Background: Dabigatran is an oral direct thrombin inhibitor that has been shown to be an effective alternative to warfarin in patients with atrial fibrillation. We evaluated the use of dabigatran in patients with mechanical heart valves.
Methods: In this phase 2 dose-validation study, we studied two populations of patients: those who had undergone aortic- or mitral-valve replacement within the past 7 days and those who had undergone such replacement at least 3 months earlier. Patients were randomly assigned in a 2:1 ratio to receive either dabigatran or warfarin. The selection of the initial dabigatran dose (150, 220, or 300 mg twice daily) was based on kidney function. Doses were adjusted to obtain a trough plasma level of at least 50 ng per milliliter. The warfarin dose was adjusted to obtain an international normalized ratio of 2 to 3 or 2.5 to 3.5 on the basis of thromboembolic risk. The primary end point was the trough plasma level of dabigatran.
Results: The trial was terminated prematurely after the enrollment of 252 patients because of an excess of thromboembolic and bleeding events among patients in the dabigatran group. In the as-treated analysis, dose adjustment or discontinuation of dabigatran was required in 52 of 162 patients (32%). Ischemic or unspecified stroke occurred in 9 patients (5%) in the dabigatran group and in no patients in the warfarin group; major bleeding occurred in 7 patients (4%) and 2 patients (2%), respectively. All patients with major bleeding had pericardial bleeding.
Conclusions: The use of dabigatran in patients with mechanical heart valves was associated with increased rates of thromboembolic and bleeding complications, as compared with warfarin, thus showing no benefit and an excess risk. (Funded by Boehringer Ingelheim; ClinicalTrials.gov numbers, NCT01452347 and NCT01505881.).