The Randomized Evaluation of Long-Term Anticoagulation Therapy trial (RE-LY) is a landmark study involving 18,113 patients with atrial fibrillation. The RE-LY researchers tested two doses of dabigatran (110 mg or 150 mg po bid) in comparison to warfarin. They found that high-dose dabigatran is 34% better than warfarin at prevention of ischemic stroke and systemic embolism. Low-dose dabigatran is as good as warfarin at preventing thrombotic events, with fewer major bleeding events, especially intracranial.

Rate of major bleeds were 2.71% (low dose) and 3.11% (high dose) compared with 3.36% for warfarin. Annualized mortality rates from hemorrhagic events were 3.75% and 3.64% compared with 4.13% for warfarin (NEJM 2009; 361:1139-51).

In this non-inferiority analysis, the direct thrombin inhibitor dabigatran, at both tested doses, proved non-inferior to warfarin, a feat that the combination of aspirin and clopidogrel failed to achieve.

Dabigatran is also more convenient to use, as unlike warfarin it requires no monthly monitoring of INR. It’s unclear, however, whether this will have a significant impact on individuals who have had problems with warfarin compliance in the past.

The new drug is taken twice a day and 80% of the dose is renally excreted. Subgroup analysis of RE-LY should be interpreted with caution, but raises the concern that dabigatran’s anticoagulant effect is somewhat reduced in older patients.

High-dose dabigatran is associated with increased rate of MI compared to warfarin (0.72% vs 0.53%). This finding came as a surprise because an older direct thrombin inhibitor, ximelagatran, had shown no increased MI risk when studied against warfarin in patients with atrial fibrillation. Ximelagatran offered many of the benefits we’re now seeing with dabigatran, but it turned out to be hepatotoxic. Serial measurements of liver function in RE-LY, however, showed no evidence of hepatotoxicity with dabigatran.

Dabigatran is associated with a higher rate of dyspepsia. In fact subjects on high-dose dabigatran actually experienced more GI bleeds than those on warfarin. The reduction in hemmorhagic risk seen with dabigatran was largely concentrated in the critical intracranial space.

To summarize, dabigatran is available at 2 doses: 150 mg bid which is 34% more effective at reducing stroke than warfarin, and 110 mg bid, which is as good as warfarin at preventing stroke, but causes less bleeding, especially intracranial events. The drug costs close to $4 a day — an important consideration — but it has already become an important part of the management of AF. Nevertheless, in my patients who have done extremely well on warfarin therapy, I won’t be switching, at least not for the moment.

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