Dabigatran vs. Placebo in Patients With Acute Coronary Syndromes on Dual Antiplatelet Therapy: A Randomized, Double-Blind, Phase II Trial

Study Questions:

What are the safety and indicators of efficacy of the novel oral direct thrombin inhibitor, dabigatran, after an acute coronary syndrome?

Methods:

In RE-DEEM, a double-blind, placebo-controlled, dose-escalation trial, 1,861 patients (99.2% on dual antiplatelet treatment) in 161 centers were enrolled at a mean 7.5 days (standard deviation, 3.8) after an ST-elevation (60%) or non-ST-elevation (40%) myocardial infarction and randomized to twice daily treatment with dabigatran 50 mg (n = 369), 75 mg (n = 368), 110 mg (n = 406), 150 mg (n = 347), or placebo (n = 371). Primary outcome was the composite of major or clinically relevant minor bleeding during the 6-month treatment period. The proportion of patients experiencing the primary outcome, major or clinically relevant minor bleeding per-treatment group, was analyzed by the Cochran–Armitage linear trend test. Kaplan–Meier plots were generated for the primary outcome.

Results:

There were 96 primary outcome events and, compared with placebo, a dose-dependent increase with dabigatran (hazard ratio [HR] 1.77, 95% confidence interval [CI] 0.70-4.50 for 50 mg; HR 2.17, 95% CI 0.88- 5.31 for 75 mg; HR 3.92, 95% CI 1.72-8.95 for 110 mg; and HR 4.27, CI 1.86-9.81 for 150 mg). Compared with placebo, D-dimer concentrations were reduced in all dabigatran dose groups by an average of 37% and 45% at weeks 1 and 4, respectively (p < 0.001). Fourteen (3.8%) patients died, had a myocardial infarction, or had a stroke in the placebo group, compared with 17 (4.6%) in the 50 mg, 18 (4.9%) in the 75 mg, 12 (3.0%) in the 110 mg, and 12 (3.5%) in the 150 mg dabigatran groups.

Conclusions:

The authors concluded that dabigatran, in addition to dual antiplatelet therapy, was associated with a dose-dependent increase in bleeding events and significantly reduced coagulation activity in patients with a recent myocardial infarction.

Perspective:

This study suggests that among patients with a recent myocardial infarction on antiplatelet treatment with both aspirin and clopidogrel, the addition of dabigatran, a direct thrombin inhibitor, was associated with a dose-dependent increase in major or clinically relevant minor bleeding. Dabigatran significantly reduced coagulation activity and may have the potential to reduce cardiovascular events when added to dual antiplatelet treatment, but in general, novel anticoagulants added to double antiplatelet therapy have shown marginal or no benefit at the cost of increased bleeding. The net clinical benefit of dabigatran, balancing the reduction of thromboembolic events versus the increased risk of bleeding, can only be appropriately evaluated in a large-scale, adequately powered phase III study. The large ATLAS II TIMI 51 phase III trial of 16,000 patients should also provide additional insight about the clinical usefulness of antithrombotics (rivaroxaban) in this clinical context.

Clinical Topics: Acute Coronary Syndromes, Novel Agents

Keywords: Myocardial Infarction, Acute Coronary Syndrome, Morpholines, Benzimidazoles, Pyridines


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