Dabigatran association with higher risk of acute coronary events.
Meta-analysis of noninferiority randomized controlled trials.
Uchino K, Hernandez AV.
Arch Intern Med 2012;172:397-402.
For EPCCS reviewed and commented by dr Frans Rutten, Utrecht The Netherlands
Comment:
This analysis is driven primarily by the RE-LY trial,(1) which contributes 75% of the weight to the overall effect size. It is noteworthy that the results are rendered non-significant (OR 1.16; 95%CI 0.69 to 1.94) when RE-LY is excluded from the analysis. Despite this limitation, the risk of an acute coronary event with dabigatran use cannot be ruled out and requires inquiry of a potential mechanism. One such possible mechanism could be related to the use of a proton-pump inhibitor (PPI) with dabigatran. Co -administration of pantoprazole has shown to reduce dabigatran bioavailability by 24% (day 4, 90%CI: 7.4 to 37.8)(2). This may explain RE-LY subgroup results where patients taking dabigatran 150mg twice daily with a PPI trended towards a reduced benefit. PPI-induced dabigatran inefficacy, resulting in an increased risk of acute coronary events, needs particular evaluation. Another mechanism was suggested in the PETRO trial.(3); dabigatran in the absence of concomitant aspirin could lead to elevated thrombotic risk due to increased thromboxane excretion (suggesting platelet-activation). (3).
Conclusion: The result of this meta-analysis calls for more studies to elucidate the true association between dabigatran and the risk of cardiovascular events.
Background:
The original RE-LY (Randomized Evaluation of Long-term Anticoagulant Therapy) trial suggested a small increased risk of myocardial infarction (MI) with the use of dabigatran etexilate vs warfarin in patients with atrial fibrillation. We systematically evaluated the risk of MI or acute coronary syndrome (ACS) with the use of dabigatran, a direct thrombine blocker.
Methods:
The authors searched PubMed, Scopus, and the Web of Science for randomized controlled trials of dabigatran that reported on MI or ACS as secondary outcomes. The fixed-effects Mantel-Haenszel test was used to evaluate the effect of dabigatran on MI or ACS. The associations are expressed as odds ratios (ORs) and their 95% CIs.
Results:
Seven trials were selected (N = 30,514), including 2 studies of stroke prophylaxis in atrial fibrillation, 1 in acute venous thromboembolism, 1 in ACS, and 3 of short-term prophylaxis of deep venous thrombosis. Control arms included warfarin, enoxaparin, or placebo administration. Dabigatran was significantly associated with a higher risk of MI or ACS than that seen with agents used in the control group (dabigatran, 237 of 20,000 [1.19%] vs control, 83 of 10,514 [0.79%]; OR 1.33; 95%CI 1.03 to 1.71; p= 0.03). The risk of MI or ACS was similar when using revised RE-LY trial results (OR 1.27; 95%CI 1.00 to 1.61; p= 0.05) or after exclusion of short-term trials (OR 1.33; 95%CI 1.03 to 1.72; p= 0.03). Risks were not heterogeneous for all analyses (I2 = 0%; p 0.30) and were consistent using different methods and measures of association.
Conclusions:
Dabigatran is associated with an increased risk of MI or ACS in a broad spectrum of patients when tested against different controls. Clinicians should consider the potential of these serious harmful cardiovascular effects with use of dabigatran.
1. Connolly SJ, Ezekowitz MD, Yusuf S, Eikelboom J, Oldgren J, Parekh A, Pogue J, Reilly PA, Themeles E, Varrone J, Wang S, Alings M, Xavier D, Zhu J, Diaz R, Lewis BS, Darius H, Diener HC, Joyner CD, Wallentin L; RE-LY Steering Committee and Investigators. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009;361:1139-51. Erratum in: N Engl J Med 2010;363:1877.
2. Stangier J, Stahle H, Rathgen K, Fuhr R. Pharmacokinetics and pharmacodynamics of the direct oral thrombin inhibitor dabigatran in healthy elderly subjects. Clin Pharmacokinet 2008; 47:47-59.
3. Ezekowitz MF, Reilly PA, Nehmiz G, et al. Dabigatran with or without concomitant aspirin compared with warfarin alone in patients with nonvalvular atrial fibrillation (PETRO Study). Am J Cardiol 2007; 199:1419 -1426.