AMSTERDAM, The Netherlands – Treatment with the oral anticoagulant dabigatran etexilate resulted in a higher number of thromboembolic and bleeding events compared to warfarin treatment in patients with mechanical heart valve replacements, according to results of the RE-ALIGN (Randomized, phase II study to Evaluate the sAfety and pharmacokinetics of oraL dabIGatran etexilate in patients after heart valve replacemeNt) trial presented here at the European Society of Cardiology congress.
In December 2012 the European Medicines Agency and the U.S. Food and Drug Administration issued a contraindication for the drug in this patient population after RE-ALIGN, a phase II dose-validation trial, was voluntarily discontinued by the drug’s manufacturer Boehringer Ingelheim.
“The RE-ALIGN trial results do not support the use of dabigatran etexilate in patients with mechanical heart valves” confirmed lead investigator Frans Van de Werf, MD, PhD, from the Department of Cardiovascular Sciences at University Hospitals Leuven, Belgium.
RE-ALIGN, a prospective, randomized, open-label, blinded-endpoint trial was conducted at 39 centres in 10 countries, and was intended to validate a new dabigatran dosing regimen for the prevention of thromboembolic complications in patients with mechanical heart valves.
Two populations comprising a total of 252 patients were investigated; those who had undergone mechanical aortic and/or mitral valve replacements within 7 days after surgery and those who had received a mechanical mitral valve replacement at least 3 months earlier. Treatment with dabigatran etexilate for at least 12 weeks was compared to warfarin, which is the standard of care.
An interim analysis by the trial’s Data Safety Monitoring Board revealed a higher rate of strokes and major bleeding in patients on dabigatran (5.4% and 4.2% respectively), compared to those on warfarin (0% and 2.4%), although there were fewer deaths in patients treated with dabigatran (0.6% vs 2.4%). The results of the RE-ALIGN study will be published on line in the New England Journal of Medicine on September 1, 2013.
Dabigatran is currently approved in more than 95 countries worldwide for venous thromboembolism prophylaxis after hip- and knee-replacement surgery, but is not approved in the US for this indication. In the US and elsewhere, it is approved for reducing the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation.
“Dabigatran etexilate has been shown to be effective and safe in other indications, and there are several potential reasons for these results ” said Prof. Van de Werf.
“The presence of a mechanical heart valve is a clinical condition distinct from atrial fibrillation,” he explained. “In patients with a mechanical heart valve, coagulation activation and thrombin generation seem to be partially induced by the exposure of blood to the artificial surfaces of the valve leaflets and sewing ring (“contact thrombosis”), whereas in atrial fibrillation, under low blood flow conditions, thrombin generation is believed to be triggered by blood stasis and endothelial dysfunction.”
A likely explanation for why warfarin is more effective in the setting of mechanical valves is that “warfarin also inhibits synthesis of factor IX of the contact pathway while dabigatran exclusively inhibits thrombin,” he added.
If this hypothesis is correct, “the consequence could also be that factor Xa inhibitors such as rivaroxaban or apixaban won’t work for this indication and that patients with a mechanical heart valve will have to take warfarin or other vitamin K antagonists for the next 5 to 10 years,“ he said.
SOURCES OF FUNDING :
The study was funded by Boehringer Ingelheim.
Link to NEJM