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Dabigatran versus Warfarin in Patients with Mechanical Heart Valves: the RE-ALIGN trial Dr. I.Meynet

The oral direct thrombin inhibitor dabigatran has proven efficacy in preventing thrombosis in patients with atrial fibrillation (RE-LY study), but its role as an alternative to warfarin in patients with prosthetic valves is still unclear. RE-ALIGN was a prospective, randomized, phase 2, open label trial with the aim to validate the use and the dosing of dabigatran in patients with mechanical heart valves.
Patients undergoing implantation of a mechanical bileaflet valve in the aortic or mitral position or both (population A), or carriers of a mechanical bileaflet mitral valve from more than 3 months (population B), were enrolled from November 2011 in 39 centers worldwide. All included patients were randomized to receive dabigatran or warfarin in a ratio of 2:1; the starting dose of dabigatran was targeted on the basis of renal function (150, 220 or 300 mg twice-a-day), and the following dose was adjusted in order to obtain a plasma level of dabigatran of 50 mg/ml or higher; the dose of warfarin was adjusted to obtain an international normalized ratio (INR) of 2 to 3.5, according to the risk profile of each patient. After 12 weeks of treatment, patients in the dabigatran group could choose to switch to warfarin or to continue. The study was discontinued after 12 months due to excess thromboembolic and bleeding events among the dabigatran group. 5 out of the 252 enrolled patients experienced valve thrombosis, 9 had stroke and 3 had myocardial infarction, all in the dabigatran group; a major bleeding episode occurred in 7 patients in the dabigatran group and in 2 patients in the warfarin group (HR 2.45, p = 0.01), and all of them were pericardial bleeding (see table). Patients in the dabigatran group reached the targeted plasma level of 50 ng/ml for an average of 86% of the time, and dose adjustment or discontinuation of the drug was required in 52 of 162 patients (32%).
Warfarin may be more effective because it inhibits both the coagulation pathways as well as the common thrombin pathway, while dabigatran exclusively inhibits thrombin. In the setting of patients with prosthetic valves, the triggers for the formation of thrombi are probably more complex and stronger (including the exposure of the blood to the artificial surface of the valve and the damage of tissues during surgery) than in patients with atrial fibrillation (in whom thrombi form in low-flow, low-shear, low-stress conditions in the left atrial appendage). Taken together, those two reasons may explain the lack of protection from thrombosis with dabigatran. Dabigatran is therefore not appropriate as an alternative to warfarin in patients who require anticoagulation after the implant of a prosthetic valve, showing no benefit and being associated with an increased risk of bleeding. N Engl J Med. 2013 Sep 26;369(13):1206-14.

writed  at 20-10-2013 23:01:29