Dabigatran is associated with an increased risk of MI or acute coronary syndrome in a broad spectrum of patients when tested against different controls. That led researchers to recommend that “clinicians should consider the potential of these serious harmful cardiovascular effects with use of dabigatran.” Jeremy M. Jacobs, MBBS, one Archives of Internal Medicine editorialist, who published his article Jan. 9 along with the study, told Cardiovascular Business that “caution is needed, especially among patients with known active ischemic heart disease.”

The original RE-LY (Randomized Evaluation of Long-term Anticoagulant Therapy) trial suggested a small increased risk of MI with the use of dabigatran etexilate (Pradaxa, Boehringer Ingelheim) vs. warfarin in patients with atrial fibrillation. This trial systematically evaluated the risk of MI or acute coronary syndrome (ACS) with the use of dabigatran.

In this meta-analysis, Ken Uchino, MD, and Adrian V. Hernandez, MD, PhD, MSc, of the Cleveland Clinic, and colleagues evaluated PubMed, Scopus and the Web of Science for randomized controlled trials of dabigatran that reported on MI or ACS as secondary outcomes. They used the fixed-effects Mantel-Haenszel test to evaluate the effect of dabigatran on MI or ACS.

The researchers selected seven trials (30,514 patients), including two studies of stroke prophylaxis in atrial fibrillation, one in acute venous thromboembolism, one in ACS and three of short-term prophylaxis of deep venous thrombosis. The control arms included warfarin, enoxaparin or placebo administration.

This meta-analysis showed that dabigatran was significantly associated with a higher risk of MI or ACS than that seen with agents used in the control group (dabigatran, 1.19 percent vs. control, 0.79 percent). The risk of MI or ACS was similar when using revised RE-LY trial results or after exclusion of short-term trials. Risks were not heterogeneous for all analyses and were consistent using different methods and measures of association, according to the authors.

Uchino and Hernandez concluded that while the overall benefit and risk balance of dabigatran “appears to be favorable in patients with AF because of reduction in ischemic stroke,” the cardiac risk of dabigatran should be investigated further, especially if it is used in populations at high risk of MI or ACS.

“Uchino and Hernandez suggest that physicians step back for a moment, take their own pulse and retain a critical view as a powerful new drug enters clinical use on a potentially massive scale,” wrote Jacobs and Jochanan Stessman, MD, of the Hadassah-Hebrew University Medical Center and Hebrew University-Hadassah Medical School in Jerusalem. 

“The findings of this meta-analysis indeed suggest a small but nonetheless significant rise in the rate of MI among patients treated with dabigatran in contrast to those with warfarin on the RE-LY and other comparators from other randomized controlled trials,” said Jacobs.

“The issue of drug safety is of paramount importance, and the design of the randomized controlled trials which exist to secure its clinical use are generally underpowered to detect all but the most common side effects,” he explained. “The real clinical dilemma which surrounds the introduction of any new drug is the fact that only relatively long-term usage may provide sufficient data to reveal rare side effects, or more subtle negative balance of unwanted clinical outcomes.

“Among older people with rising comorbidity, polypharmacy is a true problem, and unraveling the overall net benefits of drug usage among this population is a challenge yet to be met,” Jacobs said. “The dabigatran debate is a good example, which raises issues concerning post-marketing surveillance, and pharmaco-vigilance.

"Who takes responsibility? Industry? Independent researchers? National bodies? I personally favor the latter, since the stakes are very high for new drugs, and it is difficult for industry-backed research to overcome conflicts of interest that inevitably arise,” he concluded.