Milestone results assessing novel anticoagulation dabigatran etexilate versus warfarin in the treatment of acute deep vein thrombosis and pulmonary embolism to be presented at ASH 2009

Ingelheim, Germany, 2 December 2009 - Boehringer Ingelheim will announce positive results from the landmark RE-COVER™ study at the 51st Annual Meeting of the American Society of Hematology on 6 December 2009. The RE-COVER™ study assessed dabigatran etexilate in a head-to-head comparison with the current standard in care, warfarin, for the treatment of acute venous thromboembolism (VTE), enabling healthcare professionals to make direct comparisons and care based value judgements.¹

VTE includes deep vein thrombosis (DVT) and its potentially fatal acute complication pulmonary embolism (PE) and affects around 1.5 million Europeans² and 3 million Americans³. It is the third most prevalent cardiovascular disease and places a significant burden on healthcare systems.^4,5 Each year VTE kills around half a million people in the EU - more than double the total number of deaths from AIDS, breast cancer, prostate cancer and traffic accidents combined.² Due to the many restrictions and complications of current therapy with warfarin there is a huge need for a better therapeutic alternative.

The RE-COVER™ study involved 2,539 pateints with acute VTE and investigated the effects of the oral direct thrombin inhibitor dabigatran etexilate (150 mg twice daily in a fixed dose) with warfarin (dose adjusted to an International Normalized Ratio, INR, of 2.0 and 3.0), each given for 6 months. Primary efficacy endpoints for the RE-COVER™ study included recurrent symptomatic VTE and deaths related to VTE. Safety endpoints included incidence of bleeding, acute cororonary syndrome, liver function tests and adverse events.¹

The data will be presented within the main plenary scientific sessions at 14:00 Eastern Standard Time on Sunday 6 December in Hall F, Ernest N. Morial Convention Centre, New Orleans, Louisiana, USA.

The positive results from the RE-COVER™ study follow closely behind the groundbreaking results of the RE-LY® study, which involved over 18,000 patients.⁶ With existing results from the RE-LY® study, the RE-COVER™ study further expands the growing body of evidence supporting the efficacy and safety of dabigatran etexilate.^1,6,7,8

Notes to editor:
About RE-COVER™¹
RE-COVER™ is a global, phase III, randomised, double blind, parallel-group study evaluating whether oral dabigatran etexilate (150 mg BID) is as effective and safe (non-inferior to) warfarin (INR 2.0-3.0) for 6 months treatment of acute symptomatic venous thromboembolism, following initial treatment (5-11 days) with a parenteral anticoagulant. The study involved 2,539 patients. The primary efficacy endpoint was a composite of recurrent symptomatic venous thromboembolism (VTE) and deaths related to VTE. The secondary efficacy endpoints were: composite of recurrent symptomatic VTE and all deaths; symptomatic DVT; symptomatic PE; deaths related to VTE and; all deaths. Safety endpoints included: incidence of bleeding events; adverse events; vital signs, laboratory measures, especially liver function tests (LFT); and acute coronary syndrome (ACS).

About VTE
Venous thromboembolism (VTE) refers to blood clots (thrombi) which originate in the veins, and includes deep vein thrombosis (DVT) and its potentially fatal acute complication pulmonary embolism (PE). PE is a leading cause of in-hospital deaths and accounts for approximately 10% of all hospital deaths (although it accounts for only 1% of all admissions).⁹ Up to half of people with DVT may develop the chronic condition post thrombotic syndrome and 4% may develop chronic thromboembolic pulmonary hypertension, both of which can cause substantial illness and a high economic burden.10,11

There is a need for an effective, safe and convenient oral anticoagulant with predictable effects, fewer drug interactions, no food interactions and no requirement for routine coagulation monitoring.

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 utilised in over 40 countries for the primary prevention of VTE in adults who have undergone elective total hip or elective total knee replacement surgery and is under expeditious review with the regulatory authorities for stroke prevention in atrial fibrillation.

About RE-LY®: The largest AF outcome trial to date^6,12
The global, phase III, randomized RE-LY® study involving 18,113 patients in over 900 centres across 44 countries showed that dabigatran etexilate 150 mg 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 110 mg 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.

Addendum: These groundbreaking results were shown in RE-LY®, a PROBE (prospective, randomized, open-label with blinded endpoint evaluation) trial designed to compare two fixed doses of the oral direct thrombin inhibitor dabigatran (110 mg and 150 mg bid) each administered in a blinded manner, with open label warfarin.

Similarly impressive were the results in key secondary and other outcomes, including superior reduction in hemorrhagic strokes with both 150mg and 110 mg BID doses (RRR 74%, p<0.001 and RRR 69%, p<0.001, respectively), and a reduction in vascular mortality with the 150 mg 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 hepatotoxicity.

The RE-LY® study aimed to investigate whether dabigatran etexilate (2 blinded doses) was 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 RE-VOLUTION®

RE-COVER™ 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-COVER™ the RE-VOLUTION® trial program encompasses studies in:

• Primary prevention of venous thromboembolism (VTE) – RE-NOVATE®, RE-NOVATE® II, RE-MODEL® and RE-MOBILIZE®
• Treatment of venous thromboembolism (VTE) in RE-COVER™ II
• Prevention of stroke in atrial fibrillation (AF) – results of RE-LY® were presented at the ESC in August 2009
• Secondary prevention of ACS – results of the phase II RE-DEEM were presented at the AHA in November 2009
• Secondary prevention of VTE in the RE-MEDY™ and RE-SONATE™ trials

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About Boehringer Ingelheim
The Boehringer Ingelheim group is one of the worlds 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.