Groundbreaking results in the RE-LY® trial - novel oral direct thrombin inhibitor dabigatran etexilate convincingly beats warfa

Groundbreaking results in the RE-LY® trial - novel oral direct thrombin inhibitor dabigatran etexilate convincingly beats warfarin - superior stroke reduction with less bleeding

Compared to well controlled warfarin, dabigatran etexilate showed:

  • Significant reduction in the risk of stroke and systemic embolism - including hemorrhagic strokes
  • Significantly lower bleeding - including life threatening and intracranial bleeding
  • Significant reduction in vascular mortality

Barcelona/Spain, 30 August 2009 - Boehringer Ingelheim today announced data from the landmark RE-LY® study - the largest atrial fibrillation (AF) outcomes trial ever conducted (18,113 patients in 44 countries worldwide) - presented for the first time at the European Society of Cardiology Congress and published online in the New England Journal of Medicine.1 Results show that dabigatran etexilate 150mg BID significantly reduces the risk of stroke and systemic embolism by 34% (p<0.001) in patients with atrial fibrillation compared to well-controlled warfarin without increasing the risk of major bleeding. Dabigatran etexilate 110mg BID clearly demonstrated similar reductions in stroke and systemic embolism compared to well controlled warfarin while delivering an impressive 20% reduction (p=0.003) in major bleeding rates compared to warfarin.

Similarly impressive are the results in key secondary and other outcomes, including superior reduction in hemorrhagic strokes with both 150mg and 110mg BID doses (RRR 74%, p<0.001 and RRR 69%, p<0.001, respectively), and a reduction in vascular mortality with the 150mg BID dose (RRR 15%, p= 0.04). For safety, both doses showed a superior reduction in life threatening, intracranial and total bleeding. Importantly, these benefits occurred without hepatoxicity.

"The results of dabigatran in RE-LY® exceeded all our expectations. We now have an oral treatment which offers superior protection from stroke with less bleeding and without the need for routine monitoring. In addition to protecting patients from strokes, we as physicians are especially concerned about life-threatening or disabling bleeding with warfarin due to its narrow therapeutic window. On top of the efficacy, dabigatran has shown equally impressive safety results, offering a wider safety margin" commented Professor Stuart Connolly, co-principal investigator of RE-LY® and Director, Division of Cardiology at The Population Health Research Institute, McMaster University, Hamilton, Canada.

Up to 3 million people worldwide suffer strokes related to AF each year,2-4 which tend to be especially severe and disabling,4 with half of people dying within one year.5 Taking into consideration only the potential of stroke reduction - and translating the RE-LY® results into clinical practice - dabigatran etexilate 150mg BID could prevent approximately 3,000 strokes per day worldwide compared to well controlled warfarin. The clinical and economic impact could be even greater when the reduction of severe or disabling bleeding is considered.

"For decades, an advance in this area has been eagerly awaited by patients and treating physicians alike" said Dr Sarah Jarvis, general practitioner in the UK. "Doctors and patients are looking forward to a new therapy that can effectively and predictably reduce their risk of stroke without imposing restrictions on their lives. The need for lifelong blood tests and dose adjustments and the numerous food and drug interactions with warfarin have had a signifcant adverse impact on patients' quality of life while placing many of them at continued risk of stroke and major bleeding. This could soon be a thing of the past."

Warfarin and other vitamin-K antagonists are highly effective when patients blood clotting value is maintained within the narrow therapeutic INR range of 2.0-3.0 as in a clinical trial setting.6 However in clinical practice - due to the well-known limitations with warfarin - only 51% of diagnosed patients with AF and at risk of stroke receive warfarin7 and fewer than half of these are controlled within the narrow therapeutic range.8

Potent antithrombotic effects are achieved with direct thrombin inhibitors by specifically blocking the activity of thrombin (both free and clot-bound), the central enzyme in the process responsible for clot (thrombus) formation. In contrast to vitamin-K antagonists, which variably act via different coagulation factors, dabigatran etexilate provides effective, predictable and consistent anticoagulation with a low potential for drug-drug interactions and no drug-food interactions, without the need for routine coagulation monitoring or dose adjustment.

