Pradaxa Linked to More MIs in Certain Patients

By Todd Neale, Senior Staff Writer, MedPage Today Published: January 09, 2012 Reviewed by Zalman S. Agus, MD; Emeritus Professor University of Pennsylvania School of Medicine and Dorothy Caputo, MA, RN, BC-ADM, CDE, Nurse Planner

In various patient populations, the anticoagulant dabigatran (Pradaxa) was associated with greater odds of myocardial infarction (MI) or acute coronary syndrome than control treatments, a meta-analysis showed. Among randomized controlled trials for multiple indications, MI or acute coronary syndrome occurred at a significantly higher rate with dabigatran than with control treatment (1.19% versus 0.79%; OR 1.33, 95% CI 1.03 to 1.71), according to Ken Uchino, MD, and Adrian Hernandez, MD, PhD, of the Cleveland Clinic. "Clinicians should consider the potential of these serious harmful cardiovascular effects with use of dabigatran," they wrote online in Archives of Internal Medicine. Action Points   This study evaluated the risk of acute coronary events with the use of dabigatran for several different clinical indications and against different control arms. Dabigatran was associated with an increased risk of myocardial infarction or acute coronary syndrome, but the authors concluded that the risk balance of dabigatran use appears to be favorable in patients with atrial fibrillation because of reduction in ischemic stroke. In the trials, dabigatran was used for stroke prevention in atrial fibrillation (versus warfarin), prophylaxis for acute venous thromboembolism (versus warfarin) and deep venous thrombosis (versus enoxaparin), and prevention of events in acute coronary syndrome (versus placebo). "The overall benefit and risk balance of dabigatran use appears to be favorable in patients with atrial fibrillation because of reduction in ischemic stroke," Uchino and Hernandez wrote. "However, the cardiac risk of dabigatran should be investigated further, especially if it is used in populations at high risk of MI or acute coronary syndrome." In an accompanying editorial, Jeremy Jacobs, MBBS, and Jochanan Stessman, MD, of Hadassah-Hebrew University Medical Center in Jerusalem, wrote, "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." "The robust finding that dabigatran is associated with increased rates of MI is alarming and emphasizes the need for continued critical appraisal of new drugs after phase III trials," they wrote. In the largest study of dabigatran -- the 18,000-patient RE-LY trial -- the higher 150-mg dose of the anticoagulant was superior to warfarin for preventing stroke and systemic embolism in patients with atrial fibrillation. But there was also a 38% relative increase in the risk of MI (P=0.048). After an additional search for events, however, the increase was no longer significant (RR 1.27, 95% CI 0.94 to 1.71). Along the same lines, a recently published post-hoc analysis of the RE-LY trial showed that the risk of MI was not significantly greater with dabigatran than with warfarin, and that the rate of overall major adverse events was significantly lower with the higher dose of dabigatran. Uchino and Hernandez performed their meta-analysis to further explore the risk of MI or acute coronary syndrome across the patient populations in which dabigatran has been tested. For the purposes of the analysis, patients receiving any dose of dabigatran were grouped together. The researchers identified seven randomized controlled trials that included 30,514 patients -- two on preventing stroke in atrial fibrillation, one on acute venous thromboembolism prophylaxis, one on preventing events in acute coronary syndrome, and three on short-term prophylaxis of deep venous thrombosis. The control arms included warfarin, enoxaparin, or placebo. Although dabigatran use was associated with a significantly higher rate of MI or acute coronary syndrome, the absolute risk increase was small -- 0.27% (95% CI 0.04% to 0.50%). Using the revised RE-LY results instead of the originally reported results weakened the association, although it maintained borderline statistical significance (OR 1.27, 95% CI 1.00 to 1.61, P=0.05). Excluding the three short-term trials of dabigatran for prophylaxis of deep venous thrombosis after joint replacement, the higher rate of MI and acute coronary syndrome with the anticoagulant was significant (OR 1.33, 95% CI 1.03 to 1.72). Uchino and Hernandez noted that they did not know of a pharmacologic mechanism to explain the higher rate of MI or acute coronary syndrome with dabigatran. They said that it could be a factor with dabigatran itself or it could be that the comparator drugs are better at preventing MI. An important limitation of the meta-analysis is the dominant effect of the RE-LY trial, which included more than 18,000 patients, the researchers said. The largest of the other trials included about 3,500 patients. In addition, patients were followed for a median of two years in RE-LY, and for six months or less in the other trials. The study authors and the editorialists reported that they had no conflicts of interest. From the American Heart Association: 2011 ACCF/AHA/HRS Focused Update on the Management of Patients With Atrial Fibrillation (Update on Dabigatran) 2011 Focused Update on the Management of Patients With Atrial Fibrillation

Primary source: Archives of Internal Medicine Source reference: Uchino K, Hernandez A "Dabigatran association with higher risk of acute coronary events" Arch Intern Med 2012; DOI: 10.1001/archinternmed.2011.1666. Additional source: Archives of Internal Medicine Source reference: Jacobs J, Stessman J "Dabigatran: do we have sufficient data?" Arch Intern Med 2012.         MedPage today link