bleeds, a more severe clinical presentation occurred in 28.5 % of apixaban versus 44.9 % of enoxaparin/warfarin related recipients (OR 0.49, 95 % confidence interval [CI] 0.14-1.78). A severe clinical course was observed in 14.3 % and in 12.2 %, respectively (OR 1.19, 95 %CI 0.21-6.69). Of the CRNM bleeding events, a more severe clinical presentation and extent of clinical care was found in 25 % of apixaban recipients compared to 22.7 % in the enoxaparin/warfarin group (OR 1.13, 95 %CI 0.65-1.97). The clinical presentation and course of major and CRNM bleeds were similar in apixaban and enoxaparin/warfarin treated patients. This finding should reassure physicians and patients that even in the absence of a specific reversal agent, apixaban is a convenient and safe choice for VTE.

A race-specific interaction between vitamin K status and statin use during warfarin therapy initiation

Science.gov (United States)

Vitamin K (VK) is required for the post-translational modification of several clotting factors. Warfarin is a vitamin K antagonist and anticoagulant. The most common dietary and circulating form of VK is phylloquinone (PK). PK is lipid soluble, carried by triglyceride-rich lipoproteins, and shares a...

Development of predictive models for estimating warfarin maintenance dose based on genetic and clinical factors.

Science.gov (United States)

Yang, Lu; Linder, Mark W

2013-01-01

In this chapter, we use calculation of estimated warfarin maintenance dosage as an example to illustrate how to develop a multiple linear regression model to quantify the relationship between several independent variables (e.g., patients' genotype information) and a dependent variable (e.g., measureable clinical outcome).

Automation of complex assays: pharmacogenetics of warfarin dosing.

Science.gov (United States)

Wu, Whei-Kuo; Hujsak, Paul G; Kureshy, Fareed

2007-10-01

AutoGenomics, Inc. (Carlsbad, CA, USA) have developed a multiplex microarray assay for genotyping both VKORC1 and CYP2C9 using the INFINITI(™) Analyzer. Multiple alleles in each DNA sample are analyzed by polymerase chain reaction amplification, followed by detection primer extension using the INFINITI Analyzer. The INFINITI Analyzer performs single-nucleotide polymorphism (SNP) analysis using universal oligonucleotides immobilized on the biochip. To genotype broader ethnic groups, genomic DNA from whole blood was tested for nine SNPs for VKORC1 and six for CYP2C9 genotypes. Information related to all 15 SNPs is needed to determine dosing of population of diverse ethnic origin. The INFINITI system provides genotyping information for same day dosing of warfarin.

Extensive small bowel intramural haematoma secondary to warfarin.

Science.gov (United States)

Limmer, Alexandra M; Clement, Zackariah

2017-03-01

Intramural haematoma is a rare complication of oral anticoagulant therapy, occurring in  1 in 2500 patients treated with warfarin. This report describes a 71-year-old gentleman who presented with tachycardia, vomiting and abdominal distension on a background of anticoagulation for a metallic aortic valve. He was found to have a supratherapeutic international normalized ratio (INR) of 9.9 with an extensive small bowel intramural haematoma and secondary small bowel obstruction. He was successfully managed non-operatively with fluid resuscitation, INR reversal, bowel rest and nasogastric decompression. The patient's presentation was atypical with a lack of classic symptoms such as abdominal pain. This highlights the importance of considering intramural haematoma as a differential diagnosis for gastrointestinal symptoms in anticoagulated patients.

The influence of VKORC1 and CYP2C9 gene sequence variants on the stability of maintenance phase warfarin treatment

DEFF Research Database (Denmark)

Skov, Jane; Bladbjerg, Else-Marie; Leppin, Anja

2013-01-01

alleles require lower doses and have increased risk of overanticoagulation. METHODS: We investigated the influence of the above sequence variants on stability of maintenance phase warfarin therapy in a prospective study of 300 consecutive patients followed for one year at an anticoagulant clinic. RESULTS...... of common gene sequence variants in CYP2C9 and VKORC1 on stability of maintenance phase warfarin therapy. Patients attending an anticoagulant clinic using computer-assisted dosage were safely monitored regardless of these sequence variants, but for the small subgroup of patients with the CYP2C9 genotype *2...

The Value of Evidence in the Decision-Making Process for Reimbursement of Pharmacogenetic Dosing of Warfarin.

Science.gov (United States)

Janzic, Andrej; Locatelli, Igor; Kos, Mitja

2017-10-01

After early clinical trials that evaluated pharmacogenetic (PG) algorithms, many healthcare payers were reluctant to cover this technology and, consequently, PG dosing of warfarin could not be translated into clinical practice. The aim of this study was to estimate the value of upgrading evidence relating to PG dosing of warfarin from the healthcare payer perspective. Randomized controlled trials (RCTs) that evaluated PG dosing of warfarin were identified through a systematic literature search, and their findings were combined by a cumulative meta-analysis. A health economic model was used to estimate economic outcomes and to calculate the expected value of perfect information (EVPI) as a measure of the value of clinical trials for decision makers. Nine RCTs were identified and included in our analysis. The estimated difference in the percentage of time in the therapeutic range was 5.6 percentage points in 2007, decreasing to 4.3 percentage points when all studies were included. At a reimbursement price of €160 per PG testing, the EVPI for the clinical benefit was estimated at €80 and €90 per patient in 2007 and 2014, respectively. A reduction in the price of PG testing to €40, which was observed in this period, resulted in an EVPI of €3 per patient. The estimated cumulative effect of PG dosing has remained similar since 2007, but additional evidence has contributed to a more precise estimation. While these variations should not affect the reimbursement decision, a large decline in the cost of PG testing in recent years calls for reconsideration.

Intramural duodenal hematoma as a complication of therapy with Warfarin: a case report and literature review; Hematoma intramural duodenal como complicacao de terapia anticoagulante com Warfarin: relato de caso e revisao da literatura

Energy Technology Data Exchange (ETDEWEB)

Faria, Juliano [Universidade Federal de Sao Paulo (UNIFESP/EPM), SP (Brazil). Dept. de Diagnostico por Imagem]. E-mail: drjuliano@uol.com.br; Pessoa, Roberta; Hudson, Marcelo; Vitoi, Silvio; Villela, Ovidio; Torres, Jose; Paula, Mara Delgado [Hospital Marcio Cunha, Ipatinga, MG (Brazil). Servico de Diagnostico por Imagem; Bemvindo, Aloisio [Hospital Marcio Cunha, Ipatinga, MG (Brazil). Servico de Terapia Intensiva

2004-12-01

We report a case of a patient receiving chronic oral anticoagulant therapy with Warfarin who presented with acute intestinal obstruction. Computed tomography showed intramural duodenal hematoma. Treatment was conservative with correction of the coagulation parameters and observation. This case exemplifies the usefulness of conservative therapy and computed tomography in patients with acute small bowel obstruction receiving anticoagulant therapy. (author)

Warfarin improves the outcome of infrainguinal vein bypass grafting at high risk for failure.

Science.gov (United States)

Sarac, T P; Huber, T S; Back, M R; Ozaki, C K; Carlton, L M; Flynn, T C; Seeger, J M

1998-09-01

Patients with marginal venous conduit, poor arterial runoff, and prior failed bypass grafts are at high risk for infrainguinal graft occlusion and limb loss. We sought to evaluate the effects of anticoagulation therapy after autogenous vein infrainguinal revascularization on duration of patency, limb salvage rates, and complication rates in this subset of patients. This randomized prospective trial was performed in a university tertiary care hospital and in a Veterans Affairs Hospital. Fifty-six patients who were at high risk for graft failure were randomized to receive aspirin (24 patients, 27 bypass grafts) or aspirin and warfarin (WAR; 32 patients, 37 bypass grafts). All patients received 325 mg of aspirin each day, and the patients who were randomized to warfarin underwent anticoagulation therapy with heparin immediately after surgery and then were started on warfarin therapy to maintain an international normalized ratio between 2 and 3. Perioperative blood transfusions and complications were compared with the Student t test or with the chi2 test. Graft patency rates, limb salvage rates, and survival rates were compared with the Kaplan-Meier method and the log-rank test. Sixty-one of the 64 bypass grafts were performed for rest pain or tissue loss, and 3 were performed for short-distance claudication. There were no differences between the groups in ages, indications, bypass graft types, risk classifications (ie, conduit, runoff, or graft failure), or comorbid conditions (except diabetes mellitus). The cumulative 5-year survival rate was similar between the groups. The incidence rate of postoperative hematoma (32% vs 3.7%; P = .004) was greater in the WAR group, but no differences were seen between the WAR group and the aspirin group in the number of packed red blood cells transfused, in the incidence rate of overall nonhemorrhagic wound complications, or in the overall complication rate (62% vs 52%). The immediate postoperative primary graft patency rates (97

Determination of a safe INR for joint injections in patients taking warfarin.

Science.gov (United States)

Bashir, M A; Ray, R; Sarda, P; Li, S; Corbett, S

2015-11-01

With an increase in life expectancy in 'developed' countries, the number of elderly patients receiving joint injections for arthritis is increasing. There are legitimate concerns about an increased risk of thromboembolism if anticoagulation is stopped or reversed for such an injection. Despite being a common dilemma, the literature on this issue is scarce. We undertook 2,084 joint injections of the knee and shoulder in 1,714 patients between August 2008 and December 2013. Within this cohort, we noted 41 patients who were taking warfarin and followed them immediately after joint injection in the clinic or radiology department, looking carefully for complications. Then, we sought clinical follow-up, correspondence, and imaging evidence for 4 weeks, looking for complications from these joint injections. We recorded International Normalised Ratio (INR) values before injection. No complications were associated with the procedure after any joint injection. The radiologists who undertook ultrasound-guided injections to shoulders re-scanned the joints looking for haemarthroses: they found none. A similar outcome was noted clinically after injections in the outpatient setting. With a mean INR of 2.77 (range, 1.7-5.5) and a maximum INR within this group of 5.5, joint injections to the shoulder and knee can be undertaken safely in primary or secondary care settings despite the patient taking warfarin.

Determination of acid dissociation constants of warfarin and hydroxywarfarins by capillary electrophoresis.

Science.gov (United States)

Nowak, Paweł; Olechowska, Paulina; Mitoraj, Mariusz; Woźniakiewicz, Michał; Kościelniak, Paweł

2015-08-10

In this work the acid dissociation constants--pKa of warfarin and its all important oxidative metabolites have been determined by capillary electrophoresis-based methods. It has resulted in a complete description of two acid-base dissociation equilibria, yet not investigated experimentally for phase I metabolites of warfarin. The capillary electrophoresis (CE) method based on the relation between effective electrophoretic mobilities and pH has proven to be a suitable tool for pKa determination, while the spectrophotometric (CE-DAD) and the internal standard methods (IS-CE), have appeared to be promising alternative approaches. The CE-DAD approach based on the change in absorbance spectra between the acidic and basic forms is a combination between capillary electrophoresis and spectrophotometric titration, and yields very consistent values of pKa1 with CE. The IS-CE, in turn, enables an estimation of pKa1 and pKa2 from only two analytical runs, however, less accurate than CE and CE-DAD. The Debye-Hückel model has been confirmed experimentally as a good predictor of pKa values at various ionic strengths. Therefore, it has been used in determination of thermodynamic pKa1 and pKa2, referring to the zero ionic strength. The results are important from the analytical, pharmacological, and theoretical points of view. Copyright © 2015 Elsevier B.V. All rights reserved.

Apixaban compared with warfarin in patients with atrial fibrillation and previous stroke or transient ischaemic attack

DEFF Research Database (Denmark)

Easton, J Donald; Lopes, Renato D; Bahit, M Cecilia

2012-01-01

In the ARISTOTLE trial, the rate of stroke or systemic embolism was reduced by apixaban compared with warfarin in patients with atrial fibrillation (AF). Patients with AF and previous stroke or transient ischaemic attack (TIA) have a high risk of stroke. We therefore aimed to assess the efficacy ...

A Retroperitoneal Leiomyosarcoma Presenting as an Adrenal Incidentaloma in a Subject on Warfarin

Directory of Open Access Journals (Sweden)

Ishrat N. Khan

2015-01-01

Full Text Available Adrenal incidentalomas (AIs are mostly benign and nonsecretory. Management algorithms lack sensitivity when assessing malignant potential, although functional status is easier to assess. We present a subject whose AI was a retroperitoneal leiomyosarcoma (RL. Case Presentation. A woman on warfarin with SLE and the antiphospholipid syndrome, presented with left loin pain. She was normotensive and clinically normal. Ultrasound scans demonstrated left kidney scarring, but CT scans revealed an AI. MRI scans later confirmed the AI without significant fat and no interval growth. Cortisol after 1 mg dexamethasone, urinary free cortisol and catecholamines, plasma aldosterone renin ratio, and 17-hydroxyprogesterone were within the reference range. Initially, adrenal haemorrhage was diagnosed because of warfarin therapy and the acute presentation. However, she underwent adrenalectomy because of interval growth of the AI. Histology confirmed an RL. The patient received adjuvant radiotherapy. Discussion. Our subject presented with an NSAI. However, we highlight the following: (a the diagnosis of adrenal haemorrhage in this anticoagulated woman was revised because of interval growth; (b the tumour, an RL, was relatively small at diagnosis; (c this subject has survived well over 60 months despite an RL perhaps because of her acute presentation and early diagnosis of a small localised tumour.

A Retroperitoneal Leiomyosarcoma Presenting as an Adrenal Incidentaloma in a Subject on Warfarin.

Science.gov (United States)

Khan, Ishrat N; Adlan, Mohamed A; Stechman, Michael J; Premawardhana, Lakdasa D

2015-01-01

Adrenal incidentalomas (AIs) are mostly benign and nonsecretory. Management algorithms lack sensitivity when assessing malignant potential, although functional status is easier to assess. We present a subject whose AI was a retroperitoneal leiomyosarcoma (RL). Case Presentation. A woman on warfarin with SLE and the antiphospholipid syndrome, presented with left loin pain. She was normotensive and clinically normal. Ultrasound scans demonstrated left kidney scarring, but CT scans revealed an AI. MRI scans later confirmed the AI without significant fat and no interval growth. Cortisol after 1 mg dexamethasone, urinary free cortisol and catecholamines, plasma aldosterone renin ratio, and 17-hydroxyprogesterone were within the reference range. Initially, adrenal haemorrhage was diagnosed because of warfarin therapy and the acute presentation. However, she underwent adrenalectomy because of interval growth of the AI. Histology confirmed an RL. The patient received adjuvant radiotherapy. Discussion. Our subject presented with an NSAI. However, we highlight the following: (a) the diagnosis of adrenal haemorrhage in this anticoagulated woman was revised because of interval growth; (b) the tumour, an RL, was relatively small at diagnosis; (c) this subject has survived well over 60 months despite an RL perhaps because of her acute presentation and early diagnosis of a small localised tumour.

Rivaroxaban vs Warfarin Sodium in the Ultra-Early Period After Atrial Fibrillation-Related Mild Ischemic Stroke: A Randomized Clinical Trial.

Science.gov (United States)

Hong, Keun-Sik; Kwon, Sun U; Lee, Sang Hun; Lee, Ji Sung; Kim, Yong-Jae; Song, Tae-Jin; Kim, Young Dae; Park, Man-Seok; Kim, Eung-Gyu; Cha, Jae-Kwan; Sung, Sang Min; Yoon, Byung-Woo; Bang, Oh Young; Seo, Woo-Keun; Hwang, Yang-Ha; Ahn, Seong Hwan; Kang, Dong-Wha; Kang, Hyun Goo; Yu, Kyung-Ho

2017-10-01

In atrial fibrillation (AF)-related acute ischemic stroke, the optimal oral anticoagulation strategy remains unclear. To test whether rivaroxaban or warfarin sodium is safer and more effective for preventing early recurrent stroke in patients with AF-related acute ischemic stroke. A randomized, multicenter, open-label, blinded end point evaluation, comparative phase 2 trial was conducted from April 28, 2014, to December 7, 2015, at 14 academic medical centers in South Korea among patients with mild AF-related stroke within the previous 5 days who were deemed suitable for early anticoagulation. Analysis was performed on a modified intent-to-treat basis. Participants were randomized 1:1 to receive rivaroxaban, 10 mg/d for 5 days followed by 15 or 20 mg/d, or warfarin with a target international normalized ratio of 2.0-3.0, for 4 weeks. The primary end point was the composite of new ischemic lesion or new intracranial hemorrhage seen on results of magnetic resonance imaging at 4 weeks. Primary analysis was performed in patients who received at least 1 dose of study medications and completed follow-up magnetic resonance imaging. Key secondary end points were individual components of the primary end point and hospitalization length. Of 195 patients randomized, 183 individuals (76 women and 107 men; mean [SD] age, 70.4 [10.4] years) completed magnetic resonance imaging follow-up and were included in the primary end point analysis. The rivaroxaban group (n = 95) and warfarin group (n = 88) showed no differences in the primary end point (47 [49.5%] vs 48 [54.5%]; relative risk, 0.91; 95% CI, 0.69-1.20; P = .49) or its individual components (new ischemic lesion: 28 [29.5%] vs 31 of 87 [35.6%]; relative risk, 0.83; 95% CI, 0.54-1.26; P = .38; new intracranial hemorrhage: 30 [31.6%] vs 25 of 87 [28.7%]; relative risk, 1.10; 95% CI, 0.70-1.71; P = .68). Each group had 1 clinical ischemic stroke, and all new intracranial hemorrhages were asymptomatic

Sensitive warfarin sensor based on cobalt oxide nanoparticles electrodeposited at multi-walled carbon nanotubes modified glassy carbon electrode (CoxOyNPs/MWCNTs/GCE)

International Nuclear Information System (INIS)

Gholivand, Mohammad Bagher; Solgi, Mohammad

2017-01-01

In this work, cobalt oxide nanoparticles were electrodeposited on multi-walled carbon nanotubes modified glassy carbon electrode (MWCNTs/GCE) to develop a new sensor for warfarin determination. The modified electrodes were characterized by cyclic voltammetry, scanning electron microscopy (SEM) along with energy dispersive x-ray spectroscopy (EDS), and electrochemical impedance spectroscopy (EIS). The presence of cobalt oxide nanoparticles on the electrode surface enhanced the warfarin accumulation and its result was the improvement in the electrochemical response. The effect of various parameters such as pH, scan rate, accumulation potential, accumulation time and pulse amplitude on the sensor response were investigated. Under optimal conditions, the differential pulse adsorptive anodic stripping voltammetric (DPASV) response of the modified electrode was linear in the ranges of 8 nM to 50 μM and 50 μM to 800 μM with correlation coefficients greater than 0.998. The limit of detection of the proposed method was 3.3 nM. The proposed sensor was applied to determine warfarin in urine and plasma samples.

Predictors of perioperative major bleeding in patients who interrupt warfarin for an elective surgery or procedure: Analysis of the BRIDGE trial.

Science.gov (United States)

Clark, Nathan P; Douketis, James D; Hasselblad, Vic; Schulman, Sam; Kindzelski, Andrei L; Ortel, Thomas L

2018-01-01

The use of low-molecular weight heparin bridge therapy during warfarin interruption for elective surgery/procedures increases bleeding. Other predictors of bleeding in this setting are not well described. BRIDGE was a randomized, double-blind, placebo-controlled trial of bridge therapy with dalteparin 100 IU/kg twice daily in patients with atrial fibrillation requiring warfarin interruption. Bleeding outcomes were documented from the time of warfarin interruption until up to 37 days postprocedure. Multiple logistic regression and time-dependent hazard models were used to identify major bleeding predictors. We analyzed 1,813 patients of whom 895 received bridging and 918 received placebo. Median patient age was 72.6 years, and 73.3% were male. Forty-one major bleeding events occurred at a median time of 7.0 days (interquartile range, 4.0-18.0 days) postprocedure. Bridge therapy was a baseline predictor of major bleeding (odds ratio [OR]=2.4, 95% CI: 1.2-4.8), as were a history of renal disease (OR=2.9, 95% CI: 1.4-6.0), and high-bleeding risk procedures (vs low-bleeding risk procedures) (OR=2.9, 95% CI: 1.4-5.9). Perioperative aspirin use (OR=3.6, 95% CI: 1.1-11.9) and postprocedure international normalized ratio >3.0 (OR=2.1, 95% CI: 1.5-3.1) were time-dependent predictors of major bleeding. Major bleeding was most common in the first 10 days compared with 11-37 days postprocedure (OR=3.5, 95% CI: 1.8-6.9). In addition to bridge therapy, perioperative aspirin use, postprocedure international normalized ratio >3.0, a history of renal failure, and having a high-bleeding risk procedure increase the risk of major bleeding around the time of an elective surgery/procedure requiring warfarin interruption. Copyright © 2017 Elsevier Inc. All rights reserved.

