title: Melagatran and ximelagatran: new drug. No real simplification of anticoagulant therapy.
abstract: (1) The reference drug for prophylaxis against venous thromboembolism after hip or knee replacement surgery is a low-molecular-weight heparin (LMWH), given subcutaneously for 1 to 5 weeks. Vitamin K antagonists, including warfarin, have similar risk-benefit balances. (2) Subcutaneous melagatran and its oral metabolic precursor ximelagatran have recently been granted marketing authorisation in France for use as prophylaxis after hip or knee replacement surgery. Melagatran, unlike LMWH, is a specific thrombin inhibitor. (3) There are four randomised double-blind trials in more than 9000 patients comparing these agents with a LMWH (enoxaparin in three trials, dalteparin in one). Melagatran was given subcutaneously for one or two days before being replaced with ximelagatran (as soon as oral feeding was possible) for 