Concomitant Use of Antiplatelet Therapy With Dabigatran or Warfarin in the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) Trial
What is the effect of concomitant antiplatelet therapy on the safety and efficacy of dabigatran versus warfarin for the prevention of stroke or systemic embolism (SSE) in atrial fibrillation?
The authors presented a re-analysis of data from the RE-LY trial, a randomized, open-label, semi-blinded, three-arm study comparing two blinded doses of dabigatran (110 mg BID or 150 mg BID) versus open-label warfarin (target international normalized ratio [INR], 2.0-3.0). Since concomitant use of antiplatelet agents was allowed, the current study used a Cox proportional hazards model, with adjustment for risk factors for bleeding, to compare those subjects who received concomitant antiplatelet agents with those who did not, in a time-dependent analysis. The endpoint of interest was stroke or SSE, with a mean duration of follow-up of 2 years. The authors also compared bleeding outcomes.
There were 6,952 out of a total of 18,113 subjects (38.4%) who received concomitant aspirin or clopidogrel during the study. The 110 mg dose of dabigatran was noninferior to warfarin in reducing SSE, both in the subgroup of subjects who received antiplatelet agents (hazard ratio [HR], 0.93; 95% confidence interval [CI], 0.70-1.25) and those who did not receive antiplatelet agents (HR, 0.87; 95% CI, 0.66-1.15; interaction p = 0.738). At this lower dose of dabigatran, there were fewer bleeding episodes in both subgroups (HR, 0.82; 95% CI, 0.67-1.00 and HR, 0.79; 95% CI, 0.64-0.97, for those taking and not taking antiplatelet agents, respectively; interaction p = 0.794). For the 150 mg dose of dabigatran, there was a reduced outcome of SSE, but this was only statistically significant without concomitant antiplatelet agents (HR, 0.80; 95% CI, 0.59-1.08 and HR, 0.52; 95% CI, 0.38-0.72, for those taking and not taking antiplatelet agents, respectively; interaction p = 0.058). Major bleeding rates were similar between groups taking dabigatran 150 mg and warfarin, regardless of antiplatelet use. Concomitant antiplatelet agent use increased the risk of major bleeding by time-dependent analysis (HR, 1.60; 95% CI, 1.42-1.82). This was increased even more with dual antiplatelet use (HR, 2.31; 95% CI, 1.79-2.98).
The authors concluded that concomitant antiplatelet drugs appeared to increase the risk of major bleeding in the RE-LY trial without affecting the advantages of dabigatran over warfarin. They further opined that choosing between the 110 mg and 150 mg dose of dabigatran requires a careful assessment of characteristics that influence the balance between benefit and harm.
This retrospective analysis of a very large, well-conducted study provides significant added support for the idea that concomitant antiplatelet agent use with warfarin for patients with atrial fibrillation increases risk without significant benefit. Furthermore, the study suggests that the relationship between outcomes with dabigatran versus warfarin is unchanged by concomitant antiplatelet use (i.e., the 110 mg dose of dabigatran is equally effective and safer than warfarin, and the 150 mg dose of dabigatran is more effective and just as safe as warfarin). Interestingly, the effectiveness of the higher dose of dabigatran was attenuated by the concomitant use of antiplatelet agents. This study adds further support to the recommendation to avoid concomitant antiplatelet and anticoagulant treatment in patients with atrial fibrillation. These data again call into question the lack of Food and Drug Administration approval in this country for the 110 mg dose of dabigatran. US physicians are denied the flexibility to prescribe a safer, but equally effective treatment to prevent thromboembolism in atrial fibrillation.
Keywords: Stroke, Follow-Up Studies, Platelet Aggregation Inhibitors, Warfarin, Risk Factors, Ticlopidine, International Normalized Ratio, Thromboembolism, Blood Coagulation, Proportional Hazards Models, beta-Alanine, Benzimidazoles, Metformin, Confidence Intervals, United States, Hemorrhage, Atrial Flutter
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