Efficacy and safety of apixaban compared with warfarin according to age for stroke prevention in atrial fibrillation: observations from the ARISTOTLE trial

Science.gov (United States)

Halvorsen, Sigrun; Atar, Dan; Yang, Hongqiu; De Caterina, Raffaele; Erol, Cetin; Garcia, David; Granger, Christopher B.; Hanna, Michael; Held, Claes; Husted, Steen; Hylek, Elaine M.; Jansky, Petr; Lopes, Renato D.; Ruzyllo, Witold; Thomas, Laine; Wallentin, Lars

2014-01-01

Aims The risk of stroke in patients with atrial fibrillation (AF) increases with age. In the ARISTOTLE trial, apixaban when compared with warfarin reduced the rate of stroke, death, and bleeding. We evaluated these outcomes in relation to patient age. Methods and results A total of 18 201 patients with AF and a raised risk of stroke were randomized to warfarin or apixaban 5 mg b.d. with dose reduction to 2.5 mg b.d. or placebo in 831 patients with ≥2 of the following criteria: age ≥80 years, body weight ≤60 kg, or creatinine ≥133 μmol/L. We used Cox models to compare outcomes in relation to patient age during 1.8 years median follow-up. Of the trial population, 30% were 0.11 for all). Results were also consistent for the 13% of patients ≥80 years. No significant interaction with apixaban dose was found with respect to treatment effect on major outcomes. Conclusion The benefits of apixaban vs. warfarin were consistent in patients with AF regardless of age. Owing to the higher risk at older age, the absolute benefits of apixaban were greater in the elderly. PMID:24561548

Non-vitamin K antagonist oral anticoagulants versus warfarin for the prevention of spontaneous echo-contrast and thrombus in patients with atrial fibrillation or flutter undergoing cardioversion: A trans-esophageal echocardiography study.

Science.gov (United States)

Kim, Yun Gi; Choi, Jong-Il; Kim, Mi-Na; Cho, Dong-Hyuk; Oh, Suk-Kyu; Kook, Hyungdon; Park, Hee-Soon; Lee, Kwang No; Baek, Yong-Soo; Roh, Seung-Young; Shim, Jaemin; Park, Seong-Mi; Shim, Wan Joo; Kim, Young-Hoon

2018-01-01

Spontaneous echo-contrast (SEC) and thrombus observed in trans-esophageal echocardiography (TEE) is known as a strong surrogate marker for future risk of ischemic stroke in patients with atrial fibrillation (AF) or atrial flutter (AFL). The efficacy of non-vitamin K antagonist oral anticoagulants (NOAC) compared to warfarin to prevent SEC or thrombus in patients with AF or AFL is currently unknown. AF or AFL patients who underwent direct current cardioversion (DCCV) and pre-DCCV TEE evaluation from January 2014 to October 2016 in a single center were analyzed. The prevalence of SEC and thrombus were compared between patients who received NOAC and those who took warfarin. NOAC included direct thrombin inhibitor and factor Xa inhibitors. Among 1,050 patients who were considered for DCCV, 424 patients anticoagulated with warfarin or NOAC underwent TEE prior to DCCV. Eighty patients who were anticoagulated for less than 21 days were excluded. Finally, 344 patients were included for the analysis (180 warfarin users vs. 164 NOAC users). No significant difference in the prevalence of SEC (44.4% vs. 43.9%; p = 0.919), dense SEC (13.9% vs. 15.2%; p = 0.722), or thrombus (2.2% vs. 4.3%; p = 0.281) was observed between the warfarin group and the NOAC group. In multivariate analysis, there was no association between NOAC and risk of SEC (odds ratio [OR]: 1.4, 95% CI: 0.796-2.297, p = 0.265) or thrombus (OR: 3.4, 95% CI: 0.726-16.039, p = 0.120). In conclusion, effectiveness of NOAC is comparable to warfarin in preventing SEC and thrombus in patients with AF or AFL undergoing DCCV. However, numerical increase in the prevalence of thrombus in NOAC group warrants further evaluation.

The Effect of Medicinal Education on Adherence Taking Warfarin in Acute Coronary Syndrome (ACS and Atrial Fibrilation (AF Patients at PKU Muhammadiyah Yogyakarta Hospital

Directory of Open Access Journals (Sweden)

Jastria Pusmarani

2015-12-01

Full Text Available In order to improve warfarin medication adherence in patient with Acute Coronary Syndrome (ACS and Atrial Fibrillation (AF, giving education with leaflet administration is one of the solutions. This study was aim to know the impact of pharmacist education with using prepared leaflet on the adherence to warfarin in ACS and AF patients. This study used pre test and post test with control group design. Data were collected prospectively during 8 weeks in June–July 2014 at the ambulatory ACS and AF patients at PKU Muhammadiyah Yogyakarta hospital, Indonesia. Data were collected by medical record and the questionnaire using Morisky Medication Adherence Scale (MMAS. Wilcoxon test was used for statistical analysis. The results shows pre test and post test value in the control group was p=0.194 and pre and post test value in the test group was p=0.058. There was no significant difference (p>0.05 after giving education with leaflet. The education with leaflet had no effect to adherence in warfarin in ACS and AF patients at PKU Muhammadiyah Yogyakarta hospital.

Best strategies for patient education about anticoagulation with warfarin: a systematic review

Directory of Open Access Journals (Sweden)

Singh Sonal

2008-02-01

Full Text Available Abstract Background Patient education is an essential component in quality management of the anticoagulated patient. Because it is time consuming for clinicians and overwhelming for patients, education of the anticoagulated patient is often neglected. We surveyed the medical literature in order to identify the best patient education strategies. Methods Study Selection: Two reviewers independently searched the MEDLINE and Google Scholar databases (last search March 2007 using the terms "warfarin" or "anticoagulation", and "patient education". The initial search identified 206 citations, A total of 166 citations were excluded because patients were of pediatric age (4, the article was not related to patient education (48, did not contain original data or inadequate program description (141, was focused solely on patient self-testing (1, was a duplicate citation (3, the article was judged otherwise irrelevant (44, or no abstract was available (25. Data Extraction: Clinical setting, study design, group size, content source, time and personnel involved, educational strategy and domains, measures of knowledge retention. Results Data Synthesis: A total of 32 articles were ultimately used for data extraction. Thirteen articles adequately described features of the educational strategy. Five programs used a nurse or pharmacist, 4 used a physician, and 2 studies used other personnel/vehicles (lay educators (1, videotapes (1. The duration of the educational intervention ranged from 1 to 10 sessions. Patient group size most often averaged 3 to 5 patients but ranged from as low as 1 patient to as much as 11 patients. Although 12 articles offered information about education content, the wording and lack of detail in the description made it too difficult to accurately assign categories of education topics and to compare articles with one another. For the 17 articles that reported measures of patient knowledge, 5 of the 17 sites where the surveys were

Vitamin K2 regression aortic calcification induced by warfarin via Gas6/Axl survival pathway in rats.

Science.gov (United States)

Jiang, Xiaoyu; Tao, Huiren; Qiu, Cuiting; Ma, Xiaolei; Li, Shan; Guo, Xian; Lv, Anlin; Li, Huan

2016-09-05

The aim of this study was to investigate the effect of vitamin K2 on aortic calcification induced by warfarin via Gas6/Axl survival pathway in rats. A calcification model was established by administering 3mg/g warfarin to rats. Rats were divided into 9 groups: control group (0W, 4W, 6W and 12W groups), 4W calcification group, 6W calcification group, 12W calcification group, 6W calcification+6W normal group and 6W calcification+6W vitamin K2 group. Alizarin red S staining measured aortic calcium depositions; alkaline phosphatase activity in serum was measured by a kit; apoptosis was evaluated by TUNEL assay; protein expression levels of Gas6, Axl, phosphorylated Akt (p-Akt), and Bcl-2 were determined by western blotting. The calcium content, calcium depositions, ALP activity and apoptosis were significantly higher in the calcification groups than control group. Gas6, Axl, p-Akt and Bcl-2 expression was lower in the calcification group than control group. 100μg/g vitamin K2 treatment decreased calcium depositions, ALP activity and apoptosis significantly, but increased Gas6, Axl, p-Akt and Bcl-2 expression. 100μg/g vitamin K2 reversed 44% calcification. Pearson correlation analysis showed a positive correlation between formation calcification and apoptosis (R(2)=0.8853, PK2 can inhibit warfarin-induced aortic calcification and apoptosis. The regression of aortic calcification by vitamin K2 involved the Gas6/Axl axis. This data may provide a theoretical basis for future clinical treatments for aortic calcification. Copyright © 2016 Elsevier B.V. All rights reserved.

Nonuremic calciphylaxis precipitated by teriparatide [rhPTH(1-34)] therapy in the setting of chronic warfarin and glucocorticoid treatment.

Science.gov (United States)

Spanakis, E K; Sellmeyer, D E

2014-04-01

Calciphylaxis occurs rarely in the absence of end stage renal disease. Predisposing factors for nonuremic calciphylaxis (NUC) include hyperparathyroidism, coagulopathies, connective tissue disease, liver disease, glucocorticoid use, and malignancy. Warfarin can facilitate vascular calcification by reducing vitamin K-dependent carboxylation of matrix-Gla proteins. An 86-year-old Caucasian woman with a history of polymyalgia rheumatica, two spontaneous deep venous thromboses (DVTs) and multiple fractures was treated with calcium, vitamin D, prednisone, and warfarin. The patient's low bone density was treated initially with estrogen, then oral bisphosphonate, which was discontinued due to upper gastrointestinal symptoms. Nasal calcitonin was initiated. After 10 years of calcitonin treatment, she was changed to teriparatide. Two months after initiating teriparatide, she developed lower extremity edema and painful erythematous nodular lesions on her calves bilaterally, that progressed to necrotic ulcers despite antibiotic therapy. Biopsy of the lesions showed calcification in the media of small blood vessels and subcutaneous fat with fat necrosis, consistent with calciphylaxis. Teriparatide was discontinued. Aggressive wound care, antibiotics, and intravenous zoledronic acid were initiated. With cessation of teriparatide therapy and intensive wound care, the patient's lesions resolved over 8 months. We report the first case of NUC precipitated by teriparatide therapy. Our patient had multiple underlying predisposing factors including a connective tissue disorder, glucocorticoid therapy, warfarin use, and possible underlying coagulopathy given her history of multiple DVTs. In such patients, alternative osteoporosis therapies may be preferred.

Dentists' approach to patients on anti-platelet agents and warfarin: a survey of practice.

LENUS (Irish Health Repository)

Murphy, James

2010-04-23

In everyday practice, dentists are confronted with the dilemma of patients on anti-platelet agents and warfarin who require invasive dental procedures and, more pertinently, dental extractions. There may be a divergence of opinion among dentists regarding how they manage these patients. AIMS: To assess general dental practitioners\\' approach to the management of patients taking anti-platelet agents and\\/or warfarin who are undergoing invasive dental procedures. METHODS AND DATA: A semi-structured questionnaire was designed to survey general dental practitioners in a large Irish urban area. RESULTS: A response rate of 89% was achieved in a study population of 54 general dental practitioners. A total of 25% of respondents who carry out extractions on warfarinised patients do not check the INR prior to invasive dental procedures. Some 90% of respondents stop anti-platelet agents prior to extractions. CONCLUSIONS: A significant proportion of respondents fail to check warfarinised patients\\' INR prior to invasive dental procedures. Furthermore, a trend of stopping anti-platelet agents was noted, which is in contrast with current recommendations in the dental literature. Certain practices in this small study population proved alarming and highlight the need for improved awareness of current guidelines. A further large-scale study may be justified, as variation in practice may have clinical and medico-legal repercussions.

Apixaban 5 and 2.5 mg twice-daily versus warfarin for stroke prevention in nonvalvular atrial fibrillation patients

DEFF Research Database (Denmark)

Li, Xiaoyan; Keshishian, Allison; Hamilton, Melissa

2018-01-01

Prior real-world studies have shown that apixaban is associated with a reduced risk of stroke/systemic embolism (stroke/SE) and major bleeding versus warfarin. However, few studies evaluated the effectiveness and safety of apixaban according to its dosage, and most studies contained limited numbe...

Dietary Vitamin K intake and anticoagulation control during the initiation phase of warfarin therapy: A prospective cohort study

Science.gov (United States)

The effect of varying levels of dietary vitamin K intake on therapeutic International Normalized Ratio (INR) values among patients starting warfarin therapy has not been well studied. We performed a prospective cohort study among 282 patients to explore the independent associations between usual in...

Intramural duodenal hematoma as a complication of therapy with Warfarin: a case report and literature review

International Nuclear Information System (INIS)

Faria, Juliano; Pessoa, Roberta; Hudson, Marcelo; Vitoi, Silvio; Villela, Ovidio; Torres, Jose; Paula, Mara Delgado; Bemvindo, Aloisio

2004-01-01

We report a case of a patient receiving chronic oral anticoagulant therapy with Warfarin who presented with acute intestinal obstruction. Computed tomography showed intramural duodenal hematoma. Treatment was conservative with correction of the coagulation parameters and observation. This case exemplifies the usefulness of conservative therapy and computed tomography in patients with acute small bowel obstruction receiving anticoagulant therapy. (author)

Anticoagulation Endpoints with Clinical Implementation of Warfarin Pharmacogenetic Dosing in a Real-World Setting – A Proposal for a New Pharmacogenetic Dosing Approach

Science.gov (United States)

Arwood, Meghan J.; Deng, Jiexin; Drozda, Katarzyna; Pugach, Oksana; Nutescu, Edith A.; Schmidt, Stephan; Duarte, Julio D.; Cavallari, Larisa H.

2016-01-01

Achieving therapeutic anticoagulation efficiently with warfarin is important to reduce thrombotic and bleeding risks and is influenced by genotype. Utilizing data from a diverse population of 257 patients who received VKORC1 and CYP2C9 genotype-guided warfarin dosing, we aimed to examine genotype-associated differences in anticoagulation endpoints and derive a novel pharmacogenetic nomogram to more optimally dose warfarin. We observed significant differences across patients with 0, 1, or ≥2 reduced-function VKORC1 or CYP2C9 alleles, respectively, in time to achieve therapeutic international normalized ratio (INR) (7.8±5.8, 7.2±4.7, and 5.4±4.6 days, P=0.0004) and mean percentage of time in therapeutic range in the first 28 days (22.2, 27.8, and 32.2%, P=0.0127) with use of existing pharmacogenetic algorithms. These data suggest that more aggressive dosing is necessary for patients with 0 to 1 VKORC1/CYP2C9 variants to more efficiently achieve therapeutic anticoagulation. Herein, we provide a novel kinetic/pharmacodynamic-derived dosing nomogram optimized for a heterogeneous patient population. PMID:28032893

Direct oral anticoagulants versus warfarin for preventing stroke and systemic embolic events among atrial fibrillation patients with chronic kidney disease.

Science.gov (United States)

Kimachi, Miho; Furukawa, Toshi A; Kimachi, Kimihiko; Goto, Yoshihito; Fukuma, Shingo; Fukuhara, Shunichi

2017-11-06

Chronic kidney disease (CKD) is an independent risk factor for atrial fibrillation (AF), which is more prevalent among CKD patients than the general population. AF causes stroke or systemic embolism, leading to increased mortality. The conventional antithrombotic prophylaxis agent warfarin is often prescribed for the prevention of stroke, but risk of bleeding necessitates regular therapeutic monitoring. Recently developed direct oral anticoagulants (DOAC) are expected to be useful as alternatives to warfarin. To assess the efficacy and safety of DOAC including apixaban, dabigatran, edoxaban, and rivaroxaban versus warfarin among AF patients with CKD. We searched the Cochrane Kidney and Transplant Specialised Register (up to 1 August 2017) through contact with the Information Specialist using search terms relevant to this review. Studies in the Specialised Register are identified through searches of CENTRAL, MEDLINE, and EMBASE, conference proceedings, the International Clinical Trials Register (ICTRP) Search Portal, and ClinicalTrials.gov. We included all randomised controlled trials (RCTs) which directly compared the efficacy and safety of direct oral anticoagulants (direct thrombin inhibitors or factor Xa inhibitors) with dose-adjusted warfarin for preventing stroke and systemic embolic events in non-valvular AF patients with CKD, defined as creatinine clearance (CrCl) or eGFR between 15 and 60 mL/min (CKD stage G3 and G4). Two review authors independently selected studies, assessed quality, and extracted data. We calculated the risk ratio (RR) and 95% confidence intervals (95% CI) for the association between anticoagulant therapy and all strokes and systemic embolic events as the primary efficacy outcome and major bleeding events as the primary safety outcome. Confidence in the evidence was assessing using GRADE. Our review included 12,545 AF participants with CKD from five studies. All participants were randomised to either DOAC (apixaban, dabigatran, edoxaban

Efficacy and safety of a pharmacist-managed inpatient anticoagulation service for warfarin initiation and titration.

Science.gov (United States)

Wong, Y M; Quek, Y-N; Tay, J C; Chadachan, V; Lee, H K

2011-10-01

Anticoagulation consultations provided by a pharmacist-staffed inpatient service, similar to the experience reported in outpatient anticoagulation clinics, can potentially improve anticoagulation control and outcomes. At Tan Tock Seng Hospital, a 1200-bed acute care teaching hospital in Singapore, pharmacist-managed anticoagulation clinics have been in place since 1997. Pharmacist-managed services were extended to inpatient consultations in anticoagulation management from April 2006. Our objective was to assess the effect of implementing a pharmacist-managed inpatient anticoagulation service. This was a single-centre cohort study. Baseline data from 1 January 2006 to 31 March 2006 were collected and compared with post-implementation data from 1 April 2006 to 31 March 2007. Patients newly started on warfarin for deep vein thrombosis, pulmonary embolism or atrial fibrillation in general medicine and surgery departments were included. The three endpoints were as follows: (i) percentage of international normalized ratios (INRs) achieving therapeutic range within 5 days, (ii) INRs more than 4 during titration and (iii) subtherapeutic INRs on discharge. A total of 26 patients in the control period were compared with 144 patients who had received dosing consultations by a pharmacist during the initiation of warfarin. The provision of pharmacist consult resulted in 88% compared to 38% (P < 0·001) of INR values achieving therapeutic range within 5 days. There was a reduction in INR values of more than 4 during titration from 27% to 2% (P < 0·001), and subtherapeutic INR values on discharge without low molecular weight heparin from 15% to 0% (P < 0·001). The mean time to therapeutic INR was reduced from 6·5 to 3·9 days (P < 0·001) and mean length of stay after initiation of warfarin from 11 to 7·7 days (P = 0·004). Inpatient anticoagulation care and outcomes were significantly improved by a pharmacist-managed anticoagulation service. The time to therapeutic INR was

Solitary pulmonary nodule by pulmonary hematoma under warfarin therapy

International Nuclear Information System (INIS)

Scheppach, W.; Kulke, H.; Liebau, G.; Braun, H.; Wuerzburg Univ.

1983-01-01

Pulmonary hematoma is a rare cause of a pulmonary nodule. Mostly it results from penetrating or blunt chest injuries. The case of a patient is reported, whose chest X-ray showed a pulmonary nodule suspected of malignancy. This patient was maintained permanently on anticoagulants (warfarin derivates) after cardiac valve replacement with a prosthesis. A definite diagnosis could not be established by non-invasive methods. A needle biopsy of the lung was impracticable because of the location of the pulmonary lesion; an exploratory thoracotomy could not be carried out due to a general indication of nonoperability. Control examinations showed that the pulmonary nodule had vanished completely within four months. In consideration of the patient's clinical situation it can be concluded that the pulmonary lesion was caused by a hematoma of the lung. (orig.) [de

Solitary pulmonary nodule by pulmonary hematoma under warfarin therapy

Energy Technology Data Exchange (ETDEWEB)

Scheppach, W.; Kulke, H.; Liebau, G.; Braun, H.

1983-06-01

Pulmonary hematoma is a rare cause of a pulmonary nodule. Mostly it results from penetrating or blunt chest injuries. The case of a patient is reported, whose chest X-ray showed a pulmonary nodule suspected of malignancy. This patient was maintained permanently on anticoagulants (warfarin derivates) after cardiac valve replacement with a prosthesis. A definite diagnosis could not be established by non-invasive methods. A needle biopsy of the lung was impracticable because of the location of the pulmonary lesion; an exploratory thoracotomy could not be carried out due to a general indication of nonoperability. Control examinations showed that the pulmonary nodule had vanished completely within four months. In consideration of the patient's clinical situation it can be concluded that the pulmonary lesion was caused by a hematoma of the lung.

