Long-Term Results of Dabigatran vs Warfarin for Stroke Prevention in AF Patients
Abstract & Commentary
By Edward P. Gerstenfeld, MD
Professor of Medicine, Chief, Cardiac Electrophysiology, University of California, San Francisco
Dr. Gerstenfeld does research for Biosense Webster, Medtronic, and Rhythmia Medical. This article originally appeared in the September 2013 issue of Clinical Cardiology Alert.
Synopsis: The authors concluded that long-term follow-up of dabigatran 150 mg vs 110 mg twice daily therapy showed similar rates of stroke and death, but a higher incidence of major bleeding on the 150 mg dose.
Source: Connolly SJ, et al. The long-term multicenter observational study of dabigatran treatment in patients with atrial fibrillation (RELY-ABLE) study. Circulation 2013;128:237-243.
Dabigatran etexilate, a direct thrombin inhibitor, is one of a new class of oral anticoagulants that was recently demonstrated in a Phase 3 trial to be effective for the prevention of stroke or systemic embolism (SSE) in patients with atrial fibrillation (AF). The original Randomized Evaluation of Long-term Anticoagulation Therapy (RE-LY) trial randomized 18,113 patients with AF and at least one stroke risk factor to either warfarin or one of two blinded doses of dabigatran, 150 mg twice daily or 110 mg twice daily.1 The 150 mg dose was superior to warfarin for preventing SSE with a similar rate of major bleeding, while the 110 mg was noninferior to warfarin for preventing SSE, but had a reduced risk of major bleeding after a mean follow-up of 2 years. The RELY-ABLE study continued to follow patients in the RE-LY study who were randomized to receive either dose of dabigatran for an additional 2.25 years.
Patients were eligible for RELY-ABLE if they were randomized to dabigatran and had not discontinued the medication at the last study visit. They continued on the original randomized, blinded dose of dabigatran. The outcomes of RELY-ABLE were identical to those of RE-LY.
There were 5851 patients (48% of those randomized to dabigatran in RE-LY) enrolled and followed for a mean of 2.3 additional years after the conclusion of RE-LY. The rates of SSE in RELY-ABLE were 1.46% and 1.60% per year for the dabigatran 150 mg and 110 mg doses, respectively (hazard ratio [HR], 0.91; 95% confidence interval [CI], 0.69-1.20). There were no differences in the rates of ischemic or hemorrhagic stroke between the two groups. Annual rates of major bleeding were significantly higher with the 150 mg dose compared to the 110 mg dabigatran dose (3.74% vs 2.99% per year; HR, 1.26; 95% CI, 1.04-1.53). There was no difference in mortality between the two groups. The authors concluded that long-term follow-up of dabigatran 150 mg vs 110 mg twice daily therapy showed similar rates of stroke and death, but a higher incidence of major bleeding on the 150 mg dose.
Dabigatran is one of a new class of anticoagulants that is rapidly replacing the old standard, warfarin, for prevention of thromboembolism in patients with AF and stroke risk factors. The major advantages of the newer anticoagulants over warfarin are: 1) fixed dosing without need for frequent blood tests, 2) lack of dietary interactions, and 3) lower rate of intracerebral hemorrhage. The negatives include cost, nuisance side effects such as dyspepsia, and lack of reversibility. Based on the results of the RE-LY trial, the Food and Drug Administration (FDA) approved the 150 mg twice-daily dose for the prevention of SSE in AF patients, but not the 110 mg dose. This was in part because the 150 mg dose met criteria for superiority to warfarin while the 110 mg dose met only the criteria for noninferiority, despite a reduction in major bleeding with the 110 mg compared to warfarin. Interestingly, the FDA also approved a twice-daily 75 mg dabigatran dose in patients with renal insufficiency based on pharmacokinetic studies, even though that dose was not included in the RE-LY randomized trial.
For those physicians who have yet to adopt the use of the newer anticoagulants over warfarin, the RELY-ABLE data should provide additional evidence supporting the long-term use of dabigatran for prevention of SSE in AF patients. The rates of stroke and major bleeding in RELY-ABLE remained similar to those reported in the original RE-LY trial, with a very low rate of intracerebral bleeding (0.13-014%/year) after a mean of 4.3 years of follow-up. The major question remaining is why the FDA did not approve the twice-daily 110 mg dabigatran dose. The dose was clearly shown to be equivalent to warfarin in preventing SSE with a lower risk of bleeding in a prospective randomized multicenter study — the "gold-standard" of evaluating new drug therapies. The RELY-ABLE data provide further support that the 110 mg dose provides stroke reduction in AF patients with a lower bleeding risk than the 150 mg dose. The lack of availability of the 110 mg dose in the United States has handicapped physicians and patients concerned about bleeding risk, particularly in elderly patients. Hopefully the RELY-ABLE data will persuade the FDA to reconsider this decision.
In summary, dabigatran 150 mg twice-daily has been shown to be superior to warfarin for the prevention of SSE in AF patients and should be considered preferred over warfarin in newly diagnosed AF patients with a CHADS2-Vasc score ≥ 1 who were eligible for the RE-LY study. For elderly AF patients or those with a higher bleeding risk, there are now several agents available for physicians and patients to consider. Clinicians should also be aware that there remains a paucity of data regarding the safety of the newer anticoagulants in patients already on aspirin/clopidogrel therapy after stent implantation.
- Connolly SJ, et al for the RE-LY Steering Committee and Investigators. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009;361: 1139-1151.