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      Dabigatran versus warfarin in patients with atrial fibrillation.

      The New England journal of medicine

      Aged, Anticoagulants, administration & dosage, adverse effects, therapeutic use, Atrial Fibrillation, complications, drug therapy, mortality, Benzimidazoles, Chi-Square Distribution, Double-Blind Method, Dyspepsia, chemically induced, Embolism, epidemiology, Female, Follow-Up Studies, Hemorrhage, Humans, Liver, drug effects, Male, Middle Aged, Myocardial Infarction, Prodrugs, Proportional Hazards Models, Pyridines, Stroke, prevention & control, Warfarin

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          Abstract

          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. In this noninferiority trial, we randomly assigned 18,113 patients who had atrial fibrillation and a risk of stroke to receive, in a blinded fashion, fixed doses of dabigatran--110 mg or 150 mg twice daily--or, in an unblinded fashion, adjusted-dose warfarin. The median duration of the follow-up period was 2.0 years. The primary outcome was stroke or systemic embolism. Rates of the primary outcome were 1.69% per year in the warfarin group, as compared with 1.53% per year in the group that received 110 mg of dabigatran (relative risk with dabigatran, 0.91; 95% confidence interval [CI], 0.74 to 1.11; P<0.001 for noninferiority) and 1.11% per year in the group that received 150 mg of dabigatran (relative risk, 0.66; 95% CI, 0.53 to 0.82; P<0.001 for superiority). The rate of major bleeding was 3.36% per year in the warfarin group, as compared with 2.71% per year in the group receiving 110 mg of dabigatran (P=0.003) and 3.11% per year in the group receiving 150 mg of dabigatran (P=0.31). The rate of hemorrhagic stroke was 0.38% per year in the warfarin group, as compared with 0.12% per year with 110 mg of dabigatran (P<0.001) and 0.10% per year with 150 mg of dabigatran (P<0.001). The mortality rate was 4.13% per year in the warfarin group, as compared with 3.75% per year with 110 mg of dabigatran (P=0.13) and 3.64% per year with 150 mg of dabigatran (P=0.051). In patients with atrial fibrillation, dabigatran given at a dose of 110 mg was associated with rates of stroke and systemic embolism that were similar to those associated with warfarin, as well as lower rates of major hemorrhage. Dabigatran administered at a dose of 150 mg, as compared with warfarin, was associated with lower rates of stroke and systemic embolism but similar rates of major hemorrhage. (ClinicalTrials.gov number, NCT00262600.) 2009 Massachusetts Medical Society

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          Major hemorrhage and tolerability of warfarin in the first year of therapy among elderly patients with atrial fibrillation.

          Warfarin is effective in the prevention of stroke in atrial fibrillation but is under used in clinical care. Concerns exist that published rates of hemorrhage may not reflect real-world practice. Few patients > or = 80 years of age were enrolled in trials, and studies of prevalent use largely reflect a warfarin-tolerant subset. We sought to define the tolerability of warfarin among an elderly inception cohort with atrial fibrillation. Consecutive patients who started warfarin were identified from January 2001 to June 2003 and followed for 1 year. Patients had to be > or = 65 years of age, have established care at the study institution, and have their warfarin managed on-site. Outcomes included major hemorrhage, time to termination of warfarin, and reason for discontinuation. Of 472 patients, 32% were > or = 80 years of age, and 91% had > or = 1 stroke risk factor. The cumulative incidence of major hemorrhage for patients > or = 80 years of age was 13.1 per 100 person-years and 4.7 for those or = 80 years, and international normalized ratio (INR) > or = 4.0 were associated with increased risk despite trial-level anticoagulation control. Within the first year, 26% of patients > or = 80 years of age stopped taking warfarin. Perceived safety issues accounted for 81% of them. Rates of major hemorrhage and warfarin termination were highest among patients with CHADS2 scores (an acronym for congestive heart failure, hypertension, age > or = 75, diabetes mellitus, and prior stroke or transient ischemic attack) of > or = 3. Rates of hemorrhage derived from younger noninception cohorts underestimate the bleeding that occurs in practice. This finding coupled with the short-term tolerability of warfarin likely contributes to its underutilization. Stroke prevention among elderly patients with atrial fibrillation remains a challenging and pressing health concern.
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            Clinical pharmacokinetics and pharmacodynamics of the oral direct thrombin inhibitor dabigatran etexilate.