Effect of Genetic Variability in the CYP4F2, CYP4F11, and CYP4F12 Genes on Liver mRNA Levels and Warfarin Response

Directory of Open Access Journals (Sweden)

J. E. Zhang

2017-05-01

Full Text Available Genetic polymorphisms in the gene encoding cytochrome P450 (CYP 4F2, a vitamin K oxidase, affect stable warfarin dose requirements and time to therapeutic INR. CYP4F2 is part of the CYP4F gene cluster, which is highly polymorphic and exhibits a high degree of linkage disequilibrium, making it difficult to define causal variants. Our objective was to examine the effect of genetic variability in the CYP4F gene cluster on expression of the individual CYP4F genes and warfarin response. mRNA levels of the CYP4F gene cluster were quantified in human liver samples (n = 149 obtained from a well-characterized liver bank and fine mapping of the CYP4F gene cluster encompassing CYP4F2, CYP4F11, and CYP4F12 was performed. Genome-wide association study (GWAS data from a prospective cohort of warfarin-treated patients (n = 711 was also analyzed for genetic variations across the CYP4F gene cluster. In addition, SNP-gene expression in human liver tissues and interactions between CYP4F genes were explored in silico using publicly available data repositories. We found that SNPs in CYP4F2, CYP4F11, and CYP4F12 were associated with mRNA expression in the CYP4F gene cluster. In particular, CYP4F2 rs2108622 was associated with increased CYP4F2 expression while CYP4F11 rs1060467 was associated with decreased CYP4F2 expression. Interestingly, these CYP4F2 and CYP4F11 SNPs showed similar effects with warfarin stable dose where CYP4F11 rs1060467 was associated with a reduction in daily warfarin dose requirement (∼1 mg/day, Pc = 0.017, an effect opposite to that previously reported with CYP4F2 (rs2108622. However, inclusion of either or both of these SNPs in a pharmacogenetic algorithm consisting of age, body mass index (BMI, gender, baseline clotting factor II level, CYP2C9∗2 rs1799853, CYP2C9∗3 rs1057910, and VKORC1 rs9923231 improved warfarin dose variability only by 0.5–0.7% with an improvement in dose prediction accuracy of ∼1–2%. Although there is complex

Anticoagulants Resumption after Warfarin-Related Intracerebral Haemorrhage: The Multicenter Study on Cerebral Hemorrhage in Italy (MUCH-Italy).

Science.gov (United States)

Poli, Loris; Grassi, Mario; Zedde, Marialuisa; Marcheselli, Simona; Silvestrelli, Giorgio; Sessa, Maria; Zini, Andrea; Paciaroni, Maurizio; Azzini, Cristiano; Gamba, Massimo; Toriello, Antonella; Tassi, Rossana; Giorli, Elisa; Calabrò, Rocco Salvatore; Ritelli, Marco; De Vito, Alessandro; Pugliese, Nicola; Martini, Giuseppe; Lanari, Alessia; Lodigiani, Corrado; Padroni, Marina; De Giuli, Valeria; Caria, Filomena; Morotti, Andrea; Costa, Paolo; Strambo, Davide; Corato, Manuel; Pascarella, Rosario; Del Sette, Massimo; Malferrari, Giovanni; Colombi, Marina; Padovani, Alessandro; Pezzini, Alessandro

2018-03-01

Whether to resume antithrombotic treatment after oral anticoagulant-related intracerebral haemorrhage (OAC-ICH) is debatable. In this study, we aimed at investigating long-term outcome associated with OAC resumption after warfarin-related ICH, in comparison with secondary prevention strategies with platelet inhibitors or antithrombotic discontinuation. Participants were patients who sustained an incident ICH during warfarin treatment (2002-2014) included in the Multicenter Study on Cerebral Hemorrhage in Italy. Primary end-point was a composite of ischemic stroke/systemic embolism (SE) and all-cause mortality. Secondary end-points were ischemic stroke/SE, all-cause mortality and major recurrent bleeding. We computed individual propensity score (PS) as the probability that a patient resumes OACs or other agents given his pre-treatment variables, and performed Cox multivariable analysis using Inverse Probability of Treatment Weighting (IPTW) procedure. A total of 244 patients qualified for the analysis. Unlike antiplatelet agents, OAC resumption was associated with a lower rate of the primary end-point (weighted hazard ratio [HR], 0.21; 95% confidence interval [CI], 0.09-0.45), as well as of overall mortality (weighted HR, 0.17; 95% CI, 0.06-0.45) and ischemic stroke/SE (weighted HR, 0.19; 95% CI, 0.06-0.60) with no significant increase of major bleeding in comparison with patients receiving no antithrombotics. In the subgroup of patients with atrial fibrillation, OACs resumption was also associated with a reduction of the primary end-point (weighted HR, 0.22; 95% CI, 0.09-0.54), and the secondary end-point ischemic stroke/SE (weighted HR, 0.09; 95% CI, 0.02-0.40). In conclusion, in patients who have an ICH while receiving warfarin, resuming anticoagulation results in a favorable trade-off between bleeding susceptibility and thromboembolic risk. Schattauer GmbH Stuttgart.

Echocardiographic Risk Factors for Stroke and Outcomes in Patients With Atrial Fibrillation Anticoagulated With Apixaban or Warfarin.

Science.gov (United States)

Vinereanu, Dragos; Lopes, Renato D; Mulder, Hillary; Gersh, Bernard J; Hanna, Michael; de Barros E Silva, Pedro G M; Atar, Dan; Wallentin, Lars; Granger, Christopher B; Alexander, John H

2017-12-01

Few data exist on the long-term outcomes of patients with spontaneous echo contrast (SEC), left atrial/left atrial appendage (LA/LAA) thrombus, and complex aortic plaque (CAP), in patients with atrial fibrillation receiving oral anticoagulation. We explored the relationship between these 3 echocardiographic findings and clinical outcomes, and the comparative efficacy and safety of apixaban and warfarin for each finding. Patients from the ARISTOTLE trial (Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation) with SEC, LA/LAA thrombus, or CAP diagnosed by either transthoracic or transesophageal echocardiography were compared with patients with none of these findings on transesophageal echocardiography. A total of 1251 patients were included: 217 had SEC, 127 had LA/LAA thrombus, 241 had CAP, and 746 had none. The rates of stroke/systemic embolism were not significantly different among patients with and without these echocardiographic findings (hazard ratio, 0.96; 95% confidence interval, 0.25-3.60 for SEC; hazard ratio, 1.27; 95% confidence interval, 0.23-6.86 for LA/LAA thrombus; hazard ratio, 2.21; 95% confidence interval, 0.71-6.85 for CAP). Rates of ischemic stroke, myocardial infarction, cardiovascular death, and all-cause death were also not different between patients with and without these findings. For patients with either SEC or CAP, there was no evidence of a differential effect of apixaban over warfarin. For patients with LA/LAA thrombus, there was also no significant interaction, with the exception of all-cause death and any bleeding where there was a greater benefit of apixaban compared with warfarin among patients with no LA/LAA thrombus. In anticoagulated patients with atrial fibrillation and risk factors for stroke, echocardiographic findings do not seem to add to the risk of thromboembolic events. URL: http://www.clinicaltrials.gov. Unique identifier: NCT00412984. © 2017 American Heart Association, Inc.

Pharmacogenetics-based warfarin dosing algorithm decreases time to stable anticoagulation and the risk of major hemorrhage: an updated meta-analysis of randomized controlled trials.

Science.gov (United States)

Wang, Zhi-Quan; Zhang, Rui; Zhang, Peng-Pai; Liu, Xiao-Hong; Sun, Jian; Wang, Jun; Feng, Xiang-Fei; Lu, Qiu-Fen; Li, Yi-Gang

2015-04-01

Warfarin is yet the most widely used oral anticoagulant for thromboembolic diseases, despite the recently emerged novel anticoagulants. However, difficulty in maintaining stable dose within the therapeutic range and subsequent serious adverse effects markedly limited its use in clinical practice. Pharmacogenetics-based warfarin dosing algorithm is a recently emerged strategy to predict the initial and maintaining dose of warfarin. However, whether this algorithm is superior over conventional clinically guided dosing algorithm remains controversial. We made a comparison of pharmacogenetics-based versus clinically guided dosing algorithm by an updated meta-analysis. We searched OVID MEDLINE, EMBASE, and the Cochrane Library for relevant citations. The primary outcome was the percentage of time in therapeutic range. The secondary outcomes were time to stable therapeutic dose and the risks of adverse events including all-cause mortality, thromboembolic events, total bleedings, and major bleedings. Eleven randomized controlled trials with 2639 participants were included. Our pooled estimates indicated that pharmacogenetics-based dosing algorithm did not improve percentage of time in therapeutic range [weighted mean difference, 4.26; 95% confidence interval (CI), -0.50 to 9.01; P = 0.08], but it significantly shortened the time to stable therapeutic dose (weighted mean difference, -8.67; 95% CI, -11.86 to -5.49; P pharmacogenetics-based algorithm significantly reduced the risk of major bleedings (odds ratio, 0.48; 95% CI, 0.23 to 0.98; P = 0.04), but it did not reduce the risks of all-cause mortality, total bleedings, or thromboembolic events. Our results suggest that pharmacogenetics-based warfarin dosing algorithm significantly improves the efficiency of International Normalized Ratio correction and reduces the risk of major hemorrhage.

Non-vitamin K antagonist oral anticoagulants compared with warfarin at different levels of INR control in atrial fibrillation: A meta-analysis of randomized trials.

Science.gov (United States)

Carmo, João; Ferreira, Jorge; Costa, Francisco; Carmo, Pedro; Cavaco, Diogo; Carvalho, Salomé; Morgado, Francisco; Adragão, Pedro; Mendes, Miguel

2017-10-01

The efficacy and safety of warfarin for stroke prevention in atrial fibrillation (AF) depend on the time in the therapeutic range (TTR) with an international normalised ratio (INR) of 2.0-3.0. This meta-analysis focused the relative efficacy and safety of non-VKA oral anticoagulants (NOAC) compared with warfarin at different thresholds of centre's TTR (cTTR). We searched PubMed, Embase, CENTRAL and websites of regulatory agencies, limiting searches to randomized phase 3 trials. Primary outcomes were stroke or systemic embolism (SSE) and major or non-major clinically relevant (NMCR) bleeding. We used a random-effects model to pool effect on outcomes according to different thresholds of cTTR. Four TTR sub-studies with a total of 71,222 patients were included. The benefit of NOAC in reducing SSE compared with warfarin was significantly higher in patients at cTTRwarfarin in patients at all sub-groups (0.67, 0.54-0.83 for patients at cTTRwarfarin for stroke prevention is lost above a cTTR threshold of approximately 70%, but the relative safety appears to be less modified by the centre-based quality of INR control. Copyright © 2017 Elsevier B.V. All rights reserved.

Contributions of procoagulants and anticoagulants to the international normalized ratio and thrombin generation assay in patients treated with warfarin: potential role of protein Z as a powerful determinant of coagulation assays.

Science.gov (United States)

Choi, Qute; Kim, Ji-Eun; Hyun, Jungwon; Han, Kyou-Sup; Kim, Hyun Kyung

2013-07-01

The effects of warfarin are measured with the international normalized ratio (INR). However, the thrombin generation assay (TGA) may offer more information about global coagulation. We analyzed the monitoring performance of the TGA and INR and investigated the impact of procoagulants (fibrinogen, factor (F)II, FVII, FIX, and FX) and anticoagulants (proteins C, S, and Z) on them. The TGA was performed on a calibrated automated thrombogram, producing lag time, endogenous thrombin potential (ETP), and peak thrombin in 239 patients treated with warfarin. Pro- and anticoagulant levels were also measured. The INR was significantly and inversely correlated with ETP. The therapeutic range of ETP comparable to an INR range of 2.0-3.0 was 290.1-494.6. ETP showed comparable performance to the INR as a warfarin-monitoring parameter with respect to clinical complication rate. The median levels of FII, FVII, FIX, and FX and proteins C and Z tended to decrease gradually with increasing anticoagulation intensity according to the INR or ETP. Of note, protein Z levels decreased dramatically with increasing anticoagulation status. INRs were significantly determined by FII, FVII, and protein Z. ETP was significantly dependent on FVII, and proteins C and Z concentration. Protein Z significantly reduced the total amount of thrombin generation and prolonged PT value in vitro. The INR and ETP exhibit similar efficacy for warfarin monitoring according to the clinical complication rate. Protein Z is considered to be a significant determinant of INR and ETP in patients on warfarin therapy. Copyright © 2013 Elsevier Ltd. All rights reserved.

Magnetic resonance venography to assess thrombus resolution with edoxaban monotherapy versus parenteral anticoagulation/warfarin for symptomatic deep vein thrombosis: A multicenter feasibility study.

Science.gov (United States)

Piazza, Gregory; Mani, Venkatesh; Goldhaber, Samuel Z; Grosso, Michael A; Mercuri, Michele; Lanz, Hans J; Schussler, Steven; Hsu, Ching; Chinigo, Amy; Ritchie, Bruce; Nadar, Venkatesh; Cannon, Kevin; Pullman, John; Concha, Mauricio; Schul, Marlin; Fayad, Zahi A

2016-08-01

The feasibility of magnetic resonance venography (MRV) for measuring change in thrombus volume with a novel anticoagulation regimen versus standard anticoagulation in patients with symptomatic deep vein thrombosis (DVT) has not been assessed. Our aim was to study the feasibility of MRV to measure change in thrombus volume in patients with acute symptomatic objectively confirmed proximal DVT in an open-label multicenter trial (edoxaban Thrombus Reduction Imaging Study, eTRIS). We randomized patients in a 2:1 allocation ratio to edoxaban 90 mg/day for 10 days followed by 60 mg/day versus parenteral anticoagulation bridging to warfarin for 3 months. The primary efficacy outcome was a surrogate end point of the relative change in MRV-quantified thrombus volume from baseline to Day 14-21. A total of 85 eligible patients from 26 study sites were randomized to edoxaban monotherapy (n=56) versus parenteral anticoagulation as a 'bridge' to warfarin (n=29). The mean relative change in MRV-quantified thrombus volume from baseline to Day 14-21 was similar in patients treated with edoxaban and parenteral anticoagulation as a 'bridge' to warfarin (-50.1% vs -58.9%; 95% confidence interval of treatment difference, -12.7%, 30.2%). However, thrombus extension was observed in eight patients in the edoxaban monotherapy group and in none in the warfarin group. Rates of recurrent venous thromboembolism (3.6% vs 3.6%, p=0.45) and clinically relevant non-major bleeding (5.4% vs 7.1%, p=0.34) were also similar. No major bleeds occurred in either on-treatment group during the study period. In conclusion, MRV can assess change in thrombus volume in patients with acute DVT randomized to two different anticoagulant regimens.ClinicalTrials.gov IDENTIFIER NCT01662908: INVESTIGATIONAL NEW DRUG IND APPLICATION EDOXABAN IND # 63266. © The Author(s) 2016.

Quality of warfarin therapy and risk of stroke, bleeding, and mortality among patients with atrial fibrillation: results from the nationwide FinWAF Registry.

Science.gov (United States)

Lehto, Mika; Niiranen, Jussi; Korhonen, Pasi; Mehtälä, Juha; Khanfir, Houssem; Hoti, Fabian; Lassila, Riitta; Raatikainen, Pekka

2017-06-01

The most important management strategy in atrial fibrillation (AF) patients is preventing stroke with oral anticoagulants. Warfarin is still used as a first-line anticoagulant, although non-vitamin K antagonist oral anticoagulants are currently recommended to manage AF. Using a large, unselected national sample of AF patients, we evaluated the relationships between quality of warfarin therapy and the risks of thromboembolism, bleeding complications, and mortality. The nationwide FinWAF study included 54 568 AF patients taking warfarin. Time in the therapeutic range (TTR) was calculated on a continuous basis using the Rosendaal method and international normalized ratio values over the previous 60 days. Adjusted Cox proportional hazard models were prepared for different TTR levels and major clinical end points. The mean age of patients was 73.1 years (standard deviation 10.8), and 47% were female. The mean follow-up time was 3.2 ± 1.6 years (median 3.4). In the TTR groups of ≤40%, 60-70%, 70-80%, and >80%, the annual risk of stroke was 9.3%, 4.7%, 4.6%, and 3.1%; bleeding events 7.5%, 4.5%, 4.3%, and 2.6%; and overall mortality 20.9%, 8.5%, 6.4%, and 3.1%, respectively. All differences among the TTR groups were highly significant (p warfarin treatment was strongly associated with the risk of stroke and the prognosis of AF patients. Patient outcomes continued to improve with increasing TTR values up to a TTR ≥80%; therefore, the target for the TTR should exceed 80% instead of the traditional range of at least 60-70%. Copyright © 2017 John Wiley & Sons, Ltd. Copyright © 2017 John Wiley & Sons, Ltd.

Adverse effects by artificial grapefruit seed extract products in patients on warfarin therapy.

Science.gov (United States)

Brandin, Helena; Myrberg, Olle; Rundlöf, Torgny; Arvidsson, Ann-Kristin; Brenning, Gunilla

2007-06-01

Grapefruit seed extract (GSE) is promoted as a natural product with antibacterial and antiviral properties. The aim of this study was to investigate the composition of some commercially available GSE products and evaluate their effect in vitro on two cytochrome P450 enzymes, CYP2C9 and CYP3A4. A couple on lifelong treatment with warfarin and continuous regular follow-ups took some drops of a GSE product for 3 days. The female patient experienced a minor subcutaneous haematoma 3 days later, and her international normalised ratio (INR) value was 7.9. This was reported to the Swedish Medical Products Agency (MPA) as a spontaneous post-marketing report concerning adverse drug reactions/interactions. The composition of the GSE products was determined by proton and carbon-13 nuclear magnetic resonance spectroscopy (NMR). The inhibitory effect of the GSE products on the cytochrome P450 enzymes was tested in an in vitro baculosome assay. The NMR analysis showed that all three investigated GSE products contained the synthetic preservative benzethonium chloride (BTC) in addition to glycerol and water. No authentic GSE extract was found in any of the three GSE products analysed. Furthermore, BTC was found to be a potent inhibitor of CYP3A4 and CYP2C9 activity in vitro. Our results suggest that BTC in the GSE products is responsible for the increase in the INR value in a patient on warfarin treatment.

Management of Major Bleeding in Patients With Atrial Fibrillation Treated With Non-Vitamin K Antagonist Oral Anticoagulants Compared With Warfarin in Clinical Practice (from Phase II of the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation [ORBIT-AF II]).

Science.gov (United States)

Steinberg, Benjamin A; Simon, DaJuanicia N; Thomas, Laine; Ansell, Jack; Fonarow, Gregg C; Gersh, Bernard J; Kowey, Peter R; Mahaffey, Kenneth W; Peterson, Eric D; Piccini, Jonathan P

2017-05-15

Non-vitamin K antagonist oral anticoagulants (NOACs) are effective at preventing stroke in patients with atrial fibrillation (AF). However, little is known about the management of bleeding in contemporary, clinical use of NOACs. We aimed to assess the frequency, management, and outcomes of major bleeding in the setting of community use of NOACs. Using the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation II registry, we analyzed rates of International Society on Thrombosis and Haemostasis major bleeding and subsequent outcomes in patients treated with NOACs versus warfarin. Outcomes of interest included acute and chronic bleeding management, recurrent bleeding, thromboembolic events, and death. In total, 344 patients with atrial fibrillation experienced major bleeding events over a median follow-up of 360 days follow-up: n = 273 on NOAC (3.3 per 100 patient-years) and n = 71 on warfarin (3.5 per 100 patient-years). Intracranial bleeding was uncommon but similar (0.34 per 100 patient-years for NOAC vs 0.44 for warfarin, p = 0.5), as was gastrointestinal bleeding (1.8 for NOAC vs 1.3 for warfarin, p = 0.1). Blood products and correction agents were less commonly used in NOAC patients with major bleeds compared with warfarin-treated patients (53% vs 76%, p = 0.0004 for blood products; 0% vs 1.5% for recombinant factor; p = 0.0499); no patients received pharmacologic hemostatic agents (aminocaproic acid, tranexamic acid, desmopressin, aprotinin). Within 30 days, 23 NOAC-treated patients (8.4%) died versus 5 (7.0%) on warfarin (p = 0.7). At follow-up, 126 NOAC-treated (46%) and 29 warfarin-treated patients (41%) were not receiving any anticoagulation. In conclusion, rates of major bleeding are similar in warfarin and NOAC-treated patients in clinical practice. However, NOAC-related bleeds require less blood product administration and rarely require factor replacement. Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights

Warfarin therapy and incidence of cerebrovascular complications in left-sided native valve endocarditis

DEFF Research Database (Denmark)

Snygg-Martin, U; Rasmussen, Rasmus Vedby; Hassager, C

2011-01-01

Anticoagulant therapy has been anticipated to increase the risk of cerebrovascular complications (CVC) in native valve endocarditis (NVE). This study investigates the relationship between ongoing oral anticoagulant therapy and the incidence of symptomatic CVC in left-sided NVE. In a prospective...... factors for CVC, while warfarin on admission (aOR 0.26, 95% CI 0.07-0.94), history of congestive heart failure (adjusted OR 0.22, 95% CI 0.1-0.52) and previous endocarditis (aOR 0.1, 95% CI 0.01-0.79) correlated with lower CVC frequency....

