Study shows dabigatran etexilate, a new oral anticoagulant is effective and safe in preventing thromboembolic disease after orthopaedic surgery

11  December 2006
For medical media, outside the US only

Ingelheim/Germany, 11 December, 2006 - In future, the prevention of venous thromboembolism (VTE) in thousands of patients after knee-replacement surgery may become much easier with a new agent in capsule form, called dabigatran etexilate. Results from the RE-MODEL™ trial demonstrate that dabigatran etexilate (from Boehringer Ingelheim research and development) is as effective as the low molecular-weight heparin, enoxaparin, in the primary prevention of VTE in patients undergoing elective knee replacement surgery. No difference in bleeding rates was observed between dabigatran etexilate and enoxaparin in the RE-MODEL trial. In contrast to standard clot-preventing therapies like low molecular weight heparin, which are given as a series of subcutaneous injections, dabigatran etexilate is given orally from early in the postoperative period, needs no coagulation monitoring and no weight-adjusted dosing and therefore could offer greater convenience. These data were presented at the 48th Annual Meeting of the American Society of Hematology, in Orlando, Florida today.¹

Bengt Eriksson, MD, PhD, Department of Orthopaedic Surgery, University Hospital Sahlgrenska / Östra, Gothenburg, Sweden said, “A new thromboprophylaxis agent which is given as a pill rather than the standard injection has great potential to decrease demands on hospital time and resources.”

Results of the RE-MODEL trial showed that both oral doses of dabigatran etexilate were as good as injected enoxaparin at reducing the risk of thrombo-embolic disease. For the primary efficacy endpoint of total VTE and all cause mortality, results were similar between all groups, occurring in 40.5 percent, 36.4 percent and 37.7 percent of patients assigned to dabigatran etexilate 150 or 220mg once daily or enoxaparin, respectively. Proximal DVT and/or PE occurred in 3.8 percent, 2.6 percent and 3.5 percent of patients receiving dabigatran etexilate 150 or 220 mg or enoxaparin, respectively. Total VTE includes all thrombotic events including distal DVT as well as the less common but clinically more relevant, potentially life threatening proximal DVT and PE.

Safety was evaluated for all 2076 patients receiving study treatment and no difference in bleeding rates was observed between the treatment groups; the rate of major bleeding was 1.3 percent, 1.5 percent and 1.3 percent of patients receiving dabigatran etexilate 150 or 220 mg or enoxaparin. Elevated levels of alanine aminotransferase (ALT>3xULN) as measured by liver function tests (LFTs) occurred in 3.7 percent, 2.8 percent and 4.0 percent of the patients treated with 150 and 220mg dabigatran etexilate or enoxaparin during the study.

Dr. Andreas Barner, Member of the Board of Boehringer Ingelheim and responsible for Research, Development and Medicine worldwide said, “We are pleased that our new oral direct thrombin inhibitor, dabigatran, has demonstrated it could fulfil the current unmet medical need for an anticoagulant that can easily be taken by orthopaedic patients also once they have left hospital, thereby continuing to protect them from a life-threatening thrombus.”

Patients undergoing hip and knee replacement surgery are at particularly high risk of developing VTE.² In fact, VTE is one of the most common causes of hospital readmission following orthopaedic surgery.² Without preventive treatment, as many as 80 percent of orthopaedic surgery patients would develop DVT (including asymptomatic thrombi), and risk developing PE.² The late consequences of DVT could also represent a serious clinical problem – up to 60 percent of patients who have a DVT can develop chronic venous insufficiency (post-thrombotic syndrome)³– symptoms of which can range from oedema and pain to chronic leg ulcers and leg deformity.

RE-MODEL was a multinational (EU, South Africa, Australia) randomised, double-blind, trial involving 2,076 patients, and compared dabigatran etexilate with enoxaparin in the prevention of VTE in patients undergoing total knee replacement surgery. Patients were randomised to either oral dabigatran etexilate 150 or 220mg once daily (half dose given on day of surgery, 1-4 hours post-operatively) or enoxaparin 40mg once daily by subcutaneous injection started 12 hours before surgery. The study treatment period was 6-10 days and patients were followed up 3 months after the operation. 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.

About dabigatran etexilate
Dabigatran etexilate is an oral direct thrombin inhibitor, a new oral anticoagulant in advanced development. It specifically and reversibly inhibits thrombin, the key enzyme for blood clot formation. It can be given in a fixed oral dose, has a rapid onset of action, provides a predictable and consistent anticoagulation effect without the need for coagulation monitoring and has a low potential for drug-drug interactions and no drug-food interactions. Following oral administration the pro-drug dabigatran etexilate is rapidly converted to its active form, dabigatran.

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™ .

About RE-VOLUTION™
The RE-MODEL trial is part of RE-VOLUTION™, a multi-centre, randomized global trial programme initiated by Boehringer Ingelheim in thromboembolic diseases investigating the novel oral direct thrombin inhibitor dabigatran etexilate. The trials will involve more than 27,000 patients from Asia, Australia, Europe, the Americas, and South Africa. RE-LY™, the largest trial in the RE-VOLUTION programme which started in December 2005, is investigating the efficacy and safety of dabigatran etexilate in preventing stroke in patients with atrial fibrillation. Total enrolment in this study alone is targeted at 15,000 patients from almost 1,000 study centres worldwide.

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 45 countries and more than 37,000 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 2005, Boehringer Ingelheim posted net sales of 9.5 billion euro while spending nearly one fifth of net sales in its largest business segment Prescription Medicines on research and development.

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