38/09 Milestone results in RE-COVER TM study

06 décembre 2009

Novel oral direct thrombin inhibitor dabigatran etexilate - as effective as well controlled warfarin with less bleeding in treatment of acute venous thromboembolism

Compared to well controlled warfarin, dabigatran etexilate showed: 1

• Equal efficacy in the reduction of recurrent venous thromboembolism (VTE) and deaths related to VTE 
  
• Significantly less bleeding events 
  
• Confirmed liver safety

Boehringer Ingelheim today announced very positive results from their landmark RE-COVER^TM study - the most advanced trial programme assessing a novel oral anticoagulant in development for acute venous thromboemolism (VTE) treatment - presented at the American Society of Hematology Annual Meeting 1 and published in the New England Journal of Medicine online.

The oral direct thrombin inhibitor, dabigatran etexilate (150 mg twice -daily, BID), showed equal efficacy compared to well-controlled warfarin at preventing recurrent VTE (2.4% vs. 2.1%, hazard ratio 1.10, 95% CI 0.65 to 1.84, p<0.001 for prespecified non-inferiority margin). For safety, dabigatran etexilate demonstrated a significant 37% reduction in major or clinically relevant non-major bleeding (p=0.002). Major bleeding  was comparable between dabigatran etexilate (20 patients, 1.6%) and warfarin (24 patients, 1.9%). For any bleeds, dabigatran etexilate showed a significant 29% reduction (p=0.0002) compared to warfarin.  These outstanding results were achieved without any evidence of liver problems. 1

"The results of RE-COVER^TM are a long-awaited breakthrough in the treatment of VTE; not only does dabigatran etexilate offer an effective therapy to prevent recurrent VTE it does so with less bleeding than warfarin." commented Dr Sam Schulman, Principal Investigator, Department of Medicine, McMaster University, Hamilton, Canada. "Warfarin is a highly effective therapy when well-controlled within its narrow therapeutic range, as in clinical trials, but in the real world sufficient control is rarely achieved and maintained, leaving patients poorly protected from VTE or at risk of bleeding. With dabigatran, we have a therapy that protects our patients effectively and safely, without need for frequent laboratory monitoring and dose changes."

VTE - which includes deep vein thrombosis (DVT) and its potentially fatal acute complication pulmonary embolism (PE) - is the third most common cardiovascular disease worldwide (after coronary heart disease and stroke). 2 VTE affects around 1.5 million Europeans 3 and 3 million Americans 4 each year and kills more than double the number of people than AIDS, breast cancer, prostate cancer and traffic accidents combined in Europe. 3

Earlier this year, the RE-LY® study (18,113 patients in 44 countries worldwide) showed groundbreaking results for dabigatran etexilate convincingly beating warfarin in stroke prevention in atrial fibrillation. 5

"The results of the RE-COVER^TM trial are very encouraging news for VTE patients." said Eve Knight, Chief Executive of the patient organisation AntiCoagulation Europe. "Although warfarin is an effective treatment it imposes many restrictions on patients' lives as they require regular blood tests, dose adjustments and have limitations placed on the food and drink they can consume. In addition, the unpredictability of warfarin places patients at risk of recurrent clots or increased bleeding if it is not sufficiently monitored. AntiCoagulation Europe therefore welcomes the news that dabigatran may offer a safer, more simple alternative to warfarin for the treatment of potentially life-threatening blood clots." Current guidelines recommend treating acute VTE with anticoagulants to prevent new blood clots from forming and old ones from getting any bigger, as well as reducing the risk of both post thrombotic syndrome and thromboembolic pulmonary hypertension. These chronic diseases can cause substantial illness and a high economic burden. 6,7 Current standard treatment involves the short-term use of a low molecular weight heparin for therapy initiation in hospital with subsequent continuation of treatment with a vitamin K antagonist (VKA, such as warfarin). 8 This provides a three-fold reduction in recurrence of VTE and extended duration of therapy reduces this risk by 50%. 9,10

While VKAs are highly effective anticoagulants, they have multiple limitations which make maintaining patients within the narrow therapeutic INR range of 2.0-3.0 challenging, requiring frequent monitoring to ensure patient safety and efficacy. Even with close monitoring, as in a clinical trial, patients only spend half their time within this range and this tends to be even lower in the "real-world setting". 11 Outside of the narrow range, the rate of bleeding is 44% and the rate of clotting is 48%. 12

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

In total, four trials involving 8,900 patients are exploring dabigatran etexilate in VTE treatment: RE-COVER^TM and RE-COVER^TMII in acute VTE and RE-MEDY^TM and RE-SONATE^TM in prevention of secondary VTE. The results of RE-COVER^TM and the very favourable results of RE-LY5 add to the growing database of evidence supporting the efficacy and safety of dabigatran etexilate across a wide range of acute and chronic thromboembolic disorders from the RE-VOLUTION® clinical development programme involving over 38,000 patients.

"Following the outstanding results from the RE-LY® trial, these impressive new data mean dabigatran etexilate has the potential to benefit even more patients and overtake warfarin as the treatment of choice", commented Dr Andreas Barner, the chairman of the Board of Managing Directors of Boehringer Ingelheim. "We look forward to submitting these results to the regulatory authorities so that the results of this landmark trial can be put into a real world setting."

Notes to editors

About RE-COVER^TM1
RE-COVER^TM is a global, phase III, randomized, double blind, parallel-group study evaluating whether oral dabigatran etexilate (150 mg BID) is as effective and safe as (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 composite of recurrent symptomatic 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). VTE has been estimated to be the third most common cardiovascular disorder after coronary heart disease and stroke. 2 It affects approximately 1.5 million Europeans 3 and 3 million Americans 4 each year and kills more than double the number of people than AIDS, breast cancer, prostate cancer, and traffic accidents combined in Europe. 3 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). 13 Up to half of people with DVT may develop the chronic condition post thrombotic syndrome (PTS) and 4% may develop chronic thromboembolic pulmonary hypertension, both of which can cause substantial illness and a high economic burden. 6,7 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.

About RE-LY®: The largest AF outcome trial to date 5,14
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.

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^TM 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^TM 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^TM 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^TM and RE-SONATE^TM trials

References

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