CATCH: a randomised clinical trial comparing long-term tinzaparin versus warfarin for treatment of acute venous thromboembolism in cancer patients

International Nuclear Information System (INIS)

Lee, Agnes YY; Bauersachs, Rupert; Janas, Mette S; Jarner, Mikala F; Kamphuisen, Pieter W; Meyer, Guy; Khorana, Alok A

2013-01-01

Low-molecular-weight heparin (LMWH) is recommended and commonly used for extended treatment of cancer-associated thrombosis (CAT), but its superiority over warfarin has been demonstrated in only one randomised study. We report here the rationale, design and a priori analysis plans of Comparison of Acute Treatments in Cancer Haemostasis (CATCH; NCT01130025), a multinational, Phase III, open-label, randomised controlled trial comparing tinzaparin with warfarin for extended treatment of CAT. The primary objective is to assess the efficacy of tinzaparin in preventing recurrent venous thromboembolism (VTE) in patients with active cancer and acute, symptomatic proximal deep vein thrombosis and/or pulmonary embolism. The secondary objectives are to determine: safety of tinzaparin given over 6 months; clinical and laboratory markers for recurrent VTE and/or major bleeding; 6-month overall mortality; incidence and severity of post-thrombotic syndrome; patient-reported quality of life; and healthcare resource utilisation. Nine hundred patients are randomised to receive tinzaparin 175 IU/kg once daily for 6 months or initial tinzaparin 175 IU/kg once daily for 5–10 days and dose-adjusted warfarin (target INR 2.0–3.0) for 6 months. The primary composite outcome is time to recurrent VTE, including incidental VTE and fatal pulmonary embolism. All patients are followed up to 6 months or death, whichever comes sooner. Blinded adjudication will be performed for all reported VTE, bleeding events and causes of death. Efficacy will be analysed using centrally adjudicated results of all patients according to intention-to-treat analysis. An independent Data Safety Monitoring Board is reviewing data at regular intervals and an interim analysis is planned after 450 patients have completed the study. The results will add significantly to the knowledge of the efficacy, safety and cost effectiveness of tinzaparin in the prevention of recurrent VTE in patients with cancer and thrombosis

The relationship of renal function to outcome: A post hoc analysis from the EdoxabaN versus warfarin in subjectS UndeRgoing cardiovErsion of Atrial Fibrillation (ENSURE-AF) study.

Science.gov (United States)

Lip, Gregory Y H; Al-Saady, Naab; Ezekowitz, Michael D; Banach, Maciej; Goette, Andreas

2017-11-01

The ENSURE-AF study (NCT 02072434) of anticoagulation for electrical cardioversion in nonvalvular atrial fibrillation (NVAF) showed comparable low rates of bleeding and thromboembolism between the edoxaban and the enoxaparin-warfarin treatment arms. This post hoc analysis investigated the relationship between renal function and clinical outcomes. ENSURE-AF was a multicenter, PROBE evaluation trial of edoxaban 60 mg, or dose reduced to 30 mg/d for weight≤60 kg, creatinine clearance (CrCl; Cockcroft-Gault) ≤50 mL/min, or concomitant P-glycoprotein inhibitors compared with therapeutically monitored enoxaparin-warfarin in 2,199 NVAF patients undergoing electrical cardioversion. Efficacy and safety outcomes and time in therapeutic range in the warfarin arm were analyzed in relation to CrCl in prespecified ranges ≥15 and ≤30, >30 and ≤50, >50 and warfarin. Mean age was 64.3±10 and 64.2±11 years. Mean time in therapeutic range was progressively lower with reducing CrCl strata, being 66.8% in those with CrCl >30 to ≤50 compared with 71.8% in those with CrCl ≥80. The odds ratios for the primary efficacy and safety end points were comparable for the different predefined renal function strata; given the small numbers, the 95% CI included 1.0. In the subset of those with CrCl ≥95, the odds ratios showed consistency with the other CrCl strata. When CrCl was assessed as a continuous variable, there was a nonsignificant trend toward higher major or clinically relevant nonmajor bleeding with reducing CrCl levels, with no significant differences between the 2 treatment arms. When we assessed CrCl at baseline compared with end of treatment, there were no significant differences in CrCl change between the edoxaban and enoxaparin-warfarin arms. The proportions with worsening of renal function (defined as a decrease of >20% from baseline) were similar in the 2 treatment arms. Given the small number of events in ENSURE-AF, no effect of renal (dys)function was

Efficacy and Safety of Apixaban Versus Warfarin in Patients with Atrial Fibrillation and a History of Cancer: Insights from the ARISTOTLE Trial.

Science.gov (United States)

Melloni, Chiara; Dunning, Allison; Granger, Christopher B; Thomas, Laine; Khouri, Michel G; Garcia, David A; Hylek, Elaine M; Hanna, Michael; Wallentin, Lars; Gersh, Bernard J; Douglas, Pamela S; Alexander, John H; Lopes, Renato D

2017-12-01

Cancer is associated with a prothrombotic state and increases the risk of thrombotic events in patients with atrial fibrillation. We described the clinical characteristics and outcomes and assessed the safety and efficacy of apixaban versus warfarin in patients with atrial fibrillation and cancer in the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) trial. The association between cancer and clinical outcomes was assessed using Cox regression models. At baseline, 1236 patients (6.8%) had a history of cancer; 12.7% had active cancer, and 87.3% had remote cancer. There were no significant associations between history of cancer and stroke/systemic embolism, major bleeding, or death. The effect of apixaban versus warfarin for the prevention of stroke/systemic embolism was consistent among patients with a history of cancer (event/100 patient-years = 1.4 vs 1.2; hazard ratio [HR], 1.09; 95% confidence interval [CI], 0.53-2.26) and no cancer (1.3 vs 1.6; HR, 0.77; 95% CI, 0.64-0.93) (P interaction = .37). The safety and efficacy of apixaban versus warfarin were preserved among patients with and without active cancer. Apixaban was associated with a greater benefit for the composite of stroke/systemic embolism, myocardial infarction, and death in active cancer (HR, 0.30; 95% CI, 0.11-0.83) versus without cancer (HR, 0.86; 95% CI, 0.78-0.95), but not in remote cancer (HR, 1.46; 95% CI, 1.01-2.10) (interaction P = .0028). Cancer was not associated with a higher risk of stroke. The superior efficacy and safety of apixaban versus warfarin were consistent in patients with and without cancer. Our positive findings regarding apixaban use in patients with atrial fibrillation and cancer are exploratory and promising, but warrant further evaluation. Copyright © 2017 Elsevier Inc. All rights reserved.

Location and characterization of the warfarin binding site of human serum albumin A comparative study of two large fragments

NARCIS (Netherlands)

Bos, O.J.M.; Remijn, J.P.M.; Fischer, M.J.E.; Wilting, J.; Janssen, L.H.M.

1988-01-01

The warfarin binding behaviour of a large tryptic fragment (residues 198–585 which comprise domains two and three) and of a large peptic fragment (residues 1–387 which comprise domains one and two) of human serum albumin has been studied by circular dichroism and equilibrium dialysis in order to

Protocol for Birmingham Atrial Fibrillation Treatment of the Aged study (BAFTA: a randomised controlled trial of warfarin versus aspirin for stroke prevention in the management of atrial fibrillation in an elderly primary care population [ISRCTN89345269

Directory of Open Access Journals (Sweden)

Fletcher Kate

2003-08-01

Full Text Available Abstract Background Atrial fibrillation (AF is an important independent risk factor for stroke. Randomised controlled trials have shown that this risk can be reduced substantially by treatment with warfarin or more modestly by treatment with aspirin. Existing trial data for the effectiveness of warfarin are drawn largely from studies in selected secondary care populations that under-represent the elderly. The Birmingham Atrial Fibrillation Treatment of the Aged (BAFTA study will provide evidence of the risks and benefits of warfarin versus aspirin for the prevention of stroke for older people with AF in a primary care setting. Study design A randomised controlled trial where older patients with AF are randomised to receive adjusted dose warfarin or aspirin. Patients will be followed up at three months post-randomisation, then at six monthly intervals there after for an average of three years by their general practitioner. Patients will also receive an annual health questionnaire. 1240 patients will be recruited from over 200 practices in England. Patients must be aged 75 years or over and have AF. Patients will be excluded if they have a history of any of the following conditions: rheumatic heart disease; major non-traumatic haemorrhage; intra-cranial haemorrhage; oesophageal varices; active endoscopically proven peptic ulcer disease; allergic hypersensitivity to warfarin or aspirin; or terminal illness. Patients will also be excluded if the GP considers that there are clinical reasons to treat a patient with warfarin in preference to aspirin (or vice versa. The primary end-point is fatal or non-fatal disabling stroke (ischaemic or haemorrhagic or significant arterial embolism. Secondary outcomes include major extra-cranial haemorrhage, death (all cause, vascular, hospital admissions (all cause, vascular, cognition, quality of life, disability and compliance with study medication.

Barriers and facilitators to reducing frequent laboratory testing for patients who are stable on warfarin: a mixed methods study of de-implementation in five anticoagulation clinics.

Science.gov (United States)

Barnes, Geoffrey D; Misirliyan, Sevan; Kaatz, Scott; Jackson, Elizabeth A; Haymart, Brian; Kline-Rogers, Eva; Kozlowski, Jay; Krol, Gregory; Froehlich, James B; Sales, Anne

2017-07-14

Patients on chronic warfarin therapy require regular laboratory monitoring to safely manage warfarin. Recent studies have challenged the need for routine monthly blood draws in the most stable warfarin-treated patients, suggesting the safety of less frequent laboratory testing (up to every 12 weeks). De-implementation efforts aim to reduce the use of low-value clinical practices. To explore barriers and facilitators of a de-implementation effort to reduce the use of frequent laboratory tests for patients with stable warfarin management in nurse/pharmacist-run anticoagulation clinics, we performed a mixed-methods study conducted within a state-wide collaborative quality improvement collaborative. Using a mixed-methods approach, we conducted post-implementation semi-structured interviews with a total of eight anticoagulation nurse or pharmacist staff members at five participating clinic sites to assess barriers and facilitators to de-implementing frequent international normalized ratio (INR) laboratory testing among patients with stable warfarin control. Interview guides were based on the Tailored Implementation for Chronic Disease (TICD) framework. Informed by interview themes, a survey was developed and administered to all anticoagulation clinical staff (n = 62) about their self-reported utilization of less frequent INR testing and specific barriers to de-implementing the standard (more frequent) INR testing practice. From the interviews, four themes emerged congruent with TICD domains: (1) staff overestimating their actual use of less frequent INR testing (individual health professional factors), (2) barriers to appropriate patient engagement (incentives and resources), (3) broad support for an electronic medical record flag to identify potentially eligible patients (incentives and resources), and (4) the importance of personalized nurse/pharmacist feedback (individual health professional factors). In the survey (65% response rate), staff report offering less

The association between GGCX, miR-133 genetic polymorphisms and warfarin stable dosage in Han Chinese patients with mechanical heart valve replacement.

Science.gov (United States)

Tang, X-Y; Zhang, J; Peng, J; Tan, S-L; Zhang, W; Song, G-B; Liu, L-M; Li, C-L; Ren, H; Zeng, L; Liu, Z-Q; Chen, X-P; Zhou, X-M; Zhou, H-H; Hu, J-X; Li, Z

2017-08-01

Warfarin is a widely used anticoagulant with a narrow therapeutic index. Polymorphisms in the VKORC1, CYP2C9 and CYP4F2 genes have been verified to correlate with warfarin stable dosage (WSD). Whether any other genes or variants affect the dosage is unknown. The aim of our study was to investigate the relationship between GGCX, miR-133 variants and the WSD in Han Chinese patients with mechanical heart valve replacement (MHVR). A total of 231 patients were enrolled in the study. Blood samples were collected for genotyping. The average WSD among subjects with different GGCX or miR-133 genotypes was compared. Regression analyses were performed to test for any association of genetic polymorphisms with WSD. The warfarin dosage in patients with the GGCX rs699664 TT and rs12714145 TT genotypes was 3.77±0.93 (95% CI: 3.35-4.19) mg/d and 3.70±1.00 (95% CI: 3.32-4.09) mg/d, respectively. The GGCX rs699664 and rs12714145 genotypes were significantly associated with WSD (Pwarfarin stable dosage between subjects with MIR133B rs142410335 wild-type and variant genotypes (P>.05). The genotypes of GGCX rs699644 and rs12714145 were significantly associated with WSD (Pwarfarin stable dosage in Han Chinese patients with MHVR neither in univariate regression nor in multivariate regression analyses. © 2017 John Wiley & Sons Ltd.

Bilateral rectus sheath haematoma complicating dengue virus infection in a patient on warfarin for mechanical aortic valve replacement: a case report.

Science.gov (United States)

Rosa, Chamith Thushanga; Navinan, Mitrakrishnan Rayno; Samarawickrama, Sincy; Hamza, Himam; Gunarathne, Maheshika; Arulanantham, Arulprashanth; Subba, Neeha; Samarasiri, Udari; Mathias, Thushara; Kulatunga, Aruna

2017-01-07

The management of Dengue virus infection can be challenging. Varied presentations and numerous complications intrinsic to dengue by itself increase the complexity of treatment and potential mortality. When burdened with the presence of additional comorbidities and the need to continue compulsory medications, clear stepwise definitive guidance is lacking and patients tend to have more complex complications and outcomes calling to question the clinical decisions that may have been taken. The use and continuation of warfarin in dengue virus infection is one such example. We report a 65 year old South Asian female who presented with dengue fever. She had a history bronchial asthma, a prior abdominal surgery, and was on warfarin and maintained a therapeutically appropriate internationalized normalized ratio for a mechanical aortic valve replacement. Though preemptive decision to stop warfarin was taken with decreasing platelet counts, her clinical course was complicated with the development of bilateral rectus sheath haematoma's requiring resuscitation with blood transfusions. Though management of dengue viral fever has seen drastic evolution with recent updated guidance, clinical scenarios seen in the course of the illness still pose challenges to the managing physician. The need to continue obligatory anticoagulation which may seem counterintuitive during a complex disease such as dengue virus infection must be considered after understanding the potential risks versus that of its benefits. Though case by case decisions maybe warranted, a clear protocol would be very helpful in making clinical decisions, as the correct preemptive decision may potentially avert catastrophic and unpredictable bleeding events.

LEFT ATRIAL APPENDAGE CLOSURE AS AN ALTERNATIVE TO WARFARIN FOR STROKE PREVENTION IN ATRIAL FIBRILLATION: A PATIENT¬LEVEL META¬ANALYSIS

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2015-01-01

Full Text Available Holmes D.R. Jr, Doshi S.K., Kar S., et al. Left Atrial Appendage Closure as an Alternative to Warfarin for Stroke Prevention in Atrial Fibrillation: A Patient­Level Meta­Analysis // J. Am. Coll. Cardiol. – 2015. – Vol. 65. – P. 2614–2623.

Stereoselective interactions of warfarin enantiomers with the pregnane X nuclear receptor in gene regulation of major drug-metabolizing cytochrome P450 enzymes

Czech Academy of Sciences Publication Activity Database

Rulcová, A.; Prokopová, I.; Krausová, L.; Bitman, M.; Vrzal, R.; Dvořák, Z.; Blahoš, Jaroslav; Pávek, P.

2010-01-01

Roč. 8, č. 12 (2010), s. 2708-2717 ISSN 1538-7933 R&D Projects: GA MŠk(CZ) LC06063 Institutional research plan: CEZ:AV0Z50520514 Keywords : CYP3A4 * gene regulation * warfarin Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 5.439, year: 2010

THE EFFECTS OF GLYCATION ON THE BINDING OF HUMAN SERUM ALBUMIN TO WARFARIN AND L-TRYPTOPHAN

OpenAIRE

Joseph, K.S.; Hage, David S.

2010-01-01

Diabetes leads to elevated levels of glucose in blood which, in turn, can lead to the non-enzymatic glycation of serum proteins such as human serum albumin (HSA). It has been suggested that this increase in glycation can alter the ability of HSA to bind to drugs and other small solutes. This study used high-performance affinity chromatography (HPAC) to see if there is any significant change related to glycation in the binding of HSA to warfarin and L-tryptophan, which are often used as probe ...

Synthesis of deuterium labelled metabolites of warfarin and phenprocoumon

Energy Technology Data Exchange (ETDEWEB)

Heimark, L.D.; Toon, S.; Low, L.K.; Swinney, D.C.; Trager, W.F.

1986-02-01

The synthesis of deuterium labelled 4'-,6-,7- and 8-hydroxy metabolites of warfarin and phenprocoumon is described. The pentadeuterio labelled 6-,7- and 8-hydroxyphenprocoumons were prepared via alkylation of the respective 6-, 7- and 8-methoxy-4-hydroxycoumarins with 1-(phenyl-d/sub 5/)-1-bromopropane and subsequent cleavage of the methyl protecting group with boron tribromide. The synthesis of 1-(pentadeuteriophenyl)-1-bromopropane and the 6-, 7-and 8-methoxy-4-hydroxycoumarins are also presented. The pentadeuterio labelled 6-, 7- and 8-hydroxywarfarins were obtained by reaction of 4-(phenyl-d/sub 5/)-3-buten-2-one with the respective 6-, 7- and 8-hydroxy-4-hydroxycoumarins in methanol followed by hydrolysis of the intermediate cyclic methyl ketals in aqueous acid. 4-Hydroxycoumarin-5,6,7,8-d/sub 4/, prepared from phenyl-d/sub 6/ and tetradeuteriomalonic acid, was reacted with 1-(p-hydroxyphenyl)-1-propanol and 4-(p-hydroxyphenyl)-3-buten-2-one to yield labelled 4'-hydroxyphenprocoumon and 4'-hydroxywarfarin respectively.

VKORC1-1639G>A, CYP2C9, EPHX1691A>G genotype, body weight, and age are important predictors for warfarin maintenance doses in patients with mechanical heart valve prostheses in southwest China.

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Gu, Qiang; Kong, Yan; Schneede, Jörn; Xiao, Ying-Bin; Chen, Lin; Zhong, Qian-Jin; Wang, Xue-Feng; Hao, Jia; Chen, Bai-Cheng; Chen, Jing-Jin

2010-12-01

To investigate the contribution of genetic polymorphisms of vitamin K epoxide reductase complex subunit 1 gene VKORC1-1639G>A, cytochrome P450 2C9 gene (CYP2C9), EPHXI, and clinical factors to warfarin sensitivity in southwest Chinese Han patients with mechanical heart valve prostheses. A total of 127 patients with mechanical heart valve prostheses who have been followed up at our department during the past 23 years were enrolled in this study and compared to a control group that consisted of 133 randomly selected healthy blood donors. These Chinese patients met stable warfarin dosage requirements and had reached the target international normalized ratio (INR) of 1.5-2.0. PCR and direct sequencing were carried out to identify the polymorphisms of VKORC1-1639G>A (rs9923231), CYP2C9*3 (rs1057910), CYP2C9 IVS3-65G>C (rs9332127), and EPHX1691A>G (rs4653436). In addition, total and free (non-protein-bound) warfarin concentrations were analyzed. There were great interindividual differences in warfarin maintenance dosage (ranging from 0.6 to 8.4 mg/day) among the 127 patients with mechanical heart valve prostheses. VKORC1-1639G>A, CYP2C9, EPHX1691A>G polymorphism, body weight, and age were found to affect the dose demands. Multiple linear regression models incorporating genetic polymorphisms of VKORC1, CYP2C9, EPHX1691A>G, and the nongenetic factors of age and body weight were developed, and explained up to 76.8% of the total variation (adjusted R (2) of 0.743) in warfarin maintenance doses in southwest Chinese patients with mechanical heart valve prostheses.

Patients' time in therapeutic range on warfarin among US patients with atrial fibrillation: Results from ORBIT-AF registry.

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Pokorney, Sean D; Simon, DaJuanicia N; Thomas, Laine; Fonarow, Gregg C; Kowey, Peter R; Chang, Paul; Singer, Daniel E; Ansell, Jack; Blanco, Rosalia G; Gersh, Bernard; Mahaffey, Kenneth W; Hylek, Elaine M; Go, Alan S; Piccini, Jonathan P; Peterson, Eric D

2015-07-01

Time in therapeutic range (TTR) of international normalized ratio (INR) of 2.0 to 3.0 is important for the safety and effectiveness of warfarin anticoagulation. There are few data on TTR among patients with atrial fibrillation (AF) in community-based clinical practice. Using the US Outcomes Registry for Better Informed Treatment of Atrial Fibrillation (ORBIT-AF), we examined TTR (using a modified Rosendaal method) among 5,210 patients with AF on warfarin and treated at 155 sites. Patients were grouped into quartiles based on TTR data. Multivariable logistic regression modeling with generalized estimating equations was used to determine patient and provider factors associated with the lowest (worst) TTR. Overall, 59% of the measured INR values were between 2.0 and 3.0, with an overall mean and median TTR of 65% ± 20% and 68% (interquartile range [IQR] 53%-79%). The median times below and above the therapeutic range were 17% (IQR 8%-29%) and 10% (IQR 3%-19%), respectively. Patients with renal dysfunction, advanced heart failure, frailty, prior valve surgery, and higher risk for bleeding (ATRIA score) or stroke (CHA2DS2-VASc score) had significantly lower TTR (P range. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

The synthesis of deuterium labelled metabolites of warfarin and phenprocoumon

International Nuclear Information System (INIS)

Heimark, L.D.; Toon, S.; Low, L.K.; Swinney, D.C.; Trager, W.F.

