The novel anticoagulant dabigatran (Pradaxa, Boehringer Ingelheim) should not be used to reduce the risk of stroke in patients with mechanical heart valves, the RE-ALIGN study has concluded. Its results indicate that compared with warfarin, the drug was associated with increased thromboembolic events and bleeding complications in this patient population.
Presenting the study at the annual meeting of the European Society of Cardiology (ESC; 31 August–4 September, Amsterdam, The Netherlands), Frans Van de Werf (Department of Cardiovascular Sciences, KU Leuven, University Hospital Leuven, Leuven, Belgium) said that dabigatran was seen as a possible alternative approach to warfarin for stroke prevention in patients with mechanical heart valves because another study, RE-LY, showed that the 150mg dose of the drug was superior to warfarin for stroke prevention in patients with atrial fibrillation. Also, animal studies have indicated that dabigatran may be an effective anticoagulant in patients with mechanical heart valves. Van de Werf explained: “With aortic valves, thrombus deposition was adequately controlled with dabigatran 20mg/kg over 30 days in a pig model. With mitral valves, although thrombus deposition was not fully prevented with dabigatran 20mg/kg over 90 days, survival overall was prolonged with dabigatran.”
The aim of the RE-ALIGN (Randomised, phase II study to evaluate the safety and pharmacokinetics of oral dabigatran etexilate in patients after heart valve replacement) was to test a dosing regimen of dabigatran—based on the regimen used in RE-LY—in patients with bileaflet mechanical heart valves.
There were two study populations: population A, who received a bileaflet mechanical aortic or mitral valve or both; population B, who received a bileaflet mechanical mitral valve (with or without aortic valve replacement) more than three months before randomisation.
Patients were randomised to receive dabigatran or warfarin. The dose of the study drug was dependent on a patient’s creatinine levels—an initial dose of 150mg twice daily for patients with a creatinine clearance of
Van de Werf reported: “The original sample size was based on the validation of the dosing algorithm and we calculated that with about 400 patients, we would be able to statistically prove that 10% of these patients would have a trough level of <50ng/ml of dabigatran. However, the study was prematurely stopped because of an excess of thromboembotic events and bleeding events in the dabigatran arm after recruiting the first 252 patients.”
He explained in these patients (168 on dabigatran and 84 on warfarin), there were nine strokes (all in population A), three transient ischaemic attacks (two in population A and one in population B) and three myocardial infarctions (one in population A and two in population B) in the dabigatran group compared with no strokes, no myocardial infarctions, and two transient ischaemic attacks (both in population A) in the warfarin group. There were also five cases of valve thrombosis without symptoms in the dabigatran group (two in population A and three in population B) but no cases in the warfarin group.
Regarding safety outcomes, there were seven major bleeding events in the dabigatran patients vs. two in the warfarin patients (all events were in population A). The time to first bleed (any bleeding) was significantly shorter in the dabigatran group (p<0.01).
According to Van de Werf, the differences in the mechanism of action between warfarin and dabigatran was “perhaps the most important” explanation for the negative results of the RE-AlIGN study. He noted: “Namely, the inability of dabigatran to supress activation of the coagulation cascade that occurs when blood is exposed to the artificial surface of the mechanical valve. Whereas warfarin acts on three pathways, including the contact thrombosis pathway, dabigatran—of course—is a direct thrombin inhibitor and does not act on the contact thrombosis pathway.”
“Dabigatran should not be prescribed to patients with mechanical heart valves,” he concluded.
Study discussant Alec Vahanian (Department of Cardiology, Bichat Hospital, Paris, France), said that while the study gives “unfavourable signals” for using other novel anticoagulants (ie. direct factor Xa inhibitors) in patients with mechanical heart valves, we need dedicated trials to determine whether or not these agents can be used in this population. However, he added: “We are at the beginning of the end of mechanical heart valves. Patients are getting older [so less frequently need a valve that lasts a long time]; bioprostheses are getting better; valve repair is catching up, and the use of transcatheter aortic valve implantation is increasing. Therefore, our patients may remain hopeful [that they can avoid warfarin if they receive a heart valve].”