Boehringer Ingelheim has completed enrolment of the landmark RE-LY trial to evaluate the long-term efficacy and safety of their novel, oral direct thrombin inhibitor dabigatran etexilate (Pradaxa) for the prevention of stroke and systemic embolism in patients with atrial fibrillation (AF).
The RE-LY (Randomised Evaluation of Long Term Anticoagulant Therapy) trial is comparing two blinded doses of oral dabigatran etexilate with the current standard therapy, warfarin (target INR 2.0-3.0) in patients with non-valvular atrial fibrillation who are at moderate to high risk of stroke. Currently, the best available treatment to prevent stroke in these patients is the vitamin K antagonist, warfarin. Although the efficacy of warfarin is well established, its use is often limited due to its inherent drawbacks. Warfarin is associated with an unpredictable dose response and requires careful individual dosing and costly anticoagulation monitoring. It has a slow onset and offset of action and its metabolism is affected by diet, common drugs and genetic polymorphisms. It is estimated that warfarin is currently prescribed for only half of all eligible patients.
RE-LY is the largest stroke prevention in AF trial conducted to date, with 18,114 patients, in 1,000 centres in 44 countries worldwide enrolled between December 2005 and December 2007. Currently, over 10,000 patients have been treated for at least 6 months with final study results expected to be reported in early 2009.
Dr. Salim Yusuf, Professor of Epidemiology and Cardiology and head of the study coordinating centre at McMaster University in Hamilton, Canada, said, "Patient enrolment in RE-LY has exceeded our original expectations by far, and illustrates the urgent need for a safe, effective oral anticoagulant which does not require routine monitoring."
Atrial fibrillation is the most common sustained cardiac rhythm disturbance affecting 6 of individuals over the age of 65 and 10 per cent over the age of 80. Atrial fibrillation is a leading risk factor for stroke and, despite warfarin being available as an effective treatment option, it accounts for one in six of the 15 million strokes worldwide every year. Over 5 million people die as a result of stroke and another 5 million are left permanently disabled worldwide every year. Stroke is associated with a heavy cost burden of €34 billion in Europe, largely due to hospitalisation and the need for long-term care. A recent UK economic analysis evaluated the direct cost of AF as €655 million in 2000, almost one per cent of total National Health Service expenditure.
The safety and efficacy of dabigatran etexilate in the prevention of venous thromboembolism following knee replacement and hip replacement surgery has already been published and an application for registration in Europe was submitted in February 2007. The RE-LY trial builds on existing evidence of the safety and efficacy of twice daily 150 mg dabigatran etexilate in AF patients at risk of stroke from the phase II PETRO and PETRO extension study. Over 10,000 patients have completed phase II and III trials to date, with dabigatran etexilate exhibiting a good safety profile. No evidence of liver problems for dabigatran etexilate was observed in these phase II studies, and in all phase III trials reported to date, patients with liver enzyme elevations > 3X ULN were infrequent and comparable to enoxaparin. To date, the RE-LY study has not been associated with any specific safety concerns and the planned reduction in frequency of hepatic monitoring was recently endorsed by the independent study safety committee. Completion of enrolment for RE-LY is the latest milestone in the extensive re-volution clinical trial programme investigating dabigatran etexilate in more than 34,000 patients for the prevention and treatment of a range of thromboembolic conditions and stroke.
Dr Andreas Barner, Member of the Board, Boehringer Ingelheim and responsible for Research, Development and Medicine said: "Our investment in landmark trials such as RE-LY demonstrates Boehringer Ingelheim's ongoing commitment to improving future treatment options for patients with cardiovascular conditions. Dabigatran etexilate is the most advanced novel oral anticoagulant in clinical development and we are confident it will fulfill the unmet medical need for a safe and effective oral treatment for the prevention of thrombotic events in a variety of different clinical conditions."
RE-LY™ is a global, multi-centre, non-inferiority, randomised trial comparing two blinded doses of dabigatran etexilate with open label warfarin in patients with non-valvular atrial fibrillation and at least one other major risk factor for stroke. The median treatment duration is two years with a minimum of 1 year follow-up.
Primary outcomes of the trial will measure the incidence of stroke (including haemorrhagic) and systemic embolism. Secondary outcome measures include all death, incidence of stroke (including hemorrhagic), systemic embolism, pulmonary embolism, acute myocardial infarction, or vascular deaths (including deaths from bleeding).
Dabigatran etexilate is a reversible oral direct thrombin inhibitor, a novel oral anticoagulant in late stage clinical development. It specifically and reversibly inhibits thrombin, the central and essential enzyme in the coagulation cascade responsible for thrombus (blood clot) formation. Dabigatran etexilate, developed by Boehringer Ingelheim, is currently being evaluated in a number of thromboembolic disease indications in an extensive, global clinical trial programme entitled re-volution.
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