The direct thrombin inhibitor dabigatran appears to raise the risk of myocardial infarction or acute coronary syndromes, according to a meta-analysis of seven randomized clinical trials published online Jan. 9 in the Archives of Internal Medicine.
The meta-analysis included randomized clinical trials assessing the noninferiority of dabigatran against various control treatments including adjusted-dose warfarin, enoxaparin, and placebo, in a broad spectrum of patients using the drug for a variety of indications.
"We used several meta-analytic methods and several association measures, and the results were consistent. Although the relative risk increase was 33%, the absolute risk increase was very small, at 0.27%," said Dr. Ken Uchino and Dr. Adrian V. Hernandez, both of the Cleveland Clinic.
The mechanism by which dabigatran increases the risk of MI or acute coronary syndrome (ACS) is not yet known. It is possible that the drug doesn’t actively raise this risk, but instead lacks some protective effect that the control treatments possess, the investigators noted.
The meta-analysis covered 30,514 study subjects, including patients with atrial fibrillation who used dabigatran to prevent stroke, patients with atrial fibrillation who used it to prevent acute venous thromboembolism, patients with ACS who used it to prevent recurrent ACS, and patients undergoing joint replacement who used it to prevent deep vein thrombosis.
Overall, patients who received dabigatran were at significantly higher risk of MI or ACS than were control patients. The incidence of these events was 1.19% in those taking dabigatran, compared with 0.79% in control subjects, Dr. Uchino and Dr. Hernandez said (Arch. Intern. Med. 2012 [doi:10.1001/archinternmed.2011.1666]).
Since it is possible that dabigatran’s negative effects may increase with longer duration of use, the investigators performed a separate analysis excluding three of the seven studies that had exceptionally short (less than 1 month) exposure times. The risk of MI or ACS remained high and significant in this analysis of the data, they noted.
An important limitation of the meta-analysis is that a single large trial, with a study population of 18,113 patients, overshadowed the findings from the other 6 trials, which had populations of 515 to 2,451 patients. In addition, the large trial followed patients for a median of 2 years, while the smaller trials did so for 6 months or less.
Because of this imbalance, the large trial accounted for 59% of the meta-analysis cohort and 74% of the cardiovascular events, they said.
Overall, the findings indicate that dabigatran’s cardiovascular risks should be investigated further, "especially if [the drug] is used in populations at high risk of MI or ACS," they added.
All seven studies included in the meta-analysis were sponsored by the drug manufacturer, Boehringer Ingelheim. No financial conflicts of interest were reported among the investigators for this current study.
Dr. Jacobs and Dr. Stessman reported having no financial conflicts of interest.
View New Drugs CriticallyThe "robust" finding by Dr. Uchino and Dr. Hernandez that dabigatran is associated with increased MI "is alarming and emphasizes the need for continued critical appraisal of new drugs after phase III trials," said Dr. Jeremy M. Jacobs and Dr. Jochanan Stessman.
The researchers’ results "suggest that physicians [should] 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," Dr. Jacobs and Dr. Stessman said.
The findings also highlight another deeply concerning issue: "the enthusiasm – nearly to the level of euphoria – to embrace the new," they added.
Dr. Jacobs is at the Jerusalem Institute of Aging Research at Hadassah-Hebrew University Medical Center, and Dr. Stessman is at Hebrew University–Hadassah Medical School, Jerusalem. They reported having no financial conflicts of interest. These remarks were taken from their invited commentary, which accompanied the meta-analysis (Arch. Intern. Med. 2012 [doi:10.1001/archinternmed.2011.1721]).
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