Direct Thrombin Inhibitors May Pose Increased Risk of MI

November 5, 2013

Dabigatran was shown in post-hoc analysis of the RE-LY trial to be associated with an increased risk of MI compared with warfarin.

The direct thrombin inhibitor (DTI) dabigatran has become more widely prescribed for non-valvular atrial fibrillation (AF) since it was compared head-to-head with warfarin in the Randomized Evaluation of Long-term Anticoagulation (RE-LY) Trial.1 Results showed a decrease in the rate of stroke and systemic embolism compared with warfarin. However, a post-hoc analysis of that study also showed that, compared with warafarin, there was a higher rate of myocardial infarction (MI) associated with dabigatran use, although this finding did not achieve statistical significance.2 This was followed by another meta-analysis (of non-inferiority trials) that showed an increased rate of MI with dabigatran use.3

It turns out this effect was not limited to dabigatran but also applied to other direct thrombin inhibitors, such as ximelagatran (which was studied in venous thromboembolism [VTE]). 

Multiple mechanisms have been proposed for this effect including the possibility of a rebound phenomenon after cessation, which results in increased generation of thrombin.4 Warfarin is protected from this type of rebound physiology. Others have proposed that warfarin itself may offer a protective effect against MI, resulting in the increased MI signal seen with dabigatran vs. warfarin.

To better tease out this risk relationship and improve the power of the study, a meta-analysis published recently in the American Journal of Cardiology5 attempted to answer these questions.  The authors used a MEDLINE search to identify 11 trials (39 357 patients) that included DTIs (dabigatran, ximelgatran and AZD0837) compared with warfarin and had MI as an endpoint after randomization. There was a 1.35-fold increase in the odds of having an MI (95% CI 1.10 to 1.66) with DTIs over warfarin in the entire cohort. OR went as high as 3.46-fold for ximelagatran vs. warfarin in the two VTE trials. To determine whether warfarin offered a protective effect, 8 studies (69 615 patients) were included in the secondary analysis and warfarin showed no advantage over the combined cohort of aspirin alone, aspirin plus clopidogrel, factor Xa inhibitors, or oral DTIs.

Although dabigatran offers a mortality benefit, this meta-analysis suggests that the risk of MI may be a class effect of all DTIs and therefore, is likely not a spurious finding. For this reason, it may be prudent to caution any patient being started on a DTI (or those who are already taking it) about this possible risk and for certain patients, such as those with previous coronary artery disease, an alternative oral anticoagulant may be a better choice. 

References:
1. Connolly SJ, Ezekowitz MD, Yusuf S, et al, for the RELY Steering Committee. Dabigatran
versus warfarin in patients with atrial fibrillation. N Engl J Med. 2009;361:1139-1151. doi: 10.1056/NEJMoa0905561. (Full Text)
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;125:669–676.
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;172:397–402.
4. Kohli P, Cannon CP.  Dabigatran associated with increased risk of acute coronary events. Evid Based Med. 2013 Feb;18(1):e9. doi: 10.1136/eb-2012-100733.
5. Artang R, Rome E, Nielsen JD, Vidaillet HJ. Meta-analysis of randomized controlled tirals on risk of myocardial infarction from the use of oral direct thrombin inhibitors. Am J Cardiol. 2013 Sep 25. pii: S0002-9149(13)01709-8. doi: 10.1016/j.amjcard.2013.08.027. [Epub ahead of print]