1986-01-01

The synthesis of deuterium labelled 4'-,6-,7- and 8-hydroxy metabolites of warfarin and phenprocoumon is described. The pentadeuterio labelled 6-,7- and 8-hydroxyphenprocoumons were prepared via alkylation of the respective 6-, 7- and 8-methoxy-4-hydroxycoumarins with 1-(phenyl-d 5 )-1-bromopropane and subsequent cleavage of the methyl protecting group with boron tribromide. The synthesis of 1-(pentadeuteriophenyl)-1-bromopropane and the 6-, 7- and 8-methoxy-4-hydroxycoumarins are also presented. The pentadeuterio labelled 6-, 7- and 8-hydroxywarfarins were obtained by reaction of 4-(phenyl-d 5 )-3-buten-2-one with the respective 6-, 7- and 8-hydroxy-4-hydroxycoumarins in methanol followed by hydrolysis of the intermediate cyclic methyl ketals in aqueous acid. 4-Hydroxycoumarin-5,6,7,8-d 4 , prepared from phenyl-d 6 and tetradeuteriomalonic acid, was reacted with 1-(p-hydroxyphenyl)-1-propanol and 4-(p-hydroxyphenyl)-3-buten-2-one to yield labelled 4'-hydroxyphenprocoumon and 4'-hydroxywarfarin respectively. (author)

Three- versus four-factor prothrombin complex concentrate for the reversal of warfarin-induced bleeding

Science.gov (United States)

Holt, Tara; Taylor, Scott; Abraham, Prasad; Mcmillian, Wesley; Harris, Serena; Curtis, James; Elder, Tai

2018-01-01

Objective: The objective of this study was to evaluate the effectiveness of 3-factor prothrombin complex concentrate (3F-PCC) compared to 4-factor PCC (4F-PCC) in warfarin-associated bleeding. Methods: This multicenter, retrospective, cohort study analyzed data from patients admitted between May 2011 and October 2014 who received PCC for warfarin-associated bleeding. The primary outcome was the rate of international normalized ratio (INR) normalization, defined as an INR ≤1.3, after administration of 3F-PCC compared to 4F-PCC. Other variables of interest included the incidence of additional reversal agents, new thromboembolic events, and mortality. Results: A total of 134 patients were included in the analysis. The average dose of PCC administered was 24.6 ± 9.3 units/kg versus 36.3 ± 12.8 units/kg in the 3F-PCC and 4F-PCC groups, respectively, P < 0.001. Baseline INR in the 3F-PCC and 4F-PCC groups was 3.61 ± 2.3 and 6.87 ± 2.3, respectively P < 0.001. 4F-PCC had a higher rate of INR normalization at first INR check post-PCC administration compared to 3F-PCC (84.2% vs. 51.9%, P = 0.0001). Thromboembolic events, intensive care unit and hospital length of stay, and mortality were similar among both groups. Conclusion: The use of 4F-PCC leads to a more significant reduction in INR compared to 3F-PCC though no difference in mortality or length of stay was observed. Thromboembolism rates were similar among both groups. PMID:29619338

Assessing the relative potency of (S)- and (R)-warfarin with a new PK-PD model, in relation to VKORC1 genotypes.

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Ferrari, Myriam; Pengo, Vittorio; Barolo, Massimiliano; Bezzo, Fabrizio; Padrini, Roberto

2017-06-01

The purpose of this study is to develop a new pharmacokinetic-pharmacodynamic (PK-PD) model to characterise the contribution of (S)- and (R)-warfarin to the anticoagulant effect on patients in treatment with rac-warfarin. Fifty-seven patients starting warfarin (W) therapy were studied, from the first dose and during chronic treatment at INR stabilization. Plasma concentrations of (S)- and (R)-W and INRs were measured 12, 36 and 60 h after the first dose and at steady state 12-14 h after dosing. Patients were also genotyped for the G>A VKORC1 polymorphism. The PK-PD model assumed a linear relationship between W enantiomer concentration and INR and included a scaling factor k to account for a different potency of (R)-W. Two parallel compartment chains with different transit times (MTT 1 and MTT 2 ) were used to model the delay in the W effect. PD parameters were estimated with the maximum likelihood approach. The model satisfactorily described the mean time-course of INR, both after the initial dose and during long-term treatment. (R)-W contributed to the rac-W anticoagulant effect with a potency of about 27% that of (S)-W. This effect was independent of VKORC1 genotype. As expected, the slope of the PK/PD linear correlation increased stepwise from GG to GA and from GA to AA VKORC1 genotype (0.71, 0.90 and 1.49, respectively). Our PK-PD linear model can quantify the partial pharmacodynamic activity of (R)-W in patients contemporaneously exposed to therapeutic (S)-W plasma levels. This concept may be useful in improving the performance of future algorithms aiming at identifying the most appropriate W maintenance dose.

Adherence to treatment guidelines: the association between stroke risk stratified comparing CHADS2 and CHA2DS2-VASc score levels and warfarin prescription for adult patients with atrial fibrillation.

Science.gov (United States)

Chapman, Scott A; St Hill, Catherine A; Little, Meg M; Swanoski, Michael T; Scheiner, Shellina R; Ware, Kenric B; Lutfiyya, M Nawal

2017-02-11

Ischemic stroke is a risk associated with atrial fibrillation (AF) and is estimated to occur five times more often in afflicted patients than in those without AF. Anti-thrombotic therapy is recommended for the prevention of ischemic stroke. Risk stratification tools, such as the CHADS 2 , and more recently the CHA 2 DS 2 -VASc, for predicting stroke in patients with AF have been developed to determine the level of stroke risk and assist clinicians in the selection of antithrombotic therapy. Warfarin, for stroke prevention in AF, is the most commonly prescribed anticoagulant in North America. The purpose of this study was to examine the utility of using the CHADS 2 score levels (low and high) in contrast to the CHA 2 DS 2 -VASc when examining the outcome of warfarin prescriptions for adult patients with AF. The CHA 2 DS 2 -VASc tool was not widely used in 2010, when the data analyzed were collected. It has only been since 2014 that CHA 2 DS 2 -VASc criteria has been recommended to guide anticoagulant treatment in updated AF treatment guidelines. Bivariate and multivariate data analysis strategies were used to analyze 2010 National Ambulatory Care Survey (NAMCS) data. NAMCS is designed to collect data on the use and provision of ambulatory care services nationwide. The study population for this research was US adults with a diagnosis of AF. Warfarin prescription was the dependent variable for this study. The study population was 7,669,844 AF patients. Bivariate analysis revealed that of those AF patients with a high CHADS 2 score, 25.1% had received a warfarin prescription and 18.8 for those with a high CHA 2 DS 2 -VASc score. Logistic regression analysis yielded that patients with AF had higher odds of having a warfarin prescription if they had a high CHADS 2 score, were Caucasian, lived in a zip code where guideline adherence in alignment with risk stratification for stroke prevention. Interprofessional health care teams can provide improved medical management of

Nonvitamin-K-antagonist oral anticoagulants versus warfarin in patients with atrial fibrillation and previous stroke or transient ischemic attack: An updated systematic review and meta-analysis of randomized controlled trials.

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Ntaios, George; Papavasileiou, Vasileios; Diener, Hans-Chris; Makaritsis, Konstantinos; Michel, Patrik

2017-08-01

Background In a previous systematic review and meta-analysis, we assessed the efficacy and safety of nonvitamin-K antagonist oral anticoagulants versus warfarin in patients with atrial fibrillation and stroke or transient ischemic attack. Since then, new information became available. Aim The aim of the present work was to update the results of the previous systematic review and meta-analysis. Methods We searched PubMed until 24 August 2016 for randomized controlled trials using the following search items: "atrial fibrillation" and "anticoagulation" and "warfarin" and "previous stroke or transient ischemic attack." Eligible studies had to be phase III trials in patients with atrial fibrillation comparing warfarin with nonvitamin-K antagonist oral anticoagulants currently on the market or with the intention to be brought to the market in North America or Europe. The outcomes assessed in the efficacy analysis included stroke or systemic embolism, stroke, ischemic or unknown stroke, disabling or fatal stroke, hemorrhagic stroke, cardiovascular death, death from any cause, and myocardial infarction. The outcomes assessed in the safety analysis included major bleeding, intracranial bleeding, and major gastrointestinal bleeding. We performed fixed effects analyses on intention-to-treat basis. Results Among 183 potentially eligible articles, four were included in the meta-analysis. In 20,500 patients, compared to warfarin, nonvitamin-K antagonist oral anticoagulants were associated with a significant reduction of stroke/systemic embolism (relative risk reduction: 13.7%, absolute risk reduction: 0.78%, number needed to treat to prevent one event: 127), hemorrhagic stroke (relative risk reduction: 50.0%, absolute risk reduction: 0.63%, number needed to treat: 157), any stroke (relative risk reduction: 13.1%, absolute risk reduction: 0.7%, number needed to treat: 142), and intracranial hemorrhage (relative risk reduction: 46.1%, absolute risk reduction: 0.88%, number needed

Clinical outcomes in patients with atrial fibrillation according to sex during anticoagulation with apixaban or warfarin: a secondary analysis of a randomized controlled trial.

Science.gov (United States)

Vinereanu, Dragos; Stevens, Susanna R; Alexander, John H; Al-Khatib, Sana M; Avezum, Alvaro; Bahit, Marıa Cecilia; Granger, Christopher B; Lopes, Renato D; Halvorsen, Sigrun; Hanna, Michael; Husted, Steen; Hylek, Elaine M; Mărgulescu, Andrei D; Wallentin, Lars; Atar, Dan

2015-12-07

To assess clinical outcomes, efficacy, and safety according to sex during anticoagulation with apixaban compared with warfarin in patients with atrial fibrillation. Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) was a randomized, double-blind, placebo-controlled, multicentre trial that included 11 785 (64.7%) men and 6416 (35.3%) women with atrial fibrillation or flutter randomized to receive either warfarin or apixaban. The primary efficacy endpoint was stroke or systemic embolism; secondary efficacy endpoints were death from any cause and cardiovascular death. The primary safety endpoint was major bleeding; secondary safety endpoints were a composite of major bleeding and non-major clinically relevant bleeding. The risk of stroke or systemic embolism was similar in women vs. men [adjusted hazard ratio (adjHR): 0.91; 95% confidence interval (CI): 0.74-1.12; P = 0.38]. However, among patients with history of stroke or transient ischaemic attack, women had a lower risk of recurrent stroke compared with men (adjHR: 0.70; 95% CI: 0.50-0.97; P = 0.036). Women also had a lower risk of all-cause death (adjHR: 0.63; 95% CI: 0.55-0.73; P < 0.0001) and cardiovascular death (adjHR: 0.62; 95% CI: 0.51-0.75; P < 0.0001), and a trend towards less major bleeding (adjHR: 0.86; 95% CI: 0.74-1.01; P = 0.066) and major or non-major clinically relevant bleeding (adjHR: 0.89; 95% CI: 0.80-1.00; P = 0.049). The efficacy and safety benefits of apixaban compared with warfarin were consistent regardless of sex. In the ARISTOTLE trial, women had a similar rate of stroke or systemic embolism but a lower risk of mortality and less clinically relevant bleeding than men. The efficacy and safety benefits of apixaban compared with warfarin were consistent in men and women. ARISTOTLE ClinicalTrials.gov number, NCT00412984. Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2015. For permissions please

Comparison of Thromboemboli Prophylactic Effect of Aspirin and Low Dose Warfarin in Standard Risk Multiple Myeloma Patients that Treated with Regimens Containing Thalidomide

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Seyed Amir Dadkhahi

2017-05-01

Full Text Available Abstract Background: Most of the current regimens in the treatment of multiple myeloma include thalidomide. Thalidomide is a modulator of the immune system and according to several studies, its main complication is thromboembolism. The aim of this study is to compare the thromboemboli prophylactic effect of aspirin and low dose warfarin in standard risk multiple myeloma patients that treated with regimens containing thalidomide. Materials and Methods: In this double- blind clinical trial study, sixty-six patients with multiple myeloma under treatment with thalidomide-containing regimens with standard risk for thromboembolism who were admitted to Khansari hospital, entered the study according to inclusion and exclusion criteria. The incidence of thromboembolism in these patients was evaluated. Results: Five patients in the warfarin group and 2 patients in the aspirin group had thromboemboli. Chi square analyses showed no significant difference between groups (p=0.635. Conclusion: The results showed that both drugs are effective in preventing thromboembolism and can be used as a prophylactic treatment.

Bleeding events and associated factors in a cohort of adult patients taking warfarin in Sarawak, Malaysia.

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Edwards, Frances; Arkell, Paul; Fong; Roberts, Lesley M; Gendy, David; Wong, Christina Siew-Hie; Ngu, Joanna Chee Yien; Tiong, Lee Len; Bibi, Faridha Mohd Salleh; Lai, Lana Yin Hui; Ong, Tiong Kiam; Abouyannis, Michael

2014-01-01

Evidence is emerging that rates of adverse events in patients taking warfarin may vary with ethnicity. This study investigated the rates of bleeds and thromboembolic events, the international normalised ratio (INR) status and the relationship between INR and bleeding events in Malaysia. Patients attending INR clinic at the Heart Centre, Sarawak General Hospital were enrolled on an ad hoc basis from May 2010 and followed up for 1 year. At each routine visit, INR was recorded and screening for bleeding or thromboembolism occurred. Variables relating to INR control were used as predictors of bleeds in logistic regression models. 125 patients contributed to 140 person-years of follow-up. The rates of major bleed, thromboembolic event and minor bleed per 100 person-years of follow-up were 1.4, 0.75 and 34.3. The median time at target range calculated using the Rosendaal method was 61.6% (IQR 44.6–74.1%). Of the out-of-range readings, 30.0% were below range and 15.4% were above. INR variability, (standard deviation of individuals’ mean INR), was the best predictor of bleeding events, with an odds ratio of 3.21 (95% CI 1.10–9.38). Low rates of both major bleeds and thromboembolic events were recorded, in addition to a substantial number of INR readings under the recommended target range. This may suggest that the recommended INR ranges may not represent the optimal warfarin intensity for this population and that a lower intensity of therapy, as observed in this cohort, could be beneficial in preventing adverse events.

Association between CYP4F2 genotype and circulating plasma vitamin K concentration in children on chronic warfarin therapy: Possible long-term implications for bone development and vascular health.

Science.gov (United States)

Kampouraki, Emmanouela; Avery, Peter J; Biss, Tina; Kamali, Farhad

2017-12-01

Vitamin K is essential, for the activation of clotting proteins, as well as the biosynthesis of osteocalcin in bones and the activation of matrix-Gla protein needed in maintaining vasculature health. Cytochrome p450 4F2 (CYP4F2) enzyme is involved in vitamin K catabolism. Genetic polymorphism in CYP4F2 is thus likely to affect vitamin K systemic availability. We show that children on chronic warfarin therapy have low levels of vitamin K and vitamin K levels are linked to CYP4F2 genotype. Long-term low levels of vitamin K, influenced by CYP4F2 genotype, might affect bone development and vascular health in children on chronic warfarin therapy. © 2017 Wiley Periodicals, Inc.

Major bleeding in patients with atrial fibrillation receiving apixaban or warfarin: The ARISTOTLE Trial (Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation): Predictors, Characteristics, and Clinical Outcomes.

Science.gov (United States)

Hylek, Elaine M; Held, Claes; Alexander, John H; Lopes, Renato D; De Caterina, Raffaele; Wojdyla, Daniel M; Huber, Kurt; Jansky, Petr; Steg, Philippe Gabriel; Hanna, Michael; Thomas, Laine; Wallentin, Lars; Granger, Christopher B

2014-05-27

This study sought to characterize major bleeding on the basis of the components of the major bleeding definition, to explore major bleeding by location, to define 30-day mortality after a major bleeding event, and to identify factors associated with major bleeding. Apixaban was shown to reduce the risk of major hemorrhage among patients with atrial fibrillation in the ARISTOTLE (Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation) trial. All patients who received at least 1 dose of a study drug were included. Major bleeding was defined according to the criteria of the International Society on Thrombosis and Haemostasis. Factors associated with major hemorrhage were identified using a multivariable Cox model. The on-treatment safety population included 18,140 patients. The rate of major hemorrhage among patients in the apixaban group was 2.13% per year compared with 3.09% per year in the warfarin group (hazard ratio [HR] 0.69, 95% confidence interval [CI]: 0.60 to 0.80; p < 0.001). Compared with warfarin, major extracranial hemorrhage associated with apixaban led to reduced hospitalization, medical or surgical intervention, transfusion, or change in antithrombotic therapy. Major hemorrhage followed by mortality within 30 days occurred half as often in apixaban-treated patients than in those receiving warfarin (HR 0.50, 95% CI: 0.33 to 0.74; p < 0.001). Older age, prior hemorrhage, prior stroke or transient ischemic attack, diabetes, lower creatinine clearance, decreased hematocrit, aspirin therapy, and nonsteroidal anti-inflammatory drugs were independently associated with an increased risk. Apixaban, compared with warfarin, was associated with fewer intracranial hemorrhages, less adverse consequences following extracranial hemorrhage, and a 50% reduction in fatal consequences at 30 days in cases of major hemorrhage. Copyright © 2014 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

Genetic epidemiology of pharmacogenetic variations in CYP2C9, CYP4F2 and VKORC1 genes associated with warfarin dosage in the Indian population.

Science.gov (United States)

Giri, Anil K; Khan, Nazir M; Grover, Sandeep; Kaur, Ismeet; Basu, Analabha; Tandon, Nikhil; Scaria, Vinod; Kukreti, Ritushree; Brahmachari, Samir K; Bharadwaj, Dwaipayan

2014-07-01

Warfarin, a widely used anticoagulant, exhibits large interindividual variability in dose requirements. CYP2C9 and VKORC1 polymorphisms in various ethnic groups have been extensively studied as genetic markers associated with variable drug response. However, allele frequencies of these variants have not been assessed in major ethnic groups in the Indian population. To study the functional variants known to affect warfarin dosing, we reanalyzed genotype microarray datasets generated as a part of genome-wide association studies as well as data from the Indian Genome Variation database. We examined data from 2680 individuals across 24 ethnically diverse Indian subpopulations. Allelic distribution of VKORC1 (-1639G>A) showed a greater degree of variation across Indian subpopulations, with frequencies as low as 6.5% in an out-group subpopulation to >70% in Tibeto-Burmans. Risk allele frequency of CYP4F2*3 (V433M) was higher in north Indians (0.30-0.44), as compared with other world populations, such as African-American (0.12), Caucasian (0.34) and Hispanic (0.23). TheVKORC1 variant (-1639A) was shown to be prevalent amongst Tibeto-Burmans, whereas CYP2C9 (R144C, I359L) and CYP4F2 (V433M) variants were observed in considerable variability amongst Indo-Europeans. The frequency of CYP2C9*3 (I359L) in north Indians was found to be higher than in most Asian populations. Furthermore, geographical distribution patterns of these variants in north India showed an increased trend of warfarin extensive metabolizers from the Himalayan to Gangetic region. Combined allele frequency (CYP2C9*3 and CYP4F2*3) data suggest that poor metabolizers varied in the range of 0.38-1.85% in Indo-Europeans. Based on genotypic distribution, the majority of the Indian subpopulation might require higher doses for stable anticoagulation, whereas careful assessment is required for Tibeto-Burmans who are expected to have intermediate dose requirement. This is the largest global genetic epidemiological

New oral anticoagulants are not superior to warfarin in secondary prevention of stroke or transient ischemic attacks, but lower the risk of intracranial bleeding: insights from a meta-analysis and indirect treatment comparisons.

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Partha Sardar

Full Text Available PURPOSE: Patients with Atrial Fibrillation (AF and prior stroke are classified as high risk in all risk stratification schemes. A systematic review and meta-analysis was performed to compare the efficacy and safety of New Oral Anticoagulants (NOACs to warfarin in patients with AF and previous stroke or transient ischemic attack (TIA. METHODS: Three randomized controlled trials (RCTs, including total 14527 patients, comparing NOACs (apixaban, dabigatran and rivaroxaban with warfarin were included in the analysis. Primary efficacy endpoint was ischemic stroke, and primary safety endpoint was intracranial bleeding. Random-effects models were used to pool efficacy and safety data across RCTs. RevMan and Stata software were used for direct and indirect comparisons, respectively. RESULTS: In patients with AF and previous stroke or TIA, effects of NOACs were not statistically different from that of warfarin, in reduction of stroke (Odds Ratio [OR] 0.86, 95% confidence interval [CI] 0.73- 1.01, disabling and fatal stroke (OR 0.85, 95% CI 0.71-1.04, and all-cause mortality (OR 0.90, 95% CI 0.79 -1.02. Randomization to NOACs was associated with a significantly lower risk of intracranial bleeding (OR 0.42, 95% CI 0.25-0.70. There were no major differences in efficacy between apixaban, dabigatran (110 mg BID and 150 mg BID and rivaroxaban. Major bleeding was significantly lower with apixaban and dabigatran (110 mg BID compared with dabigatran (150 mg BID and rivaroxaban. CONCLUSION: NOACs may not be more effective than warfarin in the secondary prevention of ischemic stroke in patients with a prior history of cerebrovascular ischemia, but have a lower risk of intracranial bleeding.