            The direct thrombin inhibitor dabigatran etexilate is currently in phase III of development for the prophylaxis and treatment of thromboembolic disorders, with three trials completed in primary venous thromboembolism (VTE) prevention. Dabigatran etexilate is an orally administered prodrug, which is rapidly absorbed and converted to the active form, dabigatran. Dabigatran has been shown to specifically and reversibly inhibit thrombin, the key enzyme in the coagulation cascade. Studies in healthy volunteers and in patients undergoing orthopaedic surgery have indicated that dabigatran has a predictable pharmacokinetic/pharmacodynamic profile, allowing for a fixed-dose regimen. Peak plasma concentrations of dabigatran are reached approximately 2 hours after oral administration in healthy volunteers, with no unexpected accumulation of drug concentrations upon multiple dosing. Excretion is predominantly via the renal route as unchanged drug. Dabigatran is not metabolized by cytochrome P450 isoenzymes. The small differences in dabigatran pharmacokinetics associated with age and gender are attributed to variations in renal function. Additional studies have shown that the pharmacokinetic/pharmacodynamic profile of dabigatran is consistent across a range of patient populations, with no effect of moderate hepatic impairment being observed. Drug-drug interactions are not observed with concomitant administration of atorvastatin, diclofenac or digoxin. The pharmacodynamic profile of dabigatran demonstrates effective anticoagulation combined with a low risk of bleeding. Further phase III studies are ongoing, including acute VTE treatment and stroke prevention in atrial fibrillation; the results obtained so far show that dabigatran etexilate is well tolerated and effective in the treatment and prevention of thromboembolic events.
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              Warfarin, aspirin, or both after myocardial infarction.

              The role of antithrombotic therapy in secondary prevention after myocardial infarction is well established. Although the available literature suggests that warfarin is superior to aspirin, aspirin is currently the more widely used drug. We studied the efficacy and safety of warfarin, aspirin, or both after myocardial infarction. In a randomized, multicenter trial in 3630 patients, 1216 received warfarin (in a dose intended to achieve an international normalized ratio [INR] of 2.8 to 4.2), 1206 received aspirin (160 mg daily), and 1208 received aspirin (75 mg daily) combined with warfarin (in a dose intended to achieve an INR of 2.0 to 2.5). The mean duration of observation was four years. The primary outcome, a composite of death, nonfatal reinfarction, or thromboembolic cerebral stroke, occurred in 241 of 1206 patients receiving aspirin (20.0 percent), 203 of 1216 receiving warfarin (16.7 percent; rate ratio as compared with aspirin, 0.81; 95 percent confidence interval, 0.69 to 0.95; P=0.03), and 181 of 1208 receiving warfarin and aspirin (15.0 percent; rate ratio as compared with aspirin, 0.71; 95 percent confidence interval, 0.60 to 0.83; P=0.001). The difference between the two groups receiving warfarin was not statistically significant. Episodes of major, nonfatal bleeding were observed in 0.62 percent of patients per treatment-year in both groups receiving warfarin and in 0.17 percent of patients receiving aspirin (P<0.001). Warfarin, in combination with aspirin or given alone, was superior to aspirin alone in reducing the incidence of composite events after an acute myocardial infarction but was associated with a higher risk of bleeding. Copyright 2002 Massachusetts Medical Society
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                Author and article information

                Journal
                19717844
                10.1056/NEJMoa0905561

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