Regular ArticleProphylaxis of venous thromboembolism with subcutaneous melagatran in total hip or total knee replacement: results from Phase II studies☆
Introduction
The establishment of effective and safe therapy for venous thromboembolism (VTE) prophylaxis has significantly reduced postoperative morbidity for patients undergoing total hip replacement (THR) or total knee replacement (TKR) [1]. Nevertheless, the risk of VTE following orthopaedic surgery remains considerable [1].
It has been proposed that direct thrombin inhibitors may be superior to low-dose unfractionated heparin and low-molecular-weight heparins (LMWH) due to their ability to inhibit clot-bound thrombin [2], [3], [4]. Direct thrombin inhibitors are also suitable alternatives for patients with heparin-induced thrombocytopenia and antithrombin deficiency. Melagatran, a novel, direct thrombin inhibitor, has recently been developed [5]. Melagatran, which is administered subcutaneously, is well tolerated in toxicity studies in rats and dogs, and is effective in animal models of venous [6], [7] and arterial [8] thrombosis. In healthy volunteers, melagatran is well tolerated and is primarily (80%) excreted renally [9]. The predictable pharmacokinetic profile found in healthy volunteers [10] suggests that no routine coagulation monitoring is necessary.
To assess melagatran as prophylaxis for postoperative thromboembolism in patients undergoing major orthopaedic surgery, the aim of the present studies was first to investigate the safety and efficacy of a dose range of melagatran, and second to evaluate alternative vehicles for depot formulation of subcutaneous melagatran, in order to optimise the pharmacokinetic properties.
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Study population
In Study I, patients scheduled for primary elective THR who were aged 50–85 years and weighed 50–100 kg were included. In Study II, patients scheduled for primary elective THR or TKR who were aged 18–85 years and weighed 50–110 kg were enrolled.
The primary exclusion criteria for both studies were as follows: immobilisation within 12 weeks before surgery; treatment with anticoagulant or antiplatelet drugs within 7 days prior to surgery or planned use of these drugs during study treatment; a
Demography
A total of 170 patients were enrolled: 66 patients in Study I and 104 patients in Study II. In Study I, one patient received the first dose of subcutaneous melagatran 4.5 mg but did not undergo surgery, and one patient received the first 6-mg dose of subcutaneous melagatran and was withdrawn due to excessive bleeding. Thus, the ITT population for venography analyses consisted of 64 patients. In Study II, one patient withdrew consent before drug administration, reducing the ITT population for
Discussion
In these dose-ranging studies, administration of subcutaneous melagatran was assessed after high-risk, elective orthopaedic surgery. Following THR or TKR, a dose range of subcutaneous melagatran between 1.5 and 4.5 mg bid for 8–11 days for the prophylaxis of VTE was well tolerated. The frequency of VTE was low, and no unexpected adverse drug reactions were found. The absence of late-occurring VTE might also reflect the study procedure, which involved mandatory bilateral venography at the end of
Acknowledgements
For their assistance in the preparation of formulations of melagatran used in these studies, the following are acknowledged: Anna Lundgren, Ulla Stjernfelt, and Urban Skantze at AstraZeneca, Mölndal, Sweden.
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2010, Cochrane Database of Systematic ReviewsThe antithrombotic effect of melagatran in combination with clopidogrel and/or aspirin (carotid artery primary thrombosis study)
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Presented as an oral communication at the American Society of Hematology, New Orleans, LA, December 3–7, 1999 and as a poster communication at the American College of Clinical Pharmacy, Los Angeles, November 5–8, 2000.