PRESS RELEASE: The Lancet publishes major study of Boehringer Ingelheim's novel oral direct thrombin inhibitor dabigatran etexil

The Lancet publishes major study of Boehringer Ingelheim's novel oral direct thrombin inhibitor dabigatran etexilate

New drug effective in extended thromboprophylaxis following total hip replacement surgery

For medical media, outside the US only

Ingelheim/Germany, 14 September 2007 – Boehringer Ingelheim today announced the publication of the RE-NOVATE study in the September 15 issue of The Lancet1. The results demonstrate that the oral direct thrombin inhibitor (DTI), dabigatran etexilate, administered once daily for a median of 33 days, was as effective as injectable enoxaparin in reducing the risk of venous thromboembolism (VTE) after total hip replacement surgery, with a similar low bleeding profile.

Bengt Eriksson, MD, PhD, Principal Investigator, Department of Orthopaedic Surgery, University Hospital Sahlgrenska/ Östra, Göteborg, Sweden said,
“Given the trend for shorter hospital stays following joint replacement surgery and longer duration of thromboprophylaxis, it is becoming increasingly important to have anticoagulant treatments available which are safe and easy to use in an out-patient setting. Based on the positive results demonstrated in the RE-NOVATE trial, once daily oral dabigatran etexilate may be an attractive alternative to other thromboprophylaxis regimens currently used to prevent VTE in patients undergoing hip replacement surgery.”

The RE-NOVATE trial demonstrated the efficacy of thromboprophylaxis with the novel oral anticoagulant dabigatran etexilate for the extended period (28 to 35 days) which current guidelines now recommend following hip replacement surgery2. Reported trends for increasing duration of prophylaxis and shorter hospital stays (decreasing to 3.7 days for total hip replacement)3 highlight the shifting burden of thromboprophylaxis from in- to out-of-hospital, and focus on the need for anticoagulant prophylaxis with a low rate of bleeding, that is well tolerated and easy to use as an outpatient. The ability to extend thromboprophylaxis in order to further reduce the risk of VTE beyond the hospital stay is limited with currently available anticoagulants (injection-only or requirement for coagulation monitoring), so a significant unmet medical need exists for a fixed dose oral anticoagulant with no requirements for monitoring.

Both dabigatran etexilate doses (220mg and 150mg) were non-inferior to 40mg enoxaparin for the primary efficacy outcome (a composite of total venous thromboembolic events, defined as deep-vein thrombosis - venographic or symptomatic - and/or symptomatic pulmonary embolism, and all-cause mortality during treatment) which occurred in 6.0% and 8.6% of the dabigatran etexilate 220 mg and 150mg groups versus 6.7% of the enoxaparin group. Importantly, a pre-specified secondary outcome of major venous thromboembolism and venous thromboembolism-related mortality (sometimes referred to as a more clinically relevant endpoint) was also similar between groups, occurring in 3.1% and 4.3% of the dabigatran etexilate 220 mg and 150 mg groups versus 3.9% of the enoxaparin group.

Dr. Andreas Barner, Vice-Chairman, Board of Managing Directors and Head of Corporate Board Division Pharma Research, Development and Medicine, Boehringer Ingelheim said,
“Guidelines recommending extended prophylaxis have proven to offer superior protection to patients from potentially life-threatening blood clots. We are pleased that our new oral direct thrombin inhibitor could offer the potential for physicians to ensure all patients receive effective thromboprophylaxis for the recommended treatment period.”

Anticoagulation-related bleeding is the primary safety concern during hip replacement surgery, since major bleeding into the replaced joint can have a detrimental impact on clinical outcome4. Few major bleeding events were reported, occurring at 2.0% and 1.3% for dabigatran etexilate 220 mg and 150mg groups versus 1.6% in the enoxaparin group. Notably, about half of all major bleeding events started before treatment. There were no major bleeding events reported after hospital discharge in the dabigatran etexilate groups.

Data from frequent liver function monitoring showed that the frequency of increases in liver enzyme concentrations with dabigatran etexilate is low during the entire extended treatment period, with alanine aminotransferase (ALT) elevation greater than three times the upper limit of normal occurring in slightly more patients in the enoxaparin group (3·0%, 3·0% and 5·3% of the 220 mg, 150 mg dabigatran etexilate and enoxaparin groups, respectively). Similarly, the incidence of acute coronary events was low, with no significant differences between all groups.

Dabigatran etexilate is a novel oral direct thrombin inhibitor which specifically and reversibly inhibits thrombin, the central and essential enzyme in the coagulation cascade responsible for thrombus (clot) formation5,6. It provides a predictable and consistent anticoagulant effect with no requirements for the coagulation monitoring that can limit the utility of existing oral treatments such as warfarin.

Please be advised
Dabigatran is an investigational compound. It has already been submitted to European authorities for approval in a first intended indication; primary VTE prevention following major orthopaedic surgery (such as total knee, total hip replacement). 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.

Note to editors
RE-NOVATE was a multinational, randomised, double-blind, non-inferiority, phase III trial involving 3494 patients undergoing total hip replacement surgery in the European Union, South Africa, and Australia. Patients were randomised to receive either oral dabigatran etexilate 150 mg or 220 mg once daily (half dose given on day of surgery, 1-4 hours post-operatively) or enoxaparin 40 mg once daily by subcutaneous injection started 12 hours before surgery. The median treatment duration was 33 days for all treatment groups, with 87% of patients receiving treatment for 28 to 35 days, and patients were followed-up for 3 months after surgery. Presence of VTE was determined by centrally adjudicated objective clinical testing for symptomatic events, and centrally adjudicated bilateral venograms on the last day of treatment for asymptomatic events. The methodological approach employed for the RE-NOVATE study is one that has been used in all studies conducted in this therapeutic area over the last 20 years. It is a well defined approach that has been accepted by clinicians, consensus guidelines and regulatory authorities for testing the efficacy of a new prophylactic anticoagulant.

About dabigatran etexilate
Dabigatran etexilate is a reversible oral direct thrombin inhibitor, a novel oral anticoagulant in advanced development. It specifically and reversibly inhibits thrombin, the central and essential enzyme in the coagulation cascade responsible for thrombus (blood clot) formation5,6.

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 coagulation monitoring, exhibits no drug-food interactions and has a low potential for drug-drug interactions7,8,9. Following oral administration the pro-drug dabigatran etexilate is rapidly converted to its active form, dabigatran7.

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-VOLUTIONâ„¢.

Further studies investigating dabigatran etexilate
The RE-VOLUTIONâ„¢ trial program 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 27,000 patients from Asia, Australia, Europe, the Americas, and South Africa. Patients will be divided into different treatment arms involving dabigatran etexilate compared with warfarin or enoxaparin.

RE-MODELâ„¢ investigated thromboembolism prevention after knee replacement surgery in more than 2,000 patients throughout the European Union, South Africa and Australia. It started in November 2004. RE-MOBILIZEâ„¢ investigated dabigatran etexilate for the same indication in a similar patient population in North America (> 2,600 patients).

RE-LYâ„¢, a phase III study also under the RE-VOLUTIONâ„¢ trial program, is investigating dabigatran etexilate as a potential treatment for stroke prevention in atrial fibrillation. Total enrolment for this study is targeted at >15,000 patients from almost 1,000 study centres worldwide. RE-COVERâ„¢ and RE-MEDYâ„¢ are investigating dabigatran etexilate for acute treatment and secondary prevention of venous thromboembolism.

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.