Dabigatran was not effective in prevention of thromboembolic complications in patients with mechanical heart valves and is associated with an increased risk of bleeding as compared with warfarin, according to findings presented Sept. 1 at the ESC Congress 2013 in Amsterdam and simultaneously published in the New England Journal of Medicine.

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The RE-ALIGN trial was a prospective, randomized, phase 2 dose-validation study conducted at 39 centers in 10 countries, but was terminated after the enrollment of 252 patients due to the "excess of thromboembolic and bleeding events found in the dabigatran group." Two populations of patients were studied — "those who had undergone aortic- or mitral-valve replacement within the past seven days and those who had undergone such replacement at least three months earlier." Patients were randomly assigned to dabigatran or warfarin, and results showed "ischemic or unspecified stroke occurred in nine patients (5 percent) in the dabigatran group and in no patients in the warfarin group; major bleeding occurred in seven patients (4 percent) and two patients (2 percent), respectively." The investigators note that "all patients with major bleeding had pericardial bleeding."

They add that most thromboembolic events among patients in the dabigatran group occurred in the patients who had started a steady drug within seven days after valve surgery, with fewer occurring in the patients who had undergone valve implantation more than three months prior to randomization. However, "excess bleeding events among patients receiving dabigatran occurred in the two study populations."

"These results might be explained by the relative inability of dabigatran to suppress activation of coagulation that occurs when blood is exposed to the artificial surfaces of the valve prosthesis," said the investigators. However, they conclude that "the use of dabigatran has no positive value and was associated with excess risk in patients with mechanical heart valves."

In an editorial comment, Elaine M. Hyleck, MD, MPH, of the Boston University School of Medicine, Boston, explains that the Food and Drug Administration and the European Medicines Agency have recommended against the use of dabigatran in patients with mechanical heart valves. "The results of RE-ALIGN are disappointing, but there is a palpable downside as well to the potential premature abandonment of research into the use of such drugs in patients with mechanical heart valves," she adds.

The U.S. Food and Drug Administration had previously made a safety announcement  about dabigatran in December 2012 informing health care professionals and the public that dabigatran "should not be used to prevent stroke or blood clots (major thromboembolic events) in patients with mechanical heart valves." In April 2013, Boehringer Ingelheim Pharmaceuticals, Inc. announced  that a Boxed Warning would be added to the dabigatran label. This warning has also been applied to apixaban and rivaroxaban.

Keywords: Prostheses and Implants, Stroke, beta-Alanine, Morpholines, United States Food and Drug Administration, Benzimidazoles, Warfarin, Pyrazoles, Pyridones, Heart Valves

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