Meta-Analysis of Randomized Controlled Trials on Risk of Myocardial Infarction from the Use of Oral Direct Thrombin Inhibitors.

Artang R, Rome E, Nielsen JD, Vidaillet HJ
Am J Cardiol. 2013 Sep 25. doi: 10.1016/j.amjcard.2013.08.027

Background

The Randomized Evaluation of Long-term Anticoagulation Therapy (RE-LY) trial showed that treatment with the oral direct thrombin inhibitor (DTI) dabigatran was associated with lower rates of stroke and systemic embolism in comparison to warfarin [1]. A non-statistically significant increase in myocardial infarction (MI) was seen in relation to dabigatran use as compared with warfarin [2]. A recent meta-analysis concluded that dabigatran was associated with an increased risk of coronary events [3]. Ximelagatran, another DTI that is no longer available for clinical use, was associated with a significantly higher risk of myocardial ischemia than warfarin, in patients with acute deep vein thrombosis [4].
Warfarin has been proposed to provide a protective effect against MI as compared to non-warfarin anticoagulants, when used for prevention of stroke in patients with atrial fibrillation [5]. This meta-analysis was set up to investigate whether the excess rate of MI with dabigatran is a DTI class effect of specific to dabigatran, and to evaluate whether warfarin indeed provides protection against MI.

Main results

• The entire cohort of oral DTIs was associated with a significantly higher rate of MI as compared to warfarin. MI was reported in 285/23333 subjects on oral DTs, while 133/16024 subjects treated with warfarin underwent MI (OR: 1.35, 95%CI: 1.10-1.66, P=0.005).
• Focussing on the 4 trials that compared dabigatran with warfarin gave an OR of 1.41 (95%CI: 1.09-1.83, P=0.009: 212 MIs /14954 subjects on dabigatran vs. 78/8803 on warfarin).
• Ximelagatran showed a trend towards increased rates of MI, as compared to warfarin (OR: 1.23, 95%CI: 0.86 – 1.76, P=0.25. 70/7581 with ximelagatran vs. 54/6821 with warfarin). In a treatment indication subgroup of patients treated for venous thromboembolism and thromboprophylaxis, ximelagatran was associated with more than 3 times increased risk of MI than warfarin.
• No significant differences were seen in MI rate between patients receiving the DTI AXD0837 and warfarin (OR: 1.17, 95%CI: 0.17-7.94, P=0.87).
• Comparison of studies testing warfarin vs. comparator anticoagulant showed significant heterogeneity among the studies.
  Overall, subjects receiving warfarin showed a similar rate of MI to those treated with other anticoagulants (OR: 1.06, 95%CI: 0.85-1.34, P=0.59, 403/31867 on warfarin, 503/37748 on comparator agents).

Conclusion

This meta-analysis shows that oral DTIs as a group are associated with an increased risk of MI, in comparison with warfarin. No significant difference was seen in the rate of MI between patients treated with warfarin vs. those treated with other anticoagulant therapy. Thus, increased MI risk in patients treated with oral DTIs appears to be a class effect of oral DTIs, rather than that warfarin confers a protective effect.

References

1. Connolly SJ, Ezekowitz MD, Yusuf S, et al. N Engl J Med 2009;361:1139e1151.
2. Hohnloser SH, Oldgren J, Yang S, et al. Myocardial ischemic events in patients with atrial fibrillation treated with dabigatran or warfarin in the RE-LY trial. Circulation 2012;125: 669e676.
3. Uchino K, Hernandez AV. Dabigatran association with higher risk of acute coronary events: meta-analysis of noninferiority randomized controlled trials. Arch Intern Med 2012;172:397e402.
4. Fiessinger JN, Huisman MV, Davidson BL, et al. Ximelagatran vs low-molecular-weight heparin and warfarin for the treatment of deep vein thrombosis: a randomized trial. JAMA 2005;293:681e689.
5. Lip GY, Lane DA. Does warfarin for stroke thromboprophylaxis protect against MI in atrial fibrillation patients? Am J Med 2010;23:785e789.

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