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Frans Van de Werf,
Presenter abstract | Discussant report | All the Scientific resources on ESC Congress 365
By Frans Van De WerfOther authors: Dr Martina Brueckmann, Germany; Dr Stuart Connolly, Canada; Dr Jeffrey Friedman, USA; Dr Chris Granger, USA; Dr Michael Mack, USA; Dr Arie Pieter Kappetein, The Netherlands; Dr Yasser Khder, France; Dr Ruth Harper, United Kingdom; Dr. John Eikelboom, Canada
Background:Vitamin K antagonists are the only available oral anticoagulants for patients with a mechanical valve. Inadequate levels of anticoagulation may lead to valve thrombosis or serious bleeding complications.Dabigatran, a direct oral thrombin inhibitor, has been shown to be more effective than warfarin in patients with non-valvular atrial fibrillation with a better safety profile.The aim of the study was to test a dosing algorithm of dabigatran in patients with a mechanical heart valve.
Methods and results:Patients were randomized to dabigatran or warfarin in a 2:1 ratio for a 12 week study period. After this time patients could continue to take the allocated study medication until possible registration of dabigatran for this indication.A total number of 405 patients was originally planned. On November 28th, 2012, in consultation with the DSMB, the study was stopped because of an excess of thromboembolic and bleeding events. A first group of 191 in-hospital patients who underwent bi-leaflet aortic and/or mitral valve replacement were randomized and started study medication within 3 to 7 days after surgery (dabigatran) or immediately after randomization (warfarin).A second group of 52 patients with a bi-leaflet mitral valve replacement at least 3 months before, were randomized at the out-patient clinic. Doses of dabigatran ranged from 150 bid to 300 bid depending on renal function and exposure levels. Dose adjustments of dabigatran were based on plasma concentrations measured at steady state. A trough level of 50 ng/ml of dabigatran was assumed to be required for effective anticoagulation based on the results of the RE-LY study. Thromboembolic events, bleeding complications and echocardiographic findings were recorded and adjudicated blinded to the allocated treatment.
Conclusion: RE-ALIGN is the first randomized study ever performed comparing a new oral anticoagulant with warfarin in patients with a mechanical valve.The results will be available for first presentation at the congress. Possible explanations for the inferiority of dabigatran and the consequences for future studies on antithrombotic therapies in patients with mechanical heart valves will be provided.
Alec VahanianThe authors should be congratulated for running what is the first randomised study on the new anticoagulant agent. Dabigatran in patients with mechanical prostheses. It is a very challenging endeavour but the trial was needed because thromboembolism & bleeding represent the main complications experienced by patients with prosthetic valves.Let’s see the possible explanations for the negative findings in this trial.Dosing is always a concern at the early stage of investigation of such agents especially when extrapolating doses from another indication. It’s not expected that higher doses would prove any better when looking at the high rate of bleeds.On the other hand the higher incidence of thromboembolism over the whole study period does not favour decreasing the dose.Play of chance is always possible because the study was not powered for clinical end points but I don’t anticipate that we’ll see a much larger trial with this agent in this indication. More concerning is the hypothesis based on the inability of Dabigatran to suppress activation of coagulation at the contact of the prosthetic valve. The findings in the study also emphasize that clinical efficacy may be missing even if preclinical studies were encouraging, as was the case with Dabigatran and also Rivaroxaban.As Churchill used to say, “is it the beginning of the end or the end of the beginning?” of the new oral anticoagulants in patients with mechanical prosthesis. I’ll favour the former statement as far as dabigatran is concerned. For the other agents, especially the anti-Xa, the answer is that we don’t know yet, despite somewhat unfavourable signals, and we won’t be able to answer without a dedicated trial. Obviously dabigatran should not be prescribed in patients with mechanical valve prosthesis. I think that it is adequate for the time being to explain this statement to patients with bioprosthesis and any patients with significant valve disease, because we don’t have the studies yet.
Finally, as far as patients who will be operated are concerned, we should probably attenuate the consequences of the findings in this study because indications for mechanical prosthesis are continuously decreasing as bioprostheses are improving, patients with Valvular Heart Disease are older, repair is catching up and percutaneous techniques are steadily developing.
Session Title: RE-ALIGN: Dabigatran in patients with a mechanical heart valve
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