Evaluation of the interactions between human serum albumin (HSA and warfarin or diflunisal by using molecular fluorescence using two approaches

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Susana Amézqueta

2018-03-01

Full Text Available Serum albumin is the main drug transporter of the bloodstream and contains two main binding sites:  Sudlow I or acidic drug binding site, and Sudlow II or benzodiazepine binding site. Warfarin, a well-known anticoagulant drug commonly used in the prevention of thrombosis and thromboembolism, binds to Sudlow I site, whereas non-steroidal antiinflammatory drugs (NSAIDs such as diflunisal bind preferentially to Sudlow II site.  Albumin is a fluorophore that modifies its fluorescence (quenching or enhancement effect when it is bound to a drug. The application of the double logarithm Stern-Volmer equation allows the calculation of the stoichiometry and the binding constant of the process. This procedure does not consider the possible interferences coming from the fluorescence of the drug though. Another strategy to evaluate the binding constants is to consider the whole spectrum, taking into account all the possible species in equilibrium; in this case we have used an extended version of the STAR program, which can deal with 300 spectra, each containing up to 300 data points. The aim of this work is to compare both approaches to evaluate the interaction between warfarin (Sudlow I and diflunisal (Sudlow II and HSA: the double logarithm Stern-Volmer equation and the STAR program.

Impact of renal function on ischemic stroke and major bleeding rates in nonvalvular atrial fibrillation patients treated with warfarin or rivaroxaban: a retrospective cohort study using real-world evidence.

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Weir, Matthew R; Berger, Jeffrey S; Ashton, Veronica; Laliberté, François; Brown, Kip; Lefebvre, Patrick; Schein, Jeffrey

2017-10-01

Renal dysfunction is associated with increased risk of cardiovascular disease and is an independent predictor of stroke and systemic embolism. Nonvalvular atrial fibrillation (NVAF) patients with renal dysfunction may face a particularly high risk of thromboembolism and bleeding. The current retrospective cohort study was designed to assess the impact of renal function on ischemic stroke and major bleeding rates in NVAF patients in the real-world setting (outside a clinical trial). Medical claims and Electronic Health Records were retrieved retrospectively from Optum's Integrated Claims-Clinical de-identified dataset from May 2011 to August 2014. Patients with NVAF treated with warfarin (2468) or rivaroxaban (1290) were selected. Each treatment cohort was stratified by baseline estimated creatinine clearance (eCrCl) levels. Confounding adjustments were made using inverse probability of treatment weights (IPTWs). Incidence rates and hazard ratios of ischemic stroke and major bleeding events were calculated for both cohorts. Overall, patients treated with rivaroxaban had an ischemic stroke incidence rate of 1.9 per 100 person-years (PY) while patients treated with warfarin had a rate of 4.2 per 100 PY (HR = 0.41 [0.21-0.80], p = .009). Rivaroxaban patients with an eCrCl below 50 mL/min (N = 229) had an ischemic stroke rate of 0.8 per 100 PY, while the rate for the warfarin cohort (N = 647) was 6.0 per 100 PY (HR = 0.09 [0.01-0.72], p = .02). For the other renal function levels (i.e. eCrCl 50-80 and ≥80 mL/min) HRs indicated no statistically significant differences in ischemic stroke risks. Bleeding events did not differ significantly between cohorts stratified by renal function. Ischemic stroke rates were significantly lower in the overall NVAF population for rivaroxaban vs. warfarin users, including patients with eCrCl below 50 mL/min. For all renal function groups, major bleeding risks were not statistically different between

Combined Acute Haemolytic and Secondary Angle Closure Glaucoma following Spontaneous Intraocular Haemorrhages in a Patient on Warfarin

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Walter Andreatta

2016-11-01

Full Text Available Background: To report the first described case of combined haemolytic and acute angle closure glaucoma secondary to spontaneous intraocular haemorrhages in a patient on excessive anticoagulation. To the best of our knowledge, this is the first case reported in the literature presenting with raised intraocular pressure due to both mechanisms. Case Description: A 90-year-old woman presented with acute pain and reduction in vision in the left eye. Her intraocular pressure (IOP was 55 mm Hg. There were red tinted blood cells in the anterior chamber giving it a reddish hue. The patient was known to have advanced wet macular degeneration. She was taking oral warfarin for atrial fibrillation. Her international normalised ratio (INR was 7.7. B-scan ultrasound of posterior segment showed vitreous and suprachoroidal haemorrhages. An ultrabiomicroscopic examination confirmed open angles. A diagnosis of haemolytic glaucoma secondary to intraocular haemorrhages was made. The IOP was controlled medically. Warfarin was withdrawn and oral vitamin K therapy was initiated leading to a rapid INR reduction. Three days later, her anterior chamber became progressively shallower causing a secondary acute angle closure which was managed medically. After 2 months, the left IOP was well-controlled without any medications and the eye was not inflamed. Her vision in that eye remained perception of light. Conclusion: Patients with suprachoroidal haemorrhages should be closely monitored as they might subsequently develop acute angle closure despite an initially open angle and well-controlled INR and IOP. Excessive anticoagulation needs to be prevented to minimise the risk of sight-threatening complications.

Warfarin maintenance dose in older patients: higher average dose and wider dose frequency distribution in patients of African ancestry than those of European ancestry.

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Garwood, Candice L; Clemente, Jennifer L; Ibe, George N; Kandula, Vijay A; Curtis, Kristy D; Whittaker, Peter

2010-06-15

Studies report that warfarin doses required to maintain therapeutic anticoagulation decrease with age; however, these studies almost exclusively enrolled patients of European ancestry. Consequently, universal application of dosing paradigms based on such evidence may be confounded because ethnicity also influences dose. Therefore, we determined if warfarin dose decreased with age in Americans of African ancestry, if older African and European ancestry patients required different doses, and if their daily dose frequency distributions differed. Our chart review examined 170 patients of African ancestry and 49 patients of European ancestry cared for in our anticoagulation clinic. We calculated the average weekly dose required for each stable, anticoagulated patient to maintain an international normalized ratio of 2.0 to 3.0, determined dose averages for groups 80 years of age and plotted dose as a function of age. The maintenance dose in patients of African ancestry decreased with age (PAfrican ancestry required higher average weekly doses than patients of European ancestry: 33% higher in the 70- to 79-year-old group (38.2+/-1.9 vs. 28.8+/-1.7 mg; P=0.006) and 52% in the >80-year-old group (33.2+/-1.7 vs. 21.8+/-3.8 mg; P=0.011). Therefore, 43% of older patients of African ancestry required daily doses >5mg and hence would have been under-dosed using current starting-dose guidelines. The dose frequency distribution was wider for older patients of African ancestry compared to those of European ancestry (PAfrican ancestry indicate that strategies for initiating warfarin therapy based on studies of patients of European ancestry could result in insufficient anticoagulation and thereby potentially increase their thromboembolism risk. Copyright 2010 Elsevier Inc. All rights reserved.

Native valve disease in patients with non-valvular atrial fibrillation on warfarin or rivaroxaban

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Breithardt, Günter; Baumgartner, Helmut; Berkowitz, Scott D; Hellkamp, Anne S; Piccini, Jonathan P; Lokhnygina, Yuliya; Halperin, Jonathan L; Singer, Daniel E; Hankey, Graeme J; Hacke, Werner; Becker, Richard C; Nessel, Christopher C; Mahaffey, Kenneth W; Califf, Robert M; Fox, Keith A A; Patel, Manesh R

2016-01-01

Objective To compare the characteristics and outcomes of patients with atrial fibrillation (AF) and aortic stenosis (AS) with patients with AF with mitral regurgitation (MR) or aortic regurgitation (AR) and patients without significant valve disease (no SVD). Methods Using Rivaroxaban Once-Daily, Oral, Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF) data, we analysed efficacy and safety outcomes, adjusting hazard ratios (HRs) for potential confounders using Cox regression analysis. Results Among 14 119 intention-to-treat ROCKET AF trial patients, a trial that excluded patients with mitral stenosis or artificial valve prosthesis, 214 had AS with or without other valve abnormalities, 1726 had MR or AR and 12 179 had no SVD. After adjusting for prognostic factors, the composite of stroke, systemic embolism or vascular death increased approximately twofold in patients with AS (AS 10.84, MR or AR 4.54 and no SVD 4.31 events per 100 patient-years, p=0.0001). All-cause death also significantly increased (AS 11.22, MR or AR 4.90 and no SVD 4.39 events per 100 patient-years, p=0.0003). Major bleeding occurred more frequently in AS (adjusted HR 1.61, confidence intervals (CI) 1.03 to 2.49, p<0.05) and MR or AR (HR 1.30, 1.07 to 1.57, p<0.01) than in no SVD, but there was no difference between AS and MR or AR (HR 1.24, 0.78 to 1.97). The relative efficacy of rivaroxaban versus warfarin was consistent among patients with and without valvular disease. Rivaroxaban was associated with higher rates of major bleeding than warfarin in patients with MR or AR (HR 1.63, 1.15 to 2.31). Conclusions We found that patients with AF and AS on oral anticoagulants may have distinctly different efficacy and safety outcomes than patients with MR or AR or no SVD. Trial registration number NCT00403767; Post-results. PMID:26888572

Comparison of Dabigatran vs. Warfarin in Acute Vnous Thromboemboly: Systematic Review.

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Ganji, Reza; Ala, Shahram; Aarabi, Mohsen; Baghery, Babak; Salehifar, Ebrahim

2016-01-01

Acute Venous Thromboembolism (VTE) is a common disease associated with the significant morbidity and mortality. We reviewed clinical outcomes systematically with Dabigatran as a direct oral anticoagulants (DOAC) for treatment of acute VTE. We used Ovide, PubMed, Cochrane (CENTRAL), EMBASE, Scopus, Science Direct, LILAC(for article written not English) and also Iranian database; Magiran, Isc, Iran Medex, Iran DOC, Doaj up to May 2014 to identify randomized clinical trials of Dabigatran compared with conventional treatment for VTE. Two investigators extracted data independently. Number of 5107 patients including two trails were selected. The risk of recurrent VTE was similar with the Dabigatran and standard treatment (Hazard Ratio, 95% confidence interval 1.09 (0.76-1.57). Dabigatran reduced the risk of minor bleeding in comparison with standard treatment; Warfarin (0.62) (0.50-0.76). Finally-in minor bleeding-the Dabigatran seemed as effective as, and probably safer than standard treatment of acute VTE. But in some aspects such as adherence to treatment, pregnant patient, impact on quality of life, new researches are needed to be clarified.

Fluorescence spectrometric studies on the binding of puerarin to human serum albumin using warfarin, ibuprofen and digitoxin as site markers with the aid of chemometrics

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Zhang Guowen; Zhao Nan; Wang Lin

2011-01-01

The interaction of puerarin with human serum albumin (HSA) in pH 7.4 Tris-HCl buffer has been investigated by fluorescence, Fourier transform infrared (FT-IR) and circular dichroism (CD) spectroscopy. The results revealed the presence of static type of quenching mechanism in the binding of puerarin to HSA. The association constants (K a ) between puerarin and HSA were obtained according to Modified Stern-Volmer equation. The calculated thermodynamic parameters indicated that the binding of puerarin to HSA was driven mainly by hydrophobic interaction. The competitive experiments of site markers suggested that the binding site of puerarin to HSA was located in the region of subdomain IIA (sudlow site I). Further, a chemometrics approach, parallel factor analysis (PARAFAC), was applied to resolve the measured three-way synchronous fluorescence spectra data of the competitive interaction between puerarin and warfarin with HSA. The concentration information for the three reaction components, warfarin, puerarin and puerarin-HSA, in the system at equilibrium was obtained simultaneously. The PARAFAC analysis indicated that puerarin in the puerarin-HSA complex was displaced by warfarin, which confirmed the binding site of puerarin to HSA was located in site I. Moreover, the results of CD and FT-IR spectra demonstrated that the secondary structure of HSA was changed in the presence of puerarin. - Highlights: → Puerarin can quench the fluorescence of human serum albumin (HSA). → The HSA fluorescence is quenched by puerarin through a static quenching mechanism. → The binding of puerarin to HSA is driven mainly by hydrophobic interaction. → The parallel factor analysis confirms that puerarin is located in site I of HSA. → The binding of puerarin to HSA induces changes in the secondary structure of HSA.

Assessment and evaluation efficacy of a clinical pharmacist-led inpatient warfarin knowledge education program and follow-up at a Chinese tertiary referral teaching hospital

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Guy-Armel Bounda

2013-01-01

Conclusion: Chinese patients on warfarin therapy should benefit from periodic educational efforts reinforcing key medication safety information. Patient education is not a once-off procedure. A complete patient education program run by a clinical pharmacist in a Cardio-thoracic ward can considerably improve and enhance to reduce the hospital stays and significantly enlighten the role of the patient education in adherence to therapy.

Delayed Bleeding and Pelvic Haematoma after Low-Energy Osteoporotic Pubic Rami Fracture in a Warfarin Patient: An Unusual Cause of Abdominal Pain

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Andrea Sandri

2014-01-01

Full Text Available Introduction. Acute abdominal pain may be the presenting symptom in a wide range of diseases in the elderly. Acute abdominal pain related to a delayed bleeding and pelvic haematoma after a low-energy pubic rami fracture is rare and can have important consequences; to the best of our knowledge, only one case has been previously described. Case Report. We present an unusual case of an 83-year-old woman taking warfarin for atrial fibrillation, admitted to the Emergency Department (ED with acute abdominal pain and progressive anemia related to a delayed bleeding and pelvic haematoma 72 hours after a low-energy osteoporotic pubic rami fracture. Warfarin was withheld, anticoagulation was reversed by using fresh frozen plasma and vitamin K, and concentrated red blood cells were given. Haemoglobin level gradually returned to normal with a progressive resorption of the haematoma. Conclusion. Delayed bleeding and pelvic haematoma after osteoporotic pubic rami fracture should be considered in the differential diagnosis of acute abdominal pain in the elderly. This case indicates the need for hospital admission, careful haemodynamic monitoring, and early identification of bleeding in patients with “benign” osteoporotic pubic rami fracture, especially those receiving anticoagulants, to provide an adequate management and prevent severe complications.

Enantioselective Organocatalysis in Microreactors: Continuous Flow Synthesis of a (S-Pregabalin Precursor and (S-Warfarin

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Riccardo Porta

2015-08-01

Full Text Available Continuous flow processes have recently emerged as a powerful technology for performing chemical transformations since they ensure some advantages over traditional batch procedures. In this work, the use of commercially available and affordable PEEK (Polyetheretherketone and PTFE (Polytetrafluoroethylene HPLC (High Performance Liquid Chromatography tubing as microreactors was exploited to perform organic reactions under continuous flow conditions, as an alternative to the commercial traditional glass microreactors. The wide availability of tubing with different sizes allowed quickly running small-scale preliminary screenings, in order to optimize the reaction parameters, and then to realize under the best experimental conditions a reaction scale up for preparative purposes. The gram production of some Active Pharmaceutical Ingredients (APIs such as (S-Pregabalin and (S-Warfarin was accomplished in short reaction time with high enantioselectivity, in an experimentally very simple procedure.

Motion of left atrial appendage as a determinant of thrombus formation in patients with a low CHADS2 score receiving warfarin for persistent nonvalvular atrial fibrillation

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Ono Koji

2012-12-01

Full Text Available Abstract Background The aim of this study was to define the independent determinants of left atrial appendage (LAA thrombus among various echocardiographic parameters measured by Velocity Vector Imaging (VVI in patients with nonvalvular atrial fibrillation (AF receiving warfarin, particularly in patients with a low CHADS2 score. Methods LAA emptying fraction (EF and LAA peak longitudinal strain were measured by VVI using transesophageal echocardiography in 260 consecutive patients with nonvalvular persistent AF receiving warfarin. The patients were divided into two groups according to the presence (n=43 or absence (n=217 of LAA thrombus. Moreover, the patients within each group were further divided into subgroups according to a CHADS2 score ≤1. Results Multivariate logistic regression analysis showed that LAAEF was an independent determinant of LAA thrombus in the subgroup of 140 with a low CHADS2 score. Receiver operating characteristics curve analysis showed that an LAAEF of 21% was the optimal cutoff value for predicting LAA thrombus. Conclusions LAA thrombus formation depended on LAA contractility. AF patients with reduced LAA contractile fraction (LAAEF ≤21% require strong anticoagulant therapy to avoid thromboembolic events regardless of a low CHADS2 score (≤1.

Evaluation of In-Use Stability of Anticoagulant Drug Products: Warfarin Sodium.

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Nguyenpho, Agnes; Ciavarella, Anthony B; Siddiqui, Akhtar; Rahman, Ziyaur; Akhtar, Sohail; Hunt, Robert; Korang-Yeboah, Maxwell; Khan, Mansoor A

2015-12-01

The objective of the study was to evaluate the stability of warfarin products during use by patients or caregivers. For evaluation, three commercial products manufactured by different processes were selected and placed at 30°C/75%RH to simulate in use condition. Samples were withdrawn up to 12 weeks and analyzed for the physicochemical changes. Scanning electron microscopy demonstrated increasing holes and craters in the tablets over the timeframe. Near-infrared chemical imaging and powder X-ray powder diffraction corroborated the change arising from conversion of crystalline to amorphous forms of the drug. Hardness and disintegration time of the tablets were found to increase progressively. With increasing time, moisture contents of the products were found to increase and consequent decrease in isopropyl alcohol content of the product. Dissolution of the tablets in media at pH 4.5 demonstrated discrimination between crystalline and amorphous drug products. Overall, percent drug dissolved in each product at 30 min was found to decrease with increasing exposure time. Dissolution of drug decreased from 54% to 38% and 82% to 54% for the two products while the third product maintained consistently high level of dissolution. These results suggest that the drug product quality attributes can change during use. © 2015 Wiley Periodicals, Inc. and the American Pharmacists Association.

A case of post-irradiation lumbosacral radioculopathy successfully treated with corticosteroid and warfarin

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Anezaki, Toshiharu; Harada, Takashi; Kawachi, Izumi; Sanpei, Kazuhiro; Soma, Yoshiaki; Tsuji, Shoji [Niigata Univ. (Japan). Brain Research Inst

1999-08-01

A 33-year-old man underwent post-operative radiation therapy for the left testicular anaplastic seminoma. One year later, the patient developed muscle weakness and sensory disturbance in the left lower extremity, and muscle weakness in the right lower extremity. MRI demonstrated linear and focal gadolinium (Gd) enhancement of the anterior portion of the lumbosacral roots within the cauda equina. The neurological symptoms improved after administration of corticosteroid and warfarin. Radiation myelopathy of this type was classified as ''selective anterior horn cell injury or amyotrophy'' by Reagan, and the site of the lesion was considered to be the lower motor neurons. However, based on the clinical and MRI findings, we proposed that the disease process was injury to the spinal nerve roots rather than the lower motor neurons. Recent neuropathological studies of this syndrome have demonstrated degeneration of the proximal spinal nerve roots. We consider that primary lesions of this syndrome occur in spinal nerve roots rather than in lower motor neurons, and ''lumbosacral radiculopathy'' is a more appropriate term for this condition. (author)

A case of post-irradiation lumbosacral radioculopathy successfully treated with corticosteroid and warfarin

International Nuclear Information System (INIS)

Anezaki, Toshiharu; Harada, Takashi; Kawachi, Izumi; Sanpei, Kazuhiro; Soma, Yoshiaki; Tsuji, Shoji

1999-01-01

A 33-year-old man underwent post-operative radiation therapy for the left testicular anaplastic seminoma. One year later, the patient developed muscle weakness and sensory disturbance in the left lower extremity, and muscle weakness in the right lower extremity. MRI demonstrated linear and focal gadolinium (Gd) enhancement of the anterior portion of the lumbosacral roots within the cauda equina. The neurological symptoms improved after administration of corticosteroid and warfarin. Radiation myelopathy of this type was classified as ''selective anterior horn cell injury or amyotrophy'' by Reagan, and the site of the lesion was considered to be the lower motor neurons. However, based on the clinical and MRI findings, we proposed that the disease process was injury to the spinal nerve roots rather than the lower motor neurons. Recent neuropathological studies of this syndrome have demonstrated degeneration of the proximal spinal nerve roots. We consider that primary lesions of this syndrome occur in spinal nerve roots rather than in lower motor neurons, and ''lumbosacral radiculopathy'' is a more appropriate term for this condition. (author)

Privacy in Pharmacogenetics: An End-to-End Case Study of Personalized Warfarin Dosing.

