Dabigatran with mechanical heart valves?

This week, the RE-ALIGN study was published in the New England Journal of Medicine, examining the use of dabigatran in patients undergoing a mechanical valve replacement or who underwent one at least three months earlier.  This study was a dose-finding study for dabigatran primarily looking at plasma trough concentrations in patients receiving 150-300 mg po bid depending on renal function (Yes, higher than doses used for atrial fibrillation).  The pharmacokinetic model used in the RE-LY study (the >18,000 patient study resulting in approval of dabigatran) was used to target certain trough concentrations and dabigatran titration was performed at prespecified intervals. 

Over 252 patients were randomized to receive either dabigatran or warfarin (at conventional target INR dosing) when the study was terminated early for safety reasons.  The patient population who underwent the valve replacement at the time of randomization and the population who had received the valve replacement more than three months earlier were both found to have excess risk of thromboembolic and bleeding events with dabigatran versus warfarin.  Roughly two thirds of patients received aortic valves and one third received mitral valves and were distributed evenly between medication groups.  The mechanism for increased adverse events from dabigatran was proposed to be subtherapeutic plasma levels in the beginning of treatment; however, patients on dabigatran were found to have both increased thromboembolic events in addition to increased bleeding suggesting other factors are at play.

Take home point:

• There is no positive value in using dabigatran versus warfarin after mechanical valve replacement.  Patients receiving dabigatran experienced increase in thromboembolic events in addition to bleeding events.

Dabigatran is a direct thrombin inhibitor marketed as Pradaxa® and is approved to reduce the risk of stroke and systemic embolism in patients with non-valvular atrial fibrillation.

References:

1.  Eikelboom JW, Connolly SJ, Brueckmann M, et al.  Dabigatran versus warfarin in patients with mechanical heart valves.  N Engl J Med 2013