"The positive efficacy and safety data for dabigatran etexilate in preventing potentially life-threatening VTE after hip and knee replacement surgery signals a therapeutic advance which will be welcomed by both physicians and patients in the future."
Details of the RENOVATE trial
Results of the RE-NOVATE trial showed that both dose strengths of oral dabigatran etexilate were proven as effective and safe as injected enoxaparin at reducing the risk of thromboembolic disease after orthopaedic surgery when given for the extended average time period of 33 days. For the primary efficacy endpoint of total VTE and death from all-causes, results were similar between all groups, occurring in 8.6%, 6.0%, and 6.7% of patients assigned to 150 mg or 220 mg dabigatran etexilate once daily or 40 mg enoxaparin once daily, respectively. Safety was evaluated for 3463 patients receiving study treatment and no significant difference in major bleeding rates was observed between the groups (1.3%, 2.0%, and 1.6% respectively). The incidence of liver enzyme elevations and acute coronary events during the treatment or during the follow-up period did not differ significantly between the groups.
The total annual burden of VTE across the 25 member states of the EU (population of 454 million) has been estimated to be 640,000 symptomatic deep vein thromboses (DVT) and 383,000 pulmonary emboli (PE), and VTE-related deaths estimated at almost 500,000 annually [ii]. Current guidelines recommend that patients undergoing hip replacement surgery receive extended thromboprophylaxis (treatment to prevent VTE) with low molecular weight heparins (LMWH) such as enoxaparin or vitamin K antagonists (VKA) such as warfarin for up to 28 to 35 days [iii] following surgery; yet current hospital stays can be less than 5 days3. Although effective, both LMWHs and VKAs have drawbacks which can limit their use, especially outside the hospital setting. Unlike enoxaparin, which is only available as a subcutaneous injection, dabigatran etexilate is given as a capsule from early in the postoperative period, and does not require the frequent coagulation monitoring and dose adjustment of warfarin.
Dr. Andreas Barner, Member of the Board of Boehringer Ingelheim and responsible for Research, Development and Medicine worldwide said, "Extending prophylaxis has proven to offer superior protection to patients from potentially life-threatening blood clots. We are pleased that our new oral thrombin inhibitor offers the potential for physicians to ensure all patients receive effective and safe thromboprophylaxis for the recommended treatment period."
|
|
|
|
|
Results of the pooled analysis
Also presented at ISTH was a pre-specified pooled analysis of major VTE and VTE related death after major orthopaedic surgery across more than 8000 randomized patients that were included in the phase III primary VTE prevention programme (RE-MODELTM, RE-MOBILIZETM and RE-NOVATE studies) [iv]. The pooled analysis concluded that dabigatran etexilate was efficacious and comparable to enoxaparin in the prevention of major VTE and VTE related mortality after both knee and hip replacement. Major VTE rates for both doses of dabigatran etexilate were similar to enoxaparin - major VTE and VTE related death occurred in 3.8%, of the 150 mg dabigatran etexilate group and 3.0% of the 220 mg dabigatran etexilate group versus 3.3% of the enoxaparin group. Major bleeding events were infrequent, and were similar across all treatment groups (1.1%, 1.4% and 1.4% respectively). As part of the safety analysis, patients were frequently monitored for liver enzyme elevations. Those patients with elevations > 3 x ULN were infrequent and comparable across all treatment groups. In addition, treatment emergent acute coronary syndromes (ACS) events were infrequent and comparable across treatment groups.
Results from the European knee replacement trial (RE-MODEL) were presented in December 2006 [v] and demonstrated that once daily doses of both 150 mg and 220 mg dabigatran etexilate are as effective and safe as once daily 40 mg enoxaparin for preventing venous thromboembolism and all-cause mortality in patients undergoing elective knee replacement surgery. There was a low rate of bleeding in patients treated with both doses of dabigatran etexilate in the RE-MODEL trial, comparable with enoxaparin; and again, a low incidence of liver enzyme elevation. Results from the North American knee replacement trial (RE-MOBILIZE) were also presented at ISTH [vi]. Due to North American labelling requirements, dosage of the comparator (enoxaparin) was increased to 60 mg daily versus 150 mg or 220 mg dabigatran etexilate and the primary endpoint of equivalence for a composite of proximal DVT, distal DVT, PE and all-cause mortality (VTE) was missed (33.7% and 31.1% for 150 mg and 220 mg dabigatran etexilate respectively versus 25.3% enoxaparin). Differences were predominantly due to asymptomatic distal DVTs since major (clinically relevant) VTE occurred at similar rates in all treatment groups. Although bleeding rates were not statistically different between treatment groups, there were twice as many major bleeding events in the enoxaparin group as in the dabigatran etexilate groups.
Please be advised
Dabigatran is an investigational compound. It has already been submitted to European authorities for approval in a first indication. 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.
About RE-NOVATE
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.
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 key enzyme for blood clot formation. It 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 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™ .
Further studies investigating dabigatran etexilate
The RE-VOLUTION™ 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-MODEL™ 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-MOBILIZE™ investigated dabigatran etexilate for the same indication in a similar patient population in North America (> 2,600 patients).
RE-LY™, a phase 3 study also under the RE-VOLUTION™ trial program, is investigating dabigatran etexilate as a potential treatment for stroke prevention in atrial fibrillation. Total enrollment for this study is targeted at 15,000 patients from almost 1,000 study centres worldwide.
RE-COVER™ and RE-MEDY™ 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.
http://www.boehringer-ingelheim.com
References
[i] Eriksson BI, Dahl OE, Rosencher N et al. Dabigatran etexilate is effective and safe for the extended prevention of venous thromboembolism following total hip replacement. Abstract presented at XXIst Congress of the International Society on Thrombosis and Haemostasis in Geneva, Switzerland, July 2007
[ii] Report of the independent expert working group on the prevention of venous thromboembolism in hospitalised patients. Department of Health, March 2007
[iii] Geerts WH, Pineo GF, Heit JA et al. Prevention of Venous Thromboembolism: The Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest 2004;126:338-400
[iv] Caprini JA, Hwang E, Hantel S et al. The oral direct thrombin inhibitor dabigatran etexilate is effective and safe for prevention of major venous thromboembolism following orthopaedic surgery. Abstract presented at XXIst Congress of the International Society on Thrombosis and Haemostasis in Geneva, Switzerland, July 2007
[v] Eriksson BI, Dahl OE, van Dijk CN, et al. A New Oral Anticoagulant, Dabigatran Etexilate, is Effective and Safe in Preventing Venous Thromboembolism after Total Knee Replacement Surgery (The RE-MODEL Trial). Blood (ASH Annual Meeting Abstracts) 2006;108: Abstract 573
[vi] Friedman RJ, Caprini JA, Comp PC et al Dabigatran Etexilate Versus Enoxaparin In Preventing Venous Thromboembolism Following Total Knee Arthroplasty. Abstract presented at XXIst Congress of the International Society on Thrombosis and Haemostasis in Geneva, Switzerland, July 2007
|
|
|
|
|
