Study Confirms Efficacy And Safety For New Oral Anticoagulant In Orthopaedic Surgical Patients

Main Category: Blood / Hematology
Also Included In: Bones / Orthopedics;  Vascular
Article Date: 17 Dec 2006 - 7:00 PDT

email to a friend   printer friendly   opinions  

Successful implementation of forthcoming NICE guidelines for prevention of venous thromboembolism (VTE) in patients undergoing orthopaedic surgery and other high-risk surgical procedures(1) may become more achievable in the future with the availability of a new oral agent, called dabigatran etexilate. Results from the RE-MODELTM trial presented at the 48th Annual Meeting of the American Society of Hematology show that the oral direct thrombin inhibitor, dabigatran etexilate is as effective as the injectable low molecular-weight heparin (LMWH), enoxaparin, in the primary prevention of VTE in patients undergoing elective knee replacement surgery. No difference in bleeding rates was observed between treatment arms. In contrast to standard clot-preventing therapies like LMWH given as a series of subcutaneous injections, dabigatran etexilate is given orally from early in the postoperative period.

"Prevention of venous thromboembolism is a major challenge for healthcare systems. These new data with an orally active agent in a high risk surgical population are of great interest and show the potential for such agents in clinical practice," commented Professor Ajay Kakkar, Professor of Surgical Science, Queen Mary College and Consultant Surgeon at St Bartholomew's Hospital, London.

The need for improved thromboprophylaxis has been the focus of a recent House of Commons Health Committee report, which highlights that every year 25,000 people in England die from VTE contracted in hospital - larger than the number of deaths attributable to breast cancer, AIDS and road traffic accidents. The late consequences of deep vein thrombosis (DVT) also represent a serious clinical problem - with up to 60 percent of patients developing chronic venous insufficiency (post-thrombotic syndrome) - symptoms of which can range from oedema and pain to chronic leg ulcers and leg deformity. Units will be encouraged to review their prevention of VTE in patients undergoing orthopaedic surgery given NICE guidelines due for publication next May. The guidelines are likely to recommend thromboprophylaxis strategies for these and other patients undergoing high-risk surgical procedures.

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 40mg once daily, respectively. Proximal DVT and/or PE occurred in 3.8 percent, 2.6 percent 40mg one daily and 3.5 percent of patients receiving dabigatran etexilate 150 or 220 mg or enoxaparin, respectively.

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.

###

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.

Dabigatran etexilate product profile

• Dabigatran etexilate is an oral direct thrombin inhibitor (DTI), a new oral anticoagulant in advanced development.
• DTIs effectively bind to, and directly inhibit the activity of circulating and clot-bound thrombin
• Thrombin plays a central role in thrombosis - its multiple prothrombotic actions in the coagulation cascade make it a key target for therapeutic intervention in most thromboembolic diseases
• Preclinical studies in in vitro and in vivo models of thrombosis have shown dabigatran to be a potent, specific and reversible inhibitor of thrombin
• Dabigatran etexilate is a prodrug with no pharmacologic activity; once administered orally, it is rapidly absorbed and subsequently converted to the active drug dabigatran by plasma enzymes
• After oral administration of dabigatran etexilate, the plasma concentration of dabigatran reaches peak levels within 0.5-2.0 hours. Dabigatran has generally a linear pharmacokinetic profile, which means that its plasma concentration increases as the administered dose is increased. The half-life is 14-17 hours in healthy adults, which means that some anticoagulant activity remains 24 hours after administration of the last dose
• There is a good correlation between prolongation of blood coagulation assays and dabigatran plasma concentrations - as the plasma concentration of dabigatran increases so do the activated partial thromboplastin time (aPTT), ecarin clotting time (ECT), thrombin time (TT) and international normalised ratio (INR) values
• The anticoagulant effects of dabigatran decline in parallel with its declining plasma concentration.
• Dabigatran is eliminated from the body mainly by the kidneys (up to 80%)
• Dabigatran has a favourable safety profile - the major side effect is increased bleeding events with higher doses, which is consistent with its known pharmacologic activity
• Given that dabigatran does not undergo hepatic metabolism, there is low potential for drug-drug interactions and no potential for drug-food interactions
• In summary, dabigatran etexilate is a convenient, fixed oral dose anticoagulant, which has a rapid onset of action, provides predictable and consistent anticoagulant effects without the need for coagulation monitoring and has low potential for drug-drug interactions and no potential for drug-food interactions

References

Mungall D. Curr Opin Investig Drugs 2002; 3: 905-7.
Stangier J, et al. J Clin Pharmacol 2005; 45: 555-63.

Source:
Boehringer Ingelheim Limited Press Release
Ellesfield Avenue
Bracknell
Berkshire
RG12 8YS
United Kingdom

For further information please go to:
Boehringer Ingelheim Limited

• Additional
• References
• Citations