New Agents for Stroke Prevention in Atrial Fibrillation-The Proven and the Potential
New Agents for Stroke Prevention in Atrial Fibrillation-The Proven and the Potential
Abstract & Commentary
By Dara Jamieson, MD, Associate Professor of Clinical Neurology, Weill Cornell Medical College. Dr. Jamieson reports she is a retained consultant for Boehringer Ingelheim, Merck, and Ortho-McNeil, and is on the speaker's bureau for Boehringer Ingelheim and Merck.
Synopsis: An oral direct thrombin inhibitor, dabigatran, prevents ischemic strokes in patients with atrial fibrillation, with fewer hemorrhagic strokes as compared to warfarin.
Sources: Ellis DJ, et al. The first evaluation of a novel vitamin K antagonist, tecarfarin (ATI-5923), in patients with atrial fibrillation. Circulation 2009;120:1029-1035. Connolly SJ, et al. The RE-LY Steering Committee and Investigators. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009;361:1139-1151. Gage BF. Can we rely on RE-LY? N Engl J Med 2009;361: 1200-1202.
The vitamin K antagonist (VKA) warfarin is the standard long-term therapy for ischemic stroke prevention in patients with atrial fibrillation; other oral agents for possible ischemic stroke prevention are compared to warfarin in evaluating their efficacy and safety. However, the risk of hemorrhage and the inconvenience of monitoring, as well as warfarin's weight-based dosing and interaction with food and medications, make treatment with warfarin unacceptably onerous for many patients and healthcare providers. Some properties of VKAs may be adjusted for improved safety. Tecarfarin (ATI-5923) is a novel oral VKA which is metabolized by esterases, thus avoiding warfarin's cytochrome P450-mediated food and medication interactions as well as genetic variations in response to warfarin anticoagulation. However, both tecarfarin and warfarin must be monitored with the international normalized ratio (INR).
Ellis and colleagues conducted a 6- to 12-week open-label, multicenter, phase IIA study of 66 atrial fibrillation patients; after three weeks of tecarfarin treatment, the mean interpolated time in therapeutic range was 71.4%. Tecarfarin may improve time in a therapeutic range for patients with atrial fibrillation, but it still presents many of the problems of VKAs that have spurred development of other alternative oral anticoagulants.
Other oral anticoagulants target the serine protease factor Xa (direct factor Xa inhibitors) or bind directly and reversibly to the catalytic site of the thrombin molecule (direct thrombin inhibitors). The pro-drug dabigatran etexilate, a new oral direct thrombin inhibitor, is converted to the active compound dabigatran.
In the non-inferiority Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) trial, 18,113 patients who had atrial fibrillation and a risk of stroke were randomly assigned 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. Rates of the primary outcome (stroke or systemic embolism) 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 (P=0.003) with 110 mg and 3.11% per year (P=0.31) with 150 mg of dabigatran. The rate of hemorrhagic stroke was 0.38% per year in the warfarin group, as compared with 0.12% and 0.10% per year (both P<0.001) with 110 mg and 150 mg of dabigatran respectively. 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). Dyspepsia was the only adverse effect that was significantly more common with dabigatran than with warfarin. There was no difference in liver function tests with the two medications.
Commentary
In patients with atrial fibrillation, the oral direct thrombin inhibitor dabigatran at a dose of 110 mg twice a day was associated with rates of stroke and systemic embolism that were similar to those associated with warfarin, with lower rates of major hemorrhage. Dabigatran at a dose of 150 mg twice a day was associated with lower rates of stroke and systemic embolism but similar rates of major hemorrhage, as compared with warfarin.
While dabigatran appears to offer a safer, more user-friendly alternative to warfarin for ischemic stroke prevention in patients with atrial fibrillation, some dabigatran properties and RE-LY trial results need further investigation. Dabigatran has a peak plasma level in the range of 2-3 hours and a half-life of 12-14 hours with renal elimination. While the lack of need for routine monitoring is an advantage of direct thrombin inhibitors, the inability to assess patient compliance or the bleeding risk in treated patients needing emergent thrombolysis is problematic. Ecarin clotting time is the best measure of dabigatran concentration but it is not measured clinically; elevations in INR and activated partial thromboplastin time are not reliable for clinical monitoring.
Since recent use of dabigatran would seem to preclude intravenous thrombolysis, lack of ability to determine level of anticoagulation in the emergency department could be a concern. P-glycoprotein inhibitors, including verapamil, amiodarone, and quinidine, raise dabigatran concentration. In RE-LY, the rate of myocardial infarction was higher with both doses as compared to warfarin. The dabigatran-related dyspepsia contributed to a higher second-year dropout rate with dabigatran as compared to warfarin. Dabigatran is approved in Europe for prevention of venous thromboembolism after orthopedic surgery. The encouraging results of the RE-LY trial may eventually simplify the prevention of ischemic stroke in patients with atrial fibrillation.
An oral direct thrombin inhibitor, dabigatran, prevents ischemic strokes in patients with atrial fibrillation, with fewer hemorrhagic strokes as compared to warfarin.Subscribe Now for Access
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