Boehringer Ingelheim Announces Enrolment Completion Of The Largest Atrial Fibrillation Outcomes Trial - The RE-LY(TM) Study

Main Category: Cardiovascular / Cardiology
Also Included In: Clinical Trials / Drug Trials
Article Date: 18 Jan 2008 - 1:00 PDT

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Boehringer Ingelheim announced the enrolment completion 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). 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.

The RE-LY™ (Randomized 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.1 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.1

Dr. Salim Yusuf, Professor of Epidemiology and Cardiology and head of the study coordinating center at McMaster University in Hamilton, Canada, stated that: "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 disturbance2 affecting 6% of individuals over the age of 65 and 10% over the age of 80.3 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.4 Over 5 million people die as a result of stroke and another 5 million are left permanently disabled worldwide every year.4 Stroke is associated with a heavy cost burden of €34 billion in Europe, largely due to hospitalisation and the need for long-term care.5 A recent UK economic analysis evaluated the direct cost of AF as €655 million in 2000, almost one percent of total National Health Service expenditure.6

The safety and efficacy of dabigatran etexilate in the prevention of venous thromboembolism following knee replacement and hip replacement surgery has already been published7,8, 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,9 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 of 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™ methodology

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). The trial is led by Dr. Salim Yusuf, Professor of Epidemiology and Cardiology, Population Health Research Institute McMaster University, Hamilton, Canada; Dr. Lars Wallentin, Professor of Cardiology and Director of the Uppsala University, Sweden; Dr. Michael Ezekowitz, Vice President and Professor, Lankenau Institute for Medical Research, Wynnewood, PA, USA; Dr. Stuart Connolly, Professor of Medicine and Director, Division of Cardiology at McMaster University, Hamilton, Canada.

Please be advised

Dabigatran etexilate is an investigational compound. It has already been submitted to European authorities for approval in a first intended indication; primary VTE prevention following total hip or knee replacement surgery. This release is from the Corporate Headquarters of Boehringer Ingelheim and is intended for all international markets. This being the case, please be aware that there may be some differences between countries regarding specific medical information including licensed uses. Please take account of this when referring to the material.

About dabigatran etexilate

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.10,11

Dabigatran etexilate can be given in a fixed oral dose, has a rapid onset and offset of action, provides a predictable and consistent anticoagulation effect without the need for routine coagulation monitoring, exhibits no drug-food interactions and has a low potential for drug-drug interactions.10,11 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™.

The RE-VOLUTION™ trial programme

The RE-VOLUTION™ trial programme is designed to investigate the novel oral direct thrombin inhibitor dabigatran etexilate as a potential treatment, prevention and prophylaxis for several thromboembolic disease conditions. It is expected to involve more than 34,000 patients from Asia, Australia, Europe, the Americas, and South Africa. Patients will be divided into different treatment arms involving dabigatran etexilate compared with current standard therapy.

Completed trials, RE-NOVATE™ and RE-MODEL™ have demonstrated the efficacy of dabigatran etexilate in the primary prevention of venous thromboembolism following orthopaedic surgery.7,8 In addition to stroke prevention in AF, ongoing trials are evaluating the efficacy and safety of dabigatran etexilate in the treatment of acute VTE, secondary prevention of VTE, and in acute coronary syndrome following a myocardial infarction (MI) with the aim of reducing the risk of further cardiovascular events.

About Boehringer Ingelheim

The Boehringer Ingelheim group is one of the world's 20 leading pharmaceutical companies. Headquartered in Ingelheim, Germany, it operates globally with 144 affiliates in 47 countries and more than 38,000 employees. Since it was founded in 1885, the privately-owned company has been committed to researching, developing, manufacturing and marketing novel products of high therapeutic value for human and veterinary medicine.

In 2006, Boehringer Ingelheim posted net sales of 10.5 billion euro while spending nearly one fifth of net sales in its largest business segment, Prescription Medicines, on research and development.

Related links:

Information about global clinical trials sponsored by Boehringer Ingelheim

Fact sheet on Atrial Fillibration and Stroke

References:

1. Douketis J. Review: warfarin prevents stroke in non-rheumatic atrial fibrillation but has a higher risk for haemorrhage than other agents. Evidence-Based Medicine 2001; 6:150 Segal JB, McNamara RL, Miller MR, et al. Anticoagulants or antiplatelet therapy for non-rheumatic atrial fibrillation and flutter. Cochrane Database Syst Rev 2001;(1):CD001938 (latest version 29 Nov 2000).

2. Fuster V, Rydén LE, Asinger RW et al. ACC/AHA/ESC Guidelines for the Management of Patients with Atrial Fibrillation: Executive Summary A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the European Society of Cardiology Committee for Practice Guidelines and Policy Conferences (Committee to Develop Guidelines for the Management of Patients With Atrial Fibrillation) Developed in Collaboration with the North American Society of Pacing and Electrophysiology. Circulation 2001;104:2118--50

3. Feinberg WM, Blackshear JL, Laupacis A et al. Prevalence, age distribution, and gender of patients with atrial fibrillation: analysis and implications. Arch Intern Med 1995; 155: 469-73

4. http://www.who.int/cardiovascular_diseases/en/cvd_atlas_15_burden_stroke.pdf

5. http://www.heartstats.org/datapage.asp?id=4545

6. Stewart S, Murphy N, Walker A et al. Cost of an emerging epidemic: an economic analysis of atrial fibrillation in the UK. Heart 20054;90:286-292

7. Eriksson BI, Dahl OE, Kurth AA et al. Oral dabigatran etexilate vs. subcutaneous enoxaparin for the prevention of venous thromboembolism after total knee replacement: the RE-MODEL randomized trial. Journal of Thrombosis and Haemostasis 2007;5:2178-2185

8. Eriksson BI, Dahl OE, Rosencher N et al. Dabigatran etexilate compared with enoxaparin for the extended prevention of venous thromboembolism following total hip replacement. The Lancet 2007;370:949-956

9. Ezekowitz MD, Reilly PA, Nehmiz G et al. Dabigatran With or Without Concomitant Aspirin Compared With Warfarin Alone in Patients With Nonvalvular Atrial Fibrillation (PETRO Study). American Journal of Cardiology 2007;100(9):1419-26

10. Stangier J, Rathgen K, Staehle H et al. The pharmacokinetics, pharmacodynamics and tolerability of dabigatran etexilate, a new oral direct thrombin inhibitor, in healthy male subjects. British Journal of Clinical Pharmacology 2007;64:292-303

11. Sorbera LA, Bozza J, Castaner J et al. Dabigatran/dabigatran etexilate: prevention of DVT, prevention of ischemic stroke, thrombin inhibitor. Drugs Future 2005;30:877-885

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