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Cardiología. 20 de diciembre de 2007

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

Results of RE-MODELTM, a Phase III trial evaluating the efficacy and safety of dabigatran etexilate in patients undergoing total knee replacement (TKR) surgery, demonstrate that dabigatran is as effective as enoxaparin in preventing venous thromboembolism (VTE) and has a comparable safety profile.

Rationale of RE-MODELTM
VTE prophylaxis in orthopaedic surgery (OS) consists of low molecular weight heparins (LMWHs), including enoxaparin, which are injected subcutaneously, or the oral vitamin K antagonists, specifically warfarin. Both classes of drugs are associated with numerous limitations such as the need for monitoring and dose adjustments, drug?drug interactions and drug?food interactions or the risk of heparin-induced thrombocytopenia and osteoporosis; therefore, there is an urgent need for a new oral anticoagulant, not just for the prevention of VTE in OS, but also for the prevention and treatment of VTE in other conditions.

Trial design
The RE-MODELTM trial was conducted in over 100 centres in Europe, but also in Australia and South Africa. A total of 2076 patients were randomized to one of three treatment arms: oral dabigatran etexilate 150 mg once daily, oral dabigatran etexilate 220 mg once daily or enoxaparin 40 mg injected once daily. Patients in the enoxaparin treatment arm received their first injection preoperatively, while those in dabigatran groups received medication 1?4 hours after surgery. All patients received therapy for 6?10 days and were followed up for 12?14 weeks.

Efficacy and safety outcomes
The primary efficacy outcome was a composite endpoint consisting of total VTE events and all-cause mortality during the treatment period. VTE events were defined as:
? Deep vein thrombosis (DVT; proximal or distal) as detected by routine venography
? Symptomatic DVT confirmed by venous duplex ultrasound, venography or autopsy
? Pulmonary embolism (PE) confirmed by ventilation-perfusion (V-Q) scintigraphy and chest X-ray, pulmonary angiography or spiral computed tomography (CT)

Other efficacy outcomes during the treatment period included a composite of major VTE (defined as proximal DVT and PE) and VTE-related mortality, proximal DVT, PE and death. The efficacy endpoint during the follow-up period was a composite of total VTE and all-cause mortality. A wide range of safety outcomes was assessed in the trial, including bleeding events (major, clinically relevant and minor), volume of blood loss, blood transfusions, adverse events and laboratory measures. All efficacy and safety outcome events were adjudicated by independent committees blinded to treatment allocations of the patients. The trial was powered to detect the non inferiority of dabigatran ? the aim therefore, was to show that dabigatran is as safe and effective as enoxaparin.

Results and conclusions
Efficacy data were obtained from 1541 of the 2076 patients randomized. The composite primary efficacy outcome occurred in 40.5%, 36.4% and 37.7% of patients assigned to dabigatran etexilate 150 mg or 220 mg or enoxaparin, respectively. This finding indicated that the objective of non inferiority against enoxaparin was met with both doses of dabigatran and that dabigatran was as effective as enoxaparin in preventing VTE. Proximal DVT and/or PE occurred in 3.8%, 2.6% and 3.5% of patients receiving dabigatran etexilate 150 mg or 220 mg or enoxaparin, respectively. No statistically significant differences in any of the other secondary efficacy outcomes were noted. Three deaths occurred during the treatment period, one in each of the treatment groups. The safety profile of both doses of dabigatran and enoxaparin ? bleeding and adverse events ? were comparable. Major bleeding occurred in 1.3%, 1.5% and 1.3% of patients receiving dabigatran etexilate 150 mg or 220mg or enoxaparin. Elevations in the plasma concentration of the liver enzyme alanine aminotransferase were observed in a small minority in all three groups; 3.7%, 2.8% and 4.0% of patients in the dabigatran etexilate 150 mg, 220 mg and enoxaparin groups, respectively. There were no problems with the routine early oral use of dabigatran etexilate after surgery.

These results demonstrate that dabigatran is as effective as enoxaparin in the prevention of VTE in patients undergoing TKR. Dabigatran is also associated with a comparable bleeding and safety profile to enoxaparin.

RE-VOLUTIONTM clinical trial programme overview
Dabigatran etexilate is a novel, orally administered direct thrombin inhibitor currently being evaluated in a number of thromboembolic disease indications in an extensive, global clinical trial programme entitled RE-VOLUTIONTM . The programme encompasses six trials involving over 27,000 patients worldwide. All trials are large-scale, Phase III trials.

RE-LYTM, the largest trial in the RE-VOLUTIONTM programme, is investigating the efficacy of dabigatran etexilate in preventing stroke in patients with atrial fibrillation (AF). An anticipated 15,000 patients worldwide will be recruited to participate in this study. AF is the most common sustained rhythm disorder of the heart, affecting up to 5.5 million individuals globally. This number is predicted to rise significantly in view of the aging population. In the USA alone, the number of individuals with AF is set to increase from the current 2 million to more than 5 million by 2050.1 At present, given the limitations of warfarin, many patients fail to receive adequate therapy, significantly increasing their risk of stroke.

The RE-VOLUTIONTM programme aims to establish the efficacy and safety of dabigatran etexilate as a new, orally available anticoagulant, with fixed dosing, low potential for drug?drug interactions and no potential for drug?food interactions, predictable effects and no need for coagulation monitoring.

References
1. Go AS, et al. JAMA 2001; 285: 2370?5.

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