"With the robust results from RE-LY® dabigatran etexilate, a compound from our own research and development, can revolutionize anticoagulant treatment for physicians and patients", commented Dr Andreas Barner, the chairman of the Board of Managing Directors of Boehringer Ingelheim. "We look forward to expeditiously submitting these results to regulatory authorities around the world so that new options can be made available for millions of patients with atrial fibrillation at risk of stroke "

Notes to editors
About RE-LY®: The largest AF outcome trial to date1,13
RE-LY® (Randomized Evaluation of Long term anticoagulant therapy) is a global, phase III, randomized trial of 18,113 patients enrolled in over 900 centres in 44 countries, investigating whether dabigatran etexilate (2 blinded doses) is as effective as well controlled warfarin - INR 2.0-3.0 - (open label) for stroke prevention. Patients with non-valvular AF and at least one other risk factor for stroke (i.e. previous ischemic stroke, transient ischemic attack, or systemic embolism, left ventricular dysfunction, age 75 years, age 65 years with either diabetes mellitus, history of coronary artery disease, or hypertension) were enrolled in the study for 2 years with a minimum of 1 year follow-up.

The primary endpoint of the trial was incidence of stroke (including haemorrhagic) and systemic embolism. Secondary outcome measures included all cause death, incidence of stroke (including hemorrhagic), systemic embolism, pulmonary embolism, acute myocardial infarction, and vascular death (including death from bleeding). Additional safety endpoints included major and minor bleeding events, intracranial bleeding, intracerebral haemorrhage, elevations in liver transaminases, bilirubin and hepatic dysfunction.

The statistical design of the study allowed for a testing of superiority to the comparator once the requirement of non-inferiority was established.

The RE-LY® trial is led by Co-Chairmen Dr. SalimYusuf, Professor of Epidemiology and Cardiology, Population Health Research Institute McMaster University, Hamilton, Canada and Dr. Lars Wallentin, Professor of Cardiology and Director of the Uppsala University, Sweden. Co-prinicipal investigators for the trial are Dr. Stuart Connolly, Professor of Medicine and Director, Division of Cardiology, at McMaster University Hamilton, Canada and Dr Michael Ezekowitz, Vice President and Professor, Lankenau Institute for Medical Research, Wynnewood, PA, USA. Population Health Research Institute in Hamilton, Ontario Canada independently managed the database and performed the primary data analysis.

About AF and stroke
AF is the most common heart rhythm condition, affecting around 1% of the total population, rising to 10% in people over the age of 80.9 A total of 6.3 million people in the US, Japan, Germany, Italy, France, UK and Spain were living with AF in 2007 and this is expected to increase to 7.5 million by 2017 primarily due to the ageing population.10 People with AF are at increased risk of blood clots, 11 which raises stroke risk up to seven times.12 Up to 3 million people worldwide suffer stroke related to AF each year.2-4 Strokes due to AF tend to be severe, with an increased likelihood of death (20%), and disability (60%), with resultant societal costs and burden to the healthcare system.4 AF alone is associated with a cost of up to €13.5 billion across the European Union.12

About Pradaxa® (dabigatran etexilate)
Pradaxa® is at the forefront of a new generation of oral anticoagulants - direct thrombin inhibitors (DTIs) - targeting a high unmet medical need in the prevention and treatment of acute and chronic thromboembolic diseases. Pradaxa® has already been approved and is widely utilized in over 40 countries for the primary prevention of venous thromboembolic events (blood clots) in adults who have undergone elective total hip or elective total knee replacement surgery.

