European multi-centre trial demonstrates H 376/95 compares well with dalteparin in prevention of venous thromboembolism in orthopaedic surgery
The oral direct thrombin inhibitor H 376/95, the first new oral anticoagulant for 50 years, is effective in preventing venous thrombo-embolism in patients undergoing total hip or total knee replacement surgery, according to data presented for the first time at the 16th International Congress on Thrombosis in Porto, Portugal. The data were taken from the results of the Phase II study, known as METHRO II, which involved a total of 1916 patients in 13 European countries. A highly significant dose-dependent decrease in venous thrombo-embolism was observed with H 376/95 in both total hip (p<0.0001) and total knee replacement (p=0.0014) surgery. The incidence of venous thromboembolism was significantly lower with the highest dosage of H 376/95 compared with dalteparin (p<0.0001).
Dr Bengt Eriksson, Associate Professor of Orthopaedic Surgery, Sahlgrenska University Hospital, Östra, Gothenburg, Sweden, the METHRO II principal investigator who presented the findings, said: "The results of the METHRO II study have confirmed the promising preliminary findings of the Phase IIa study of H 376/95 in the prevention of venous thromboembolism in orthopaedic surgery. The prophylactic regimen used, starting with subcutaneous melagatran followed by oral H 376/95 (melagatran is the active form of H 376/95) seems to be superior to standard therapy, low molecular weight heparin. In addition to its proven efficacy, H 376/95 has a number of practical advantages, especially oral administration offering patients the possibility of taking tablets instead of having injections. The drug is well absorbed and has no known interactions with other drugs or food. There is no need for laboratory monitoring, which is a great relief for patients."
Dr Eriksson continued: "Patients undergoing hip or knee replacement are at high risk of venous thrombosis (formation of a blood clot in a vein) which may result in pulmonary embolism leading to death. A common approach to prevention of venous thromboembolism is the use of anticoagulant prophylaxis e.g. injectable low molecular weight heparin or oral warfarin. Warfarin requires careful and regular coagulation monitoring i.e. taking blood samples. Warfarin has limitations because of a slow onset of effect over several days. Also, bleeding complications and drug interactions are common. There is, therefore, a need for an effective and well-tolerated oral alternative to warfarin. The data from the METHRO II study indicate that H 376/95 shows considerable promise as a replacement for low molecular weight heparin and warfarin in the prophylaxis of venous thromboembolism in orthopaedic surgery."
The METHRO II study was a double-blind, dose-finding study and a comparator agent was used. The primary purpose of the study was to determine the dose-response relationship with regard to efficacy for the oral direct thrombin inhibitor, H 376/95, preceded by subcutaneous administration of melagatran. The METHRO II study was also designed to compare the efficacy of the H 376/95 regimen with conventional prophylaxis using the injectable low molecular weight heparin agent, dalteparin.
Patients were randomised to one of four melagatran/H 376/95 regimens or dalteparin for 8-11 days. The regimens were: 1mg, 1.5mg, 2.25mg or 3mg melagatran subcutaneously twice daily followed by 8mg, 12mg, 18mg or 24mg oral H 376/95 twice daily respectively or dalteparin 5000 IU once daily subcutaneously. A diagnostic procedure, phlebography, was carried out on the final day of treatment. Patient follow-up was 4-6 weeks post-operatively. Two-thirds of the patients underwent hip replacement and one-third knee replacement surgery. The age range was 18-85 years.
There was a clear relationship between the dose regimen of H 376/95 and the occurrence of venous thromboembolism in that the highest dosage was significantly associated with the lowest incidence of thromboembolic complications. The incidence of venous thromboembolism was significantly lower with the highest dose of H 376/95 compared with dalteparin (p<0.0001). Bleeding is an expected outcome in patients undergoing major surgery. In the METHRO II study total bleeding was not significantly different between the H 376/95 treatment groups or dalteparin.
AstraZeneca R&D Mölndal
S-431 83 Mölndal
Sweden.
AstraZeneca is a major international healthcare business engaged in the research, development, manufacture and marketing of ethical (prescription) pharmaceuticals and the supply of healthcare services. It is one of the top five pharmaceutical companies in the world with healthcare sales of over $15 billion and leading positions in sales of gastrointestinal, oncology, anaesthesia including pain management, cardiovascular, central nervous system (CNS) and respiratory products.
Reference: Haemostasis 2000; 30: (Supplement 1)
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