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Fredrikson, Matthew; Lantz, Eric; Jha, Somesh; Lin, Simon; Page, David; Ristenpart, Thomas

2014-08-01

We initiate the study of privacy in pharmacogenetics, wherein machine learning models are used to guide medical treatments based on a patient's genotype and background. Performing an in-depth case study on privacy in personalized warfarin dosing, we show that suggested models carry privacy risks, in particular because attackers can perform what we call model inversion : an attacker, given the model and some demographic information about a patient, can predict the patient's genetic markers. As differential privacy (DP) is an oft-proposed solution for medical settings such as this, we evaluate its effectiveness for building private versions of pharmacogenetic models. We show that DP mechanisms prevent our model inversion attacks when the privacy budget is carefully selected . We go on to analyze the impact on utility by performing simulated clinical trials with DP dosing models. We find that for privacy budgets effective at preventing attacks, patients would be exposed to increased risk of stroke, bleeding events, and mortality . We conclude that current DP mechanisms do not simultaneously improve genomic privacy while retaining desirable clinical efficacy, highlighting the need for new mechanisms that should be evaluated in situ using the general methodology introduced by our work.

Evaluation of a pharmacogenetic-based warfarin dosing algorithm in patients with low time in therapeutic range - study protocol for a randomized controlled trial.

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Marcatto, Leiliane Rodrigues; Sacilotto, Luciana; Bueno, Carolina Tosin; Facin, Mirella; Strunz, Celia Maria Cassaro; Darrieux, Francisco Carlos Costa; Scanavacca, Maurício Ibrahim; Krieger, Jose Eduardo; Pereira, Alexandre Costa; Santos, Paulo Caleb Junior Lima

2016-11-17

Time in therapeutic range (TTR) is a measurement of quality of warfarin therapy and lower TTR values (algorithm specifically calibrated for a Brazilian patient sample. The aims of this study are: to evaluate the impact of a genetic-based algorithm, compared to traditional anticoagulation, in the time to achieve the therapeutic target and in TTR percentage; and to assess the cost-effectiveness of genotype-guided warfarin dosing in a specific cohort of patients with low TTR (algorithm will be used. At the second, third, fourth and fifth consultations (with an interval of 7 days each) INR will be measured and, if necessary, the dose will be adjusted based on guidelines. Afterwards, patients who are INR stable will begin measuring their INR in 30 day intervals; if the patient's INR is not stable, the patient will return in 7 days for a new measurement of the INR. Outcomes measures will include the time to achieve the therapeutic target and the percentage of TTR at 4 and 12 weeks. In addition, as a secondary end-point, pharmacoeconomic analysis will be carried out. Ethical approval was granted by the Ethics Committee for Medical Research on Human Beings of the Clinical Hospital of the University of São Paulo Medical School. This randomized study will include patients with low TTR and it will evaluate whether a population-specific genetic algorithm might be more effective than traditional anticoagulation for a selected group of poorly anticoagulated patients. ClinicalTrials.gov, NCT02592980 . Registered on 29 October 2015.

Comparison of performance of three commercial platforms for warfarin sensitivity genotyping.

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Babic, Nikolina; Haverfield, Eden V; Burrus, Julie A; Lozada, Anthony; Das, Soma; Yeo, Kiang-Teck J

2009-08-01

We performed a 3-way comparison on the Osmetech eSensor, AutoGenomics INFINITI, and a real-time PCR method (Paragonx reagents/Stratagene RT-PCR platform) for their FDA-cleared warfarin panels, and additional polymorphisms (CYP2C9*5, *6, and 11 and extended VKORC1 panels) where available. One hundred de-identified DNA samples were used in this IRB-approved study. Accuracy was determined by comparison of genotyping results across three platforms. Any discrepancy was resolved by bi-directional sequencing. The CYP4F2 on Osmetech was validated by bi-directional sequencing. Accuracies for CYP2C9*2 and *3 were 100% for all 3 platforms. VKORC1 3673 genotyping accuracies were 100% on eSensor and 97% on Infiniti. CYP2C9*5, *6 and *11 showed 100% concordance between eSensor and Infiniti. VKORC1 6484 and 9041 variants compared between ParagonDx and Infiniti analyzer were 100% (6484) and 99% (9041) concordant. CYP4F2 was 100% concordant with sequencing results. The time required to generate the results from automated DNA extraction-to-result was approximately 8h on Infiniti, and 4h on eSensor and ParagonDx, respectively. Overall, we observed excellent CYP2C9*2 and *3 genotyping accuracy for all three platforms. For VKORC1 3673 genotyping, eSensor demonstrated a slightly higher accuracy than the Infiniti, and CYP4F2 on Osmetech was 100% accurate.

Administración oral de preparado parenteral de vitamina K en anticoagulación excesiva por warfarina Oral administration of intravenous preparation of Vitamin K for excessive anticoagulation due to warfarin

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Yoleima Lozada

2012-04-01

Full Text Available La warfarina es frecuentemente usada en la terapia anticoagulante actual, su acción debe ser monitorizada usando el tiempo de protrombina expresado como International Normalized Ratio (INR; cuando se excede el rango de seguridad se puede administrar vitamina K (Vit-K, preferentemente por vía oral. Dicha presentación no está disponible en Venezuela. Se realizó un ensayo clínico, doble ciego, donde a 20 pacientes, edad 18-60 años, sin sangrado e INR inicial de 6 a 10 inclusive; les fue suspendida la warfarina e inmediatamente agrupados al azar a recibir dosis única de Vit-K (oral 1.25mg de Vit-K fraccionada de una presentación parenteral o placebo. El punto final primario, INR Anticoagulation therapy with warfarin, a common clinical practice, needs to be monitored using protombine time expressed as the International Normalized Ratio (INR; when safety range is exceeded, Vitamin K (Vit-K could be administered with preference orally. In Venezuela the specific oral preparation for Vit-K is not available. This is a double blinded, randomized, placebo controlled, clinical trial; 20 patients, age 18-60 year with initial INR ≥ 6, ≤10, were randomized to oral Vit-K 1.25mg (prepared from intravenous presentation or placebo plus withholding warfarin. INR < 3.5 at 24 hours of treatment (the primary end point was achieved by 70% among Vit-K, and 20% among placebo patients; given an absolute risk reduction (ARR, of 50% (CI95%: 14.4-85.6 ρ = 0.028, NNT 2 (CI95%: 1.3 - 6.9. No adverse events were recorded including INR < 2 at 24 hours of treatment administration. Our results are consistent with studies where specific oral presentation of Vit-K was used. The results indicate that oral administration of Vit-K, prepared from an intravenous Vit-K preparation, is safe and more effective to revert excessive anticoagulation than simply withholding warfarin, in places where specific preparation of oral Vit-K is not available or too expensive.

Apixaban in Comparison With Warfarin in Patients With Atrial Fibrillation and Valvular Heart Disease: Findings From the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) Trial.

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Avezum, Alvaro; Lopes, Renato D; Schulte, Phillip J; Lanas, Fernando; Gersh, Bernard J; Hanna, Michael; Pais, Prem; Erol, Cetin; Diaz, Rafael; Bahit, M Cecilia; Bartunek, Jozef; De Caterina, Raffaele; Goto, Shinya; Ruzyllo, Witold; Zhu, Jun; Granger, Christopher B; Alexander, John H

2015-08-25

Apixaban is approved for the prevention of stroke and systemic embolism in patients with nonvalvular atrial fibrillation. However, the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) trial included a substantial number of patients with valvular heart disease and only excluded patients with clinically significant mitral stenosis or mechanical prosthetic heart valves. We compared the effect of apixaban and warfarin on rates of stroke or systemic embolism, major bleeding, and death in patients with and without moderate or severe valvular heart disease using Cox proportional hazards modeling. Of the 18 201 patients enrolled in ARISTOTLE, 4808 (26.4%) had a history of moderate or severe valvular heart disease or previous valve surgery. Patients with valvular heart disease had higher rates of stroke or systemic embolism and bleeding than patients without valvular heart disease. There was no evidence of a differential effect of apixaban over warfarin in patients with and without valvular heart disease in reducing stroke and systemic embolism (hazard ratio [HR], 0.70; 95% confidence interval [CI], 0.51-0.97 and HR, 0.84; 95%, CI 0.67-1.04; interaction P=0.38), causing less major bleeding (HR, 0.79; 95% CI, 0.61-1.04 and HR, 0.65; 95% CI, 0.55-0.77; interaction P=0.23), and reducing mortality (HR, 1.01; 95% CI, 0.84-1.22 and HR, 0.84; 95% CI, 0.73-0.96; interaction P=0.10). More than a quarter of the patients in ARISTOTLE with nonvalvular atrial fibrillation had moderate or severe valvular heart disease. There was no evidence of a differential effect of apixaban over warfarin in reducing stroke or systemic embolism, causing less bleeding, and reducing death in patients with and without valvular heart disease. URL: http://www.clinicaltrials.gov. Unique identifier: NCT00412984. © 2015 American Heart Association, Inc.

Safety of a clinical surveillance protocol with 3- and 6-week warfarin prophylaxis after total joint arthroplasty.

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Goldstein, W M; Jimenez, M L; Bailie, D S; Wall, R; Branson, J

2001-07-01

The charts of 1869 patients were reviewed for the occurrence of deep venous thrombosis (DVT) and pulmonary embolism after total hip or knee arthroplasty. Prophylaxis consisted of 3 (group 1; n=1235) or 6 (group 2; n=634) weeks low-dose warfarin, pneumatic compression boots worn by patients in the hospital, mobilization on the first postoperative day, and a clinical surveillance protocol. Venous ultrasound or ventilation/perfusion lung scintigraphy (V/Q) was performed only if patients became symptomatic. patients. Twenty-three (1.8%) patients were positive for DVT. Ventilation/perfusion lung scintigraphy was performed on 25 patients, and 5 (0.4%) patients were positive for pulmonary embolism. In group 2, 117 patients were evaluated for DVT, and 19 (3%) patients had positive results determined by ultrasound. Twenty-five patients were evaluated with V/Q and only 1 (0.16%) patient was positive for pulmonary embolism. No patient developed a fatal pulmonary embolism or postphlebitic syndrome. This prophylaxis protocol is an efficient and cost-effective method for the prevention of significant events after surgery.

Effect of Complexation with Arabinogalactan on Pharmacokinetics of “Guest” Drugs in Rats: For Example, Warfarin

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Mikhail V. Khvostov

2013-01-01

Full Text Available A pharmacokinetic study of the warfarin (WF : arabinogalactan (AG complex with the 1 : 10 mass ratio after its intragastric introduction to Wistar rats at a dose of 5 mg/kg (WF dose in the complex was 0.5 mg/kg once a day for three days was conducted. It was found that Cmax, T1/2, and AUC of WF in the complex form were lower than after the introduction of blank WF at the same dose, but its elimination (Cl, MRT was much faster. Significant accumulation (Cmin and an abrupt increase in plasma concentration after the third introduction were observed for blank WF, whereas the complex showed a much more moderate increase in concentration at this point. However, despite obvious differences in pharmacokinetic parameters, the efficacies of both agents were virtually identical; the complex differed from blank WF by only 15%. This value is rather insignificant and does not impair its anticoagulant activity. Thus, we can conclude that introduction of the WF : AG complex is safe in terms of reduction of the bleeding risk and accumulation.

Effects of Rolapitant Administered Intravenously on the Pharmacokinetics of a Modified Cooperstown Cocktail (Midazolam, Omeprazole, Warfarin, Caffeine, and Dextromethorphan) in Healthy Subjects.

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Wang, Xiaodong; Zhang, Zhi-Yi; Arora, Sujata; Wang, Jing; Lu, Sharon; Powers, Dan; Kansra, Vikram

2018-04-25

Rolapitant is a selective, long-acting neurokinin-1 receptor antagonist, approved in the United States and Europe for prevention of delayed chemotherapy-induced nausea and vomiting in adults. This open-label study evaluated the effects of a new intravenous formulation of rolapitant on cytochrome P450 (CYP) enzyme (CYP3A, CYP1A2, CYP2C9, CYP2C19, and CYP2D6) activity. On days 1 and 14, 36 healthy volunteers received a modified Cooperstown cocktail (midazolam 3 mg [CYP3A substrate], caffeine 200 mg [CYP1A2 substrate], S-warfarin 10 mg [CYP2C9 substrate] + vitamin K 10 mg, omeprazole 40 mg [CYP2C19 substrate], and dextromethorphan 30 mg [CYP2D6 substrate]). On day 7, subjects received the modified Cooperstown cocktail after 166.5-mg rolapitant infusion. On days 21, 28, and 35, subjects received oral dextromethorphan. Maximum plasma concentration (C max ) and area under the plasma concentration-time curve (AUC 0-last ) of probe drugs post- vs pre-rolapitant administration were assessed using geometric least-squares mean ratios (GMRs) with 90%CIs. The 90%CIs of the GMRs were within the 0.80-1.25 no-effect limits for caffeine and S-warfarin C max and AUC 0-last . For midazolam C max and AUC 0-last and omeprazole C max , the 90%CIs of the GMRs were marginally outside these limits. Intravenous rolapitant coadministration increased dextromethorphan exposure, peaking 14 days post-rolapitant administration (GMRs: C max , 2.74, 90%CI 2.21-3.40; AUC 0-last , 3.36, 90%CI 2.74-4.13). Intravenous rolapitant 166.5 mg and probe drugs were well tolerated when coadministered. These data suggest that intravenous rolapitant is not an inhibitor of CYP3A, CYP2C9, CYP2C19, or CYP1A2 but is a moderate inhibitor of CYP2D6. © 2018, The American College of Clinical Pharmacology.

Immunotoxicity of epicutaneously applied anticoagulant rodenticide warfarin: evaluation by contact hypersensitivity to DNCB in rats

International Nuclear Information System (INIS)

Kataranovski, Milena; Vlaski, Marija; Kataranovski, Dragan; Tosic, Natasa; Mandic-Radic, Slavka; Todorovic, Vera

2003-01-01

The immunotoxicity of epicutaneously administered anticoagulant rodenticide warfarin (WF) was examined in this work by using experimental contact hypersensitivity (CHS) reaction to hapten dinitrochlorobenzene (DNCB). WF (0.05 and 0.5 mg/kg) administration 24 h before the induction of CHS does not change expression of CHS evaluated by ear swelling assay. Regional draining lymph node response during sensitization phase was characterized by decreased cellularity but increased spontaneous and IL-2 stimulated proliferation of draining lymph node cells (DLC). No changes in IL-2 production and in numbers of CD25 + cells were noted and even decreased proliferative index (ratio of IL-2 stimulated to unstimulated DLC proliferation) was detected. Increase in granulocyte activity (MTT reduction and adhesion to plastic) was noted following application of WF solely with further increase following subsequent application of DNCB, when granulocyte activation (NBT reduction) was noted also. Access of WF into general circulation might be responsible for observed changes, what was supported by ex vivo changes in DLC and granulocyte functions assessed before initiation of sensitization and by in vitro effect of exogenous WF as well. Differential effects of WF on lymphocytes and granulocytes noted in this study highlight the need for simultaneous testing of both cell type activity what might constitute a more integrated approach in immunotoxicity studies

Comparison of treatment effect estimates of non-vitamin K antagonist oral anticoagulants versus warfarin between observational studies using propensity score methods and randomized controlled trials

International Nuclear Information System (INIS)

Li, Guowei; Holbrook, Anne; Jin, Yanling; Zhang, Yonghong; Levine, Mitchell A. H.; Mbuagbaw, Lawrence; Witt, Daniel M.; Crowther, Mark; Connolly, Stuart; Chai-Adisaksopha, Chatree; Wan, Zhongxiao; Cheng, Ji; Thabane, Lehana

2016-01-01

Emerging observational studies using propensity score (PS) methods assessed real-world comparative effectiveness of non-vitamin K antagonist oral anticoagulants (NOACs) versus warfarin in patients with non-valvular atrial fibrillation (AF). We aimed to compare treatment effect estimates of NOACs between PS studies and randomized controlled trials (RCTs). Electronic databases and conference proceedings were searched systematically. Primary outcomes included stroke or systemic embolism (SE) and major bleeding. A random-effects meta-analysis was performed to synthesize the data by pooling the PS- and RCT-derived hazard ratios (HRs) separately. The ratio of HRs (RHR) from the ratio of PS-derived HRs relative to RCT-derived HRs was used to determine whether there was a difference between estimates from PS studies and RCTs. There were 10 PS studies and 5 RCTs included for analysis. No significant difference of treatment effect estimates between the PS studies and RCTs was observed: RHR 1.11, 95 % CI 0.98–1.23 for stroke or SE; RHR 1.07, 95 % CI 0.87–1.34 for major bleeding. A significant association between NOACs and risk of stroke or SE was observed: HR 0.88, 95 % CI 0.83–0.94 for the PS studies; HR 0.79, 95 % CI 0.72–0.87 for the RCTs. However, no relationship between NOACs and risk of major bleeding was found: HR 0.91, 95 % CI 0.79–1.05 for the PS studies; HR 0.85, 95 % CI 0.73–1.00 for the RCTs. In this study, treatment effect estimates of NOACs versus warfarin in patients with non-valvular AF from PS studies are found to be in agreement with those from RCTs.

Factors associated with failure to correct the international normalised ratio following fresh frozen plasma administration among patients treated for warfarin-related major bleeding. An analysis of electronic health records.

Science.gov (United States)

Menzin, J; White, L A; Friedman, M; Nichols, C; Menzin, J; Hoesche, J; Bergman, G E; Jones, C

2012-04-01

This study assessed the frequency and factors associated with failure to correct international normalised ratio (INR) in patients administered fresh frozen plasma (FFP) for warfarin-related major bleeding. This retrospective database analysis used electronic health records from an integrated health system. Patients who received FFP between 01/01/2004 and 01/31/2010, and who met the following criteria were selected: major haemorrhage diagnosis the day before to the day after initial FFP administration; INR ≥2 on the day before or the day of FFP and another INR result available; warfarin prescription within 90 days. INR correction (defined as INR ≤1.3) was evaluated at the last available test up to one day following FFP. A total of 414 patients met selection criteria (mean age 75 years, 53% male, mean Charlson score 2.5). Patients presented with gastrointestinal bleeding (58%), intracranial haemorrhage (38%) and other bleed types (4%). The INR of 67% of patients remained uncorrected at the last available test up to one day following receipt of FFP. In logistic regression analysis, the INR of patients who were older, those with a Charlson score of 4 or greater, and those with non-ICH bleeds (odds ratio vs. intracranial bleeding 0.48; 95% confidence interval 0.31-0.76) were more likely to remain uncorrected within one day following FFP administration. In an alternative definition of correction, (INR ≤1.5), 39% of patients' INRs remained uncorrected. For a substantial proportion of patients, the INRs remain inadequately or uncorrected following FFP administration, with estimates varying depending on the INR threshold used.

Catastrophic cerebral antiphospholipid syndrome presenting as cerebral infarction with haemorrhagic transformation after sudden withdrawal of warfarin in a patient with primary antiphospholipid syndrome

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Wani, Abdul Majid; Hussain, Waleed Mohd; Mejally, Mousa Ali Al; Ali, Khaled Shawkat; Raja, Sadeya Hanif; Maimani, Wael Al; Bafaraj, Mazen G; Bashraheel, Ashraf; Akhtar, Mubeena; Khoujah, Amer Mohd

2010-01-01

Catastrophic antiphospholipid syndrome (APS) is caused by thrombotic vascular occlusions that affect both small and large vessels, producing ischaemia in the affected organs. The “catastrophic” variant of the antiphospholipid syndrome (cAPS) develops over a short period of time. Although patients with cAPS represent <1% of all patients with APS, they are usually life threatening with a 50% mortality rate. A strong association with concomitant infection is thought to act as the main trigger of microthromboses in cAPS. Several theories have been proposed to explain these physiopathological features. Some of them suggest the possibility of molecular mimicry between components of infectious microorganisms and natural anticoagulants, which might be involved in the production of cross-reacting antiphospholipid antibodies. We present a case of catastrophic cerebral APS characterised by massive temporal lobe infarction and subsequent haemorrhagic transformation after sudden withdrawal of warfarin. PMID:22242060

Current issues in patient adherence and persistence: focus on anticoagulants for the treatment and prevention of thromboembolism

Directory of Open Access Journals (Sweden)

Patrick P Kneeland

2010-03-01

Full Text Available Patrick P Kneeland, Margaret C FangThe University of California, San Francisco Division of Hospital Medicine, San Francisco, CA, USAAbstract: Warfarin therapy reduces morbidity and mortality related to thromboembolism. Yet adherence to long-term warfarin therapy remains challenging due to the risks of anticoagulantassociated complications and the burden of monitoring. The aim of this paper is to review determinants of adherence and persistence on long-term anticoagulant therapy for atrial fibrillation and venous thromboembolism. We evaluate what the current literature reveals about the impact of warfarin on quality of life, examine warfarin trial data for patterns of adherence, and summarize known risk factors for warfarin discontinuation. Studies suggest only modest adverse effects of warfarin on quality of life, but highlight the variability of individual lifestyle experiences of patients on warfarin. Interestingly, clinical trials comparing anticoagulant adherence to alternatives (such as aspirin show that discontinuation rates on warfarin are not consistently higher than in control arms. Observational studies link a number of risk factors to warfarin non-adherence including younger age, male sex, lower stroke risk, poor cognitive function, poverty, and higher educational attainment. In addition to differentiating the relative impact of warfarin-associated complications (such as bleeding versus the lifestyle burdens of warfarin monitoring on adherence, future investigation should focus on optimizing patient education and enhancing models of physician–patient shared-decision making around anticoagulation.Keywords: anticoagulation, warfarin, adherence, persistence, thromboembolism

Understanding effect of formulation and manufacturing variables on the critical quality attributes of warfarin sodium product.