About RE-VOLUTION®
RE-LY® is part of Boehringer Ingelheim's extensive RE-VOLUTION® clinical trial program - evaluating the efficacy and safety of dabigatran etexilate against current standard therapy in over 38,000 patients. Beyond RE-LY® the RE-VOLUTION® trial program encompasses studies in:

Primary prevention of venous thromboembolism (VTE)
Treatment of acute VTE - results expected in 2009 from the RE-COVERTM trial
Secondary prevention of VTE in the RE-MEDYTM and RE-SONATETM trials
Prevention of cardiac events in patients with acute coronary syndrome in the RE-DEEMTM trial.
Please be advised
This release is from the Corporate Headquarters of Boehringer Ingelheim and is intended for 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 Boehringer Ingelheim
The Boehringer Ingelheim group is one of the world's 20 leading pharmaceutical companies. Headquartered in Ingelheim, Germany, it operates globally with 138 affiliates in 47 countries and 41,300 employees. Since it was founded in 1885, the independent, family-owned company has been committed to researching, developing, manufacturing and marketing novel products of high therapeutic value for human and veterinary medicine.

In 2008, Boehringer Ingelheim posted net sales of 11.6 billion euro while spending one fifth of net sales in its largest business segment Prescription Medicines on research and development.

 


References:
1 Connolly SJ, Ezekowitz MD, Yusuf S. Dabigatran versus Warfarin in Patients with Atrial Fibrillation. N Eng J Med 2009; 361. Published online 30 Aug 2009.
2 Atlas of Heart Disease and Stroke, World Health Organization, September 2004. Viewed July 2009 at http://www.who.int/cardiovascular_diseases/en/cvd_atlas_15_burden_stroke.pdf
3 Wolf PA, Abbott RD, Kannel WB. Atrial fibrillation as an independent risk factor for stroke: the Framingham Study. Stroke 1991:22(8);983-8
4 Lin HJ, Wolf PA, Kelly-Hayes M, et al. Stroke severity in atrial fibrillation: the Framingham study. Stroke 1996;27:1760-4
5 Marini C, De Santis F, Sacco S, et al. Contribution of atrial fibrillation to incidence and outcome of ischemic stroke: results from a population-based study. Stroke 2005;36:1115-9
6 Hart RG, Pearce LA, Aguilar MI, et al. Meta-Analysis: antithrombotic therapy to prevent stroke in patients who have non-valvular atrial fibrillation. Ann Intern Med 2007;146:857-67
7 Hylek EM, DAntonio J, Evans-Molina C, et al. Translating the results of randomized trials into clinical practice. The challenge of warfarin candidacy among hospitalized elderly patients with atrial fibrillation. Stroke 2006;37:1075-80
8 Samsa GP, Matchar DB, Goldstein LB, et al. Quality of anticoagulation management among patients with atrial fibrillation: results of a review of medical records from 2 communities. Arch Intern Med 2000;160:967-73
9 Stewart S, Murphy N, Walker A, et al. Cost of an emerging epidemic: an economic analysis of atrial fibrillation in the UK. Heart 2004;90:286-92
10 Benyoucef S, Hughes M, Mehta N. Atrial Fibrillation. Decision Resources, December 2008 http://www.decisionresources.com/stellent/groups/public/documents/abstract/09cv03atfib-abstract.hcsp
11 Lip GHY. Does atrial fibrillation confer a hypercoagulable state? Lancet 1995;346:1313-4
12 Fuster V, Rydn LE, Cannom DS, Crijns HJ, Curtis AB, Ellenbogen KA, Halperin JL, Le Heuzey JY, Kay GN, Lowe JE, Olsson SB, Prystowsky EN, Tamargo JL, Wann S. ACC/AHA/ESC 2006 guidelines for the management of patients with atrial fibrillation executive summary. Circulation 2006;114:700-752
13 Ezekowitz MD, Connolly S, Parekh A, Reilly PA, Varrone J, Wang S, Oldgren J, Themeles E, Wallentin L, Yusuf S. Rationale and design of RE-LY: Randomized evaluation of long-term anticoagulant therapy, warfarin, compared with dabigatran. Am Heart J 2009;157: 805-810

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