Oral Direct Thrombin Inhibitors Linked to Increased MI Risk

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Oral direct thrombin inhibitors appear to increase the risk of myocardial infarction (MI) compared with warfarin in patients prescribed anticoagulants to prevent stroke. The findings, from a meta-analysis published online September 27, 2013, ahead of print in the American Journal of Cardiology, suggest the association is a class effect rather than a safety issue specific to dabigatran and argue against the idea of a protective effect of warfarin.

Ramin Artang, MD, of the University of Nebraska Medical Center (Omaha, NE), and colleagues conducted a meta-analysis of 11 trials with 39,357 patients randomized to warfarin or a direct thrombin inhibitor, for any indication. The latter class of drugs included:

• Dabigatran (4 trials)
• Ximelagatran (5 trials)
• AZD0837 (2 trials)

Overall, the use of oral direct thrombin inhibitors was associated with a higher rate of MI compared with warfarin (1.2% vs. 0.83%; OR 1.35; 95% CI 1.10-1.66; P = 0.005).

Risk Varies Somewhat with Individual Drugs

In the trials that compared dabigatran to warfarin, MI rates were clearly higher with dabigatran (1.4% vs. 0.88%; OR 1.41; 95% CI 1.09-1.83; P = 0.009), while the trials involving ximelagatran showed only a trend toward increased rates of MI (0.92% vs. 0.79%; OR 1.23; 95% CI 0.86-1.76; P = 0.25). However, meta-analysis by treatment indication found that patients with venous thromboembolism who were treated with ximelagatran had more than a threefold increased MI risk (OR 3.46; 95% CI 1.25-9.57; P = 0.017).

Only in the trials of AZD0837 was no difference in MI rates seen between the direct thrombin inhibitor and warfarin groups (0.37% vs. 0.25%; OR 1.17; 95% CI 0.17-7.94; P = 0.87).

Influence analysis of the entire cohort showed that none of the individual studies appeared to have significant impact on the overall combined effect sizes.

To investigate a possible protective effect of warfarin, the investigators also conducted a secondary analysis of 8 randomized studies involving 69,615 patients that compared warfarin with several alternative anticoagulants including factor Xa inhibitors, direct thrombin inhibitors, aspirin, and clopidogrel. There was no advantage in the MI rate with the use of warfarin vs. the comparators (OR 1.06; 95% CI 0.85-1.34; P = 0.59).

A Possible Explanation

According to the study authors, there are 2 different classes of direct thrombin inhibitors: the bivalent (including hirudin and bivalirudin) and the univalent (including ximelagatran and dabigatran). At least 1 study has shown that the direct thrombin inhibitor melagatran reduced thrombin generation at higher concentrations but enhanced it at lower concentrations.

A possible hypothesis unifying this and similar observations, the authors suggest, is that “at trough levels of univalent [direct thrombin inhibitors], the remaining enzymatically active thrombin dissociated from [direct thrombin inhibitor] molecules when exposed to tissue factor at the site of the ruptured plaque, or a mechanical valve may generate more thrombin formation and may potentially contribute to platelet activation.”

Artang R, Rome E, Nielsen JD, et al. Meta-analysis of randomized controlled trials on risk of myocardial infarction from the use of oral direct thrombin inhibitors. Am J Cardiol. 2013;Epub ahead of print.

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