Science.gov (United States)

Rahman, Ziyaur; Korang-Yeboah, Maxwell; Siddiqui, Akhtar; Mohammad, Adil; Khan, Mansoor A

2015-11-10

Warfarin sodium (WS) is a narrow therapeutic index drug and its product quality should be thoroughly understood and monitored in order to avoid clinical performance issues. This study was focused on understanding the effect of manufacturing and formulation variables on WS product critical quality attributes (CQAs). Eight formulations were developed with lactose monohydrate (LM) or lactose anhydrous (LA), and were either wet granulated or directly compressed. Formulations were granulated either with ethanol, isopropyl alcohol (IPA) and IPA-water mixture (50:50). Formulations were characterized for IPA, water content, hardness, disintegration time (DT), assay, dissolution and drug physical forms (scanning electron microscopy (SEM), near infrared chemical imaging (NIR-CI), X-ray powder diffraction (XRPD) and solid state nuclear magnetic resonance (ssNMR)), and performed accelerated stability studies at 40°C/75% RH for three days. The DT and dissolution of directly compressed formulations were faster than wet granulated formulations. This was due to phase transformation of crystalline drug into its amorphous form as indicated by SEM, NIR-CI, XRPD and ssNMR data which itself act as a binder. Similarly, LM showed faster disintegration and dissolution than LA containing formulations. Stability results indicated an increase in hardness and DT, and a decrease in dissolution rate and extent. This was due to phase transformation of the drug and consolidation with particles' bonding. In conclusion, the CQAs of WS product were significantly affected by manufacturing and formulation variables. Published by Elsevier B.V.

Hematoma de músculo iliopsoas na vigência de tratamento com varfarina Hematoma de músculo iliopsoas en la vigencia de tratamiento con warfarina Iliopsoas muscle hematoma during treatment with warfarin

Directory of Open Access Journals (Sweden)

Gabriel Zago

2010-01-01

Full Text Available A varfarina é droga amplamente utilizada na prevenção de fenômenos tromboembólicos e o conhecimento de seus efeitos adversos faz-se necessário para o acompanhamento dos pacientes. Embora o desenvolvimento de discrasias sanguíneas seja complicação potencial nesses pacientes, a ocorrência de sangramento retroperitoneal é rara. Este artigo discute o caso de um paciente que evoluiu com hematoma do músculo iliopsoas durante tratamento com a referida droga, pós-implante de prótese aórtica metálica, com quadro clínico envolvendo importantes diagnósticos diferenciais.La warfarina es un fármaco ampliamente utilizado en la prevención de fenómenos tromboembólicos, y el conocimiento de sus efectos adversos se hace necesario para el seguimiento de los pacientes. Aunque el desarrollo de discrasias sanguíneas es la complicación potencial en estos pacientes, la ocurrencia de sangrado retroperitoneal es rara. Este artículo discute el caso de un paciente que evolucionó con hematoma del músculo ileopsoas durante tratamiento con el referido fármaco en el postimplante de prótesis mitral metálica, con cuadro clínico implicando importantes diagnósticos diferenciales.Warfarin is a widely used drug for the prevention of thromboembolic events. Knowledge of its adverse effects is necessary for patient follow-up. Although the development of blood dyscrasias is a potential complication in these patients, retroperitoneal bleeding is rare. This article reports the case of a patient who developed iliopsoas muscle hematoma during treatment with warfarin after implantation of a metallic prosthetic aortic valve. The clinical manifestations involved important differential diagnoses.

Binding of coumarins to human serum albumin. Study by equilibrium dialysis; Union de cumarinas a seroalbumina humana. Estudio por dialisis en el equilibrio

Energy Technology Data Exchange (ETDEWEB)

Zaton Lopez, A.M.L.; Ferrer Lopez, J.M. [Departamento de Bioquimica y Biologia Molecular, Universidad del Pais Vasco, Facultad de Farmacia, Vitoria (Spain)

1995-12-31

In order to find the typical structure of ligands that could displace the binding of warfarin on human serum albumin, the binding parameters of several coumarin derivatives have been compared. Warfarin, hydroxy coumarin, coumarin, acetyl coumarin and chromanol, bind to two different sites on seroalbumin. In the primary binding site, the affinity for the 4-hydroxyl compounds (4-chromanol, warfarin and 4-hidroxycoumarin) are larger than for coumarin and 3-acetyl coumarin. this high-affinity binding site, warfarin binding site, is the region in which the specific binding of warfarin and 4-hydroxybenzopyrans occurs. the 4-chromanol is the smallest ligand which binds to seroalbumin with high-affinity, and its structure is typical in ligands which specifically bind to the warfarin binding site. (Author) 23 refs.

Mitral valve repair and bioprosthetic replacement without postoperative anticoagulation does not increase the risk of stroke or mortality.

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Schwann, Thomas A; Engoren, Milo; Bonnell, Mark; Clancy, Christopher; Khouri, Samer; Kabour, Ameer; Jamil, Tahir; Habib, Robert H

2013-07-01

The study aimed to determine if mitral valve repair (MVRR) or bioprosthetic mitral valve replacement (BMVR) without postoperative anticoagulation is associated with a similar risk of thromboembolism and death as anticoagulation. We retrospectively reviewed our 2004-09 experience in 249 MVRR and bioprosthetic replacement patients (53% female; 63 year mean age). Concurrent procedures principally included antiarrhythmic surgery, aortic valve replacement, tricuspid valve repair and coronary bypass grafting. Warfarin therapy was instituted at the discretion of the surgeon. Thirty-day, a period known to have the highest risk of valve-related thromboembolism, outcomes were compared relying on the incidence of stroke and death as surrogates of thromboembolic complications. Intermediate-term survival was compared between the groups using Cox proportional hazard models. The mean follow-up was 2.9 years. Given the non-randomized warfarin use, a propensity score using patient comorbidities and concurrent procedures was created and added to the Cox models. One hundred and ninety-two (77%) patients were discharged on warfarin and 57 (23%) were discharged without warfarin. Thirty-day mortality in patients discharged from the index hospitalization was 1.2% and was similar for the two groups (P = 0.99). Four ischaemic perioperative strokes were detected; 3 in the warfarin group and 1 in the no warfarin group (P = 0.99). Overall survival was 84%, with 84% survival in the warfarin group and 86% in the no warfarin group (P = 0.79). Bleeding complications were comparable between the two groups (P = 0.72). In a multivariate analysis, warfarin was not related to mortality. Despite current guidelines recommending postoperative anticoagulation following MVRR or bioprosthetic replacement, the avoidance of warfarin does not increase perioperative complications and has no impact on intermediate survival. Accordingly, a prospective randomized study to adjudicate the role of extended warfarin

Comparing new anticoagulants.

Science.gov (United States)

Wooten, James M

2012-12-01

For years, the pharmaceutical industry has been trying to find a safe and effective drug to replace warfarin. Although warfarin is an effective anticoagulant, its pharmacology, adverse effects, and risk profiles dictate that patients taking this medication must be monitored judiciously. The US Food and Drug Administration has approved two drugs for commercial use, dabigatran and rivaroxaban, that will compete directly with warfarin for use in specific indications. Because of direct marketing to patients, physicians are being asked to comment on these new medications. This brief review illustrates the data available for the two new drugs when compared to warfarin for the specified indications. For some patients, these drugs may be highly beneficial and offer an excellent alternative to warfarin. For others, warfarin may still be the preferred drug.

Newer Anticoagulants for Non-Valvular Atrial Fibrillation

Directory of Open Access Journals (Sweden)

Joseph M. Harburger

2012-05-01

Full Text Available Non-valvular atrial fibrillation is a recognized risk factor for stroke and systemic embolism. It has been clearly established that warfarin reduces the risk of stroke and systemic embolism in persons with atrial fibrillation and additional risk factors for stroke. The use of warfarin, however, requires frequent monitoring, and there is great variability in patient response to warfarin. Warfarin interacts with several medications and foods. In addition, warfarin use portends a significant risk of bleeding. For these reasons, warfarin is frequently not prescribed to persons for whom the drug would provide a clear benefit. Over the past decade, attempts have been made to develop drugs that are at least as safe and effective as warfarin for the treatment of atrial fibrillation that do not require monitoring nor have as many interactions. Initial studies of compounds in this regard ultimately failed due to safety concerns, but over the past two years two novel agents have been approved by the United States Food and Drug Association for anticoagulation in non-valvular atrial fibrillation, another drug is under review, and additional compounds are being studied. This article will review the use of warfarin and these new agents in the treatment of non-valvular atrial fibrillation.

78 FR 8123 - Rodenticides; Notice of Intent To Cancel Registrations of, and Notice of Denial of Applications...

Science.gov (United States)

2013-02-05

... ingredient Deficiency D-Con Concentrate Kills Rats & 3282-3 Reckitt Benckiser, Warfarin Consumer product in a... & 3282-4 Reckitt Benckiser, Warfarin Consumer product in a Mice. Inc. pelleted form and packaged without a protective bait station. D-Con Mouse Prufe Kills Mice.... 3282-9 Reckitt Benckiser, Warfarin...

Efficacy and safety of rivaroxaban vs warfarin in high-risk patients with antiphospholipid syndrome: Rationale and design of the Trial on Rivaroxaban in AntiPhospholipid Syndrome (TRAPS) trial.

Science.gov (United States)

Pengo, V; Banzato, A; Bison, E; Zoppellaro, G; Padayattil Jose, S; Denas, G

2016-03-01

New oral anticoagulants may simplify long-term therapy in conditions requiring anticoagulation. Rivaroxaban is a direct factor Xa inhibitor that has been extensively studied and is now approved for the prevention and therapy of a number of thromboembolic conditions. This is a multicentre, randomized, open-label, study that will evaluate if Rivaroxaban 20 mg od (or 15 mg od in patients with moderate renal insufficiency) is non-inferior to warfarin (INR target 2.5), for the prevention of thromboembolic events, major bleeding and death in high risk (triple positive) patients with antiphospholipid syndrome. Secondary endpoints will assess the incidence of any individual component of the composite end point. An external adjudication committee will evaluate all suspected outcome events. This will be a unique trial, as it will enrol the biggest homogenous cohort of high risk APS individuals. The methods and the study design should be appropriate to achieve study results that are both scientifically valid and relevant to clinical practice. © The Author(s) 2015.

Management of antithrombotic therapy during cardiac implantable device surgery.

Science.gov (United States)

AlTurki, Ahmed; Proietti, Riccardo; Birnie, David H; Essebag, Vidal

2016-06-01

Anticoagulants are commonly used drugs that are frequently encountered during device placement. Deciding when to halt or continue the use of anticoagulants is a balance between the risks of thromboembolism versus bleeding. Patients taking warfarin with a high risk of thromboembolism should continue to take their warfarin without interruption during device placement while ensuring their international normalized ratio remains below 3. For patients who are taking warfarin and have low risk of thromboembolism, either interrupted or continued warfarin may be used, with no evidence to clearly support either strategy. There is little evidence to support continuing direct acting oral anticoagulants (DOACs) for device implantation. The timing of halting these medications depends largely on renal function. If bleeding occurs, warfarin׳s anticoagulation effect is reversible with vitamin K and activated prothrombin complex concentrate. There are no DOAC reversal agents currently available, but some are under development. Regarding antiplatelet agents, aspirin alone can be safely continued while clopidogrel alone may also be continued, but with a slightly higher bleeding risk. Dual antiplatelet therapy for bare-metal stent/drug-eluting stent implanted within 4 weeks/6 months, respectively, should be continued due to high risk of stent thrombosis; however, if they are implanted after this period, then clopidogrel can be halted 5 days before the procedure and resumed soon after, while aspirin is continued. If the patient is taking both aspirin and warfarin, aspirin should be halted 5 days prior to the procedure, while warfarin is continued.

The future of anticoagulation clinics.

Science.gov (United States)

Macik, B Gail

2003-01-01

Anticoagulation therapy is the foundation of treatment for thromboembolic disorders; and coumarin derivatives (warfarin in the United States) are the only orally administered anticoagulant medications currently available. Due to the expense and relative difficulties associated with this route of administration, parenteral drugs are not used routinely for long-term therapy, leaving warfarin as the anticoagulant of choice in the outpatient setting. The management of warfarin is problematic, however, due the nuances of its pharmacodynamic and pharmacokinetic profile and the requirement for frequent monitoring of blood levels. Although management by anticoagulation clinics is considered the gold standard for warfarin therapy, management by an anticoagulation clinic may not be the optimal option from a clinician's view and, in many cases, may not be an option at all. Anticoagulation clinics may impinge on the doctor-patient relationship. Difficulties of communication and reimbursement are not ameliorated by a specialty clinic. Innovations in warfarin management, including patient self-management and computerized dosing programs, are alternatives for improved care that are available with or without input by an anticoagulation service. New oral drugs on the horizon do not require the same intensity of monitoring and do not present the same pharmacodynamic problems associated with warfarin. Warfarin will become obsolete in the foreseeable future. If anticoagulation clinics continue, they must re-define their role as the major part of the workload, warfarin management, disappears. To adapt, clinics must strengthen and enhance their role as coordinators and educators, and less so, managers of anticoagulation therapy.

Effectiveness and Safety of Non-Vitamin K Antagonist Oral Anticoagulants in Asian Patients With Atrial Fibrillation.

Science.gov (United States)

Cha, Myung-Jin; Choi, Eue-Keun; Han, Kyung-Do; Lee, So-Ryoung; Lim, Woo-Hyun; Oh, Seil; Lip, Gregory Y H

2017-11-01

There are limited real-world data comparing the effectiveness and safety of non-vitamin K antagonist oral anticoagulants (NOACs) and warfarin in Asians with nonvalvular atrial fibrillation. We aimed to compare the effectiveness and safety between NOACs and warfarin users in the Korean atrial fibrillation population, with particular focus on high-risk patients. Using the Korean National Health Insurance Service database, we analyzed the risk of ischemic stroke, intracranial hemorrhage (ICH) events, and all-cause death in NOAC users (n=11 611 total, n=5681 taking rivaroxaban, n=3741 taking dabigatran, and n=2189 taking apixaban) compared with propensity score-matched warfarin users (n=23 222) among patients with high-risk atrial fibrillation (CHA 2 DS 2 -VASc score ≥2) between 2014 and 2015. NOAC treatment was associated with similar risk of ischemic stroke and lower risk of ICH and all-cause mortality compared with warfarin. All 3 NOACs were associated with a similar risk of ischemic stroke and a lower risk of ICH compared with warfarin. Dabigatran and apixaban were associated with a lower risk of total mortality and the composite net clinical outcome (ischemic stroke, ICH, and all-cause death) compared with warfarin, whereas this was nonsignificant for rivaroxaban. Among previously oral anticoagulant-naive patients (n=23 262), dabigatran and apixaban were superior to warfarin for ICH prevention, whereas rivaroxaban and warfarin were associated with similar risk of ICH. In real-world practice among a high-risk Asian atrial fibrillation population, all 3 NOACs demonstrated similar risk of ischemic stroke and lower risk of ICH compared with warfarin. All-cause mortality was significantly lower only with dabigatran and apixaban. © 2017 American Heart Association, Inc.

The effect of the amiodarone-warfarin interaction on anticoagulation quality in a single, high-quality anticoagulation center.

Science.gov (United States)

White, Ryan D; Riggs, Kyle W; Ege, Ed J; Petroski, Gregory F; Koerber, Scott M; Flaker, Greg

2016-03-01

Clinical trials have reported a low time in therapeutic range (TTR) in patients with atrial fibrillation treated with both warfarin andamiodarone. These trials included centers and countries with both high and low TTRs. What is the impact of amiodarone on the TTR in a single, high-quality anticoagulation clinic? TTR was assessed in amiodarone and nonamiodarone-treated patients from a University anticoagulation clinic. Baseline characteristics between patients ever-taking or never-taking amiodarone were similar, except more amiodarone patients were smokers (19.5 vs. 6.1%, P = 0.0031). The TTR calculated from 8901international normalized ratios (INRs) in 249 nonamiodarone patients with a mean follow-up of 34 ± 20 months (mean INR 36 ± 18) was 66 ± 16.6% compared with 61.3 ± 16.2% (P = 0.111) from 1455 INRs in 41 amiodarone-treated patients with a mean follow-up of 28 ± 20 months (mean INR 35 ± 22). Factors associated with a low TTR were male sex (P = 0.0013), smoker (P = 0.0048), and amiodarone use (P = 0.0374). A second on-treatment analysis, in which the TTR was calculated only during amiodarone therapy, resulted in similar findings; however, amiodarone did not emerge as a predictor of a low TTR. In 11 patients, the TTR prior to amiodarone (54.5 ± 22.2%) was not significantly different in the first 3 months (54.6 ± 33.4%) or after 3 months (67.2 ± 33.7%) of amiodarone. In a single high-quality anticoagulation center, anticoagulation quality, as measured by the TTR, can be comparable in amiodarone and nonamiodarone-treated patients.

Safety of atrial fibrillation ablation with novel multi-electrode array catheters on uninterrupted anticoagulation-a single-center experience.

LENUS (Irish Health Repository)

Hayes, Christopher Ruslan

2012-02-01

INTRODUCTION: A recent single-center report indicated that the performance of atrial fibrillation ablation in patients on uninterrupted warfarin using a conventional deflectable tip electrode ablation catheter may be as safe as periprocedural discontinuation of warfarin and bridging with heparin. Novel multi-electrode array catheters for atrial fibrillation ablation are currently undergoing clinical evaluation. While offering the possibility of more rapid atrial fibrillation ablation, they are stiffer and necessitate the deployment of larger deflectable transseptal sheaths, and it remains to be determined if they increase the risk of cardiac perforation and vascular injury. Such potential risks would have implications for a strategy of uninterrupted periprocedural anticoagulation. METHOD AND RESULTS: We audited the safety outcomes of our atrial fibrillation ablation procedures using multi-electrode array ablation catheters in patients on uninterrupted warfarin (CHADS2 score>or=2) and in patients not on warfarin (uninterrupted aspirin). Two bleeding complications occurred in 49 patients on uninterrupted warfarin, both of which were managed successfully without longterm sequelae, and no bleeding complication occurred in 32 patients not on warfarin (uninterrupted aspirin). There were no thromboembolic events or other complication with either anticoagulant regimen. CONCLUSION: Despite the larger diameter and increased stiffness of multi-electrode array catheters and their deflectable transseptal sheaths, their use for catheter ablation in patients with atrial fibrillation on uninterrupted warfarin in this single-center experience does not appear to be unsafe, and thus, an adequately powered multicenter prospective randomized controlled trial should be considered.

Patients' and physicians' satisfaction with a pharmacist managed anticoagulation program in a family medicine clinic.

Science.gov (United States)

Bishop, Lisa; Young, Stephanie; Twells, Laurie; Dillon, Carla; Hawboldt, John

2015-06-09

A pharmacist managed anticoagulation service was initiated in a multi-physician family medicine clinic in December 2006. In order to determine the patient and physician satisfaction with the service, a study was designed to describe the patients' satisfaction with the warfarin education and management they received from the pharmacist, and to describe the physicians' satisfaction with the level of care provided by the pharmacist for patients taking warfarin. A self-administered survey was completed by both eligible patients receiving warfarin and physicians prescribing warfarin between December 2006 and May 2008. The patient survey collected information on patient demographics, satisfaction with warfarin education and daily warfarin management. The physician survey collected data about the satisfaction with patient education and daily anticoagulation management by the pharmacist. Seventy-six of 94 (81%) patients completed the survey. Fifty-nine percent were male with a mean age of 65 years (range 24-90). Ninety-six percent agreed/strongly agreed the pharmacist did a good job teaching the importance of warfarin adherence, the necessity of INR testing and the risks of bleeding. Eighty-five percent agreed/strongly agreed the risk of blood clots was well explained, 79% felt the pharmacist did a good job teaching about dietary considerations and 77% agreed/strongly agreed the pharmacist explained when to see a doctor. All patients felt the pharmacist gave clear instructions on warfarin dosing and INR testing. Four of nine physicians (44%) completed the survey. All agreed/strongly agreed the pharmacist was competent in the care provided, were confident in the care their patients received, would like the pharmacist to continue the service, and would recommend this program to other clinics. Patients and family physicians were satisfied with the pharmacist managed anticoagulation program and recommended continuation of the program. These results support the role of the