Meta-Analysis Shows Increased Risk of MI, ACS with Dabigatran

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New data suggest that the direct thrombin inhibitor dabigatran is associated with a significantly increased risk of myocardial infarction (MI) and acute coronary syndromes (ACS) compared with other anticoagulants. The study, published January 9, 2012, in Archives of Internal Medicine, raises the implication that enthusiasm to embrace new alternatives for older drugs should be tempered with caution.

Dabigatran (Pradaxa, Boehringer-Ingelhiem, Ridgefield, CT) was approved by the US Food and Drug Administration in 2010 for the prevention of stroke and systemic embolism in patients with nonvalvular atrial fibrillation.

Ken Uchino, MD, and Adrian V. Hernandez, MD, PhD, both of the Cleveland Clinic (Cleveland, OH), conducted a meta-analysis of the 7 core randomized controlled trials that have been published comparing dabigatran with warfarin, enoxaparin, or placebo in various clinical settings in 30,514 patients. The 7 trials include:

• 2 studies of stroke prophylaxis in atrial fibrillation (PETRO and RE-LY)
• 1 study of acute venous thromboembolism (RE-COVER)
• 1 study of ACS (RE-DEEM)
• 3 trials or short-term prophylaxis of deep venous thrombosis in joint replacement (RE-NOVATE, RE-MODEL, and RE-NOVATE II)

The largest of these trials, RE-LY, compared 2 doses of dabigatran (110 or 150 mg twice daily) with warfarin (adjusted dose) in 18,113 patients with atrial fibrillation. The results suggested a significant relative increased risk of MI in the group receiving the largest dabigatran dose compared with warfarin (RR 1.38; 95% CI 1.00-1.91; P = 0.048). The trial was later revised to include additional stroke, bleeding events, and MIs that occurred after the trial had closed. Subsequently, the revised results no longer showed a significantly higher risk of MI with dabigatran (RR 1.27; 95% CI 0.94-1.71; P = 0.12).

Increased Risk Consistent

In the new meta-analysis, patients given dabigatran showed a higher risk of MI or ACS than controls (1.19% vs. 0.79%; OR 1.33; 95% CI 1.03-1.71; P = 0.03), an association that was consistent using different statistical methods. In addition, the risk of MI or ACS was maintained when the revised RE-LY trial results were included (OR 1.27; 95% CI 1.00-1.61; P = 0.05) and after exclusion of short-term trials (OR 1.33; 95% CI 1.03-1.72; P = 0.03).

Study heterogeneity was low and there was no evidence of publication bias (P = 0.60).

Despite the higher MI/ACS risk, dabigatran was associated with lower mortality than other anticoagulants in the 6 studies that reported such data (4.83% vs. 5.02%; P = 0.04).

Drs. Uchino and Hernandez say they do not know the pharmacologic mechanism that may result in dabigatran increasing the risk of MI or ACS.

“Pharmaceutical agents have multiple effects, and unexpected risks are sometimes found in the process of drug development or clinical use,” they write. “The development of another direct thrombin inhibitor, ximelagatran, was halted when an increase in hepatic transaminase levels was observed.” The study authors add that “as a member of the same drug class, dabigatran might have effects that are unfavorable to atherosclerosis or atherosclerotic thrombotic events.”

They also acknowledge that while dabigatran might not directly increase the risk of MI, it may lack the beneficial effects that warfarin and aspirin have in preventing MI.

‘Alarming’ Findings

In an accompanying editorial, Jeremy M. Jacobs, MD, and Jochanan Stessman, MD, both of Hadassah-Hebrew University Medical Center (Jerusalem, Israel), comment that “the robust findings that dabigatran is associated with increased rates of MI is alarming and emphasizes the need for continued critical appraisal of new drugs after phase 3 trials.”

They further observe that physicians need to “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.”

Drs. Jacobs and Stessman add that new drugs have dangers that may become apparent only after the “relatively pristine data of clinical trials have given way to the gritty reality of daily clinical drug use.” Furthermore, they say, a larger issue in all of this may be that in the rush to embrace new drug therapies, physicians have forgotten the old aphorism: primum non nocere.

Dabigatran’s Benefits Outweigh Risk

But in a telephone interview with TCTMD, Stuart J. Connolly, MD, of McMaster University (Hamilton, Canada), urged caution in interpreting the results of the new meta-analysis.

“While there is evidence of a higher rate of myocardial infarction with dabigatran than with warfarin, this is greatly outweighed by the proven benefits of dabigatran over warfarin on reducing ischemic stroke, hemorrhagic stroke, and life-threatening bleeding,” he said. “In patients in whom the MI risk is low, the benefits clearly outweigh any potential hazard. And even to say a hazard, I think is incorrect, because it is more of a loss of efficacy that you would otherwise have with warfarin.”

Dr. Connolly, who was a lead investigator of the RE-LY trial, added that the choice of warfarin or dabigatran involves many factors and many well-known risk issues.

“This report doesn’t really change anything because there is still a very strong reason to use dabigatran, and in my view, it is still the preferred anticoagulant to use in a patient with atrial fibrillation compared to warfarin,” he said.

In addition, Dr. Connolly said findings published this month by his group using the RE-LY data show that the risk of MI is constant regardless of whether patients are at high or low risk for MI, so there is no particular risk factor for MI with dabigatran use that can be pinpointed at this time.

“The thing about patients who are high risk for MI is that they tend to also be high risk for other events where dabigatran is very effective compared to warfarin, so I think it’s still an unanswered question. But by no means is it a ‘slam dunk’ that you should avoid dabigatran in patients who are at high risk for MI,” Dr. Connolly said. “What’s your alternative? Right now it’s warfarin, which carries this higher rate of ischemic stroke and bleeding and hemorrhagic stroke that certainly offsets anything that goes with an MI.”

 

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Sources:
1. Uchino K, Hernandez AV. Dabigatran association with higher risk of acute coronary events. Arch Intern Med. 2012;Epub ahead of print.

2. Jacobs JM, Stessman J. Dabigatran: Do we have sufficient data? Arch Intern Med. 2012;Epub ahead of print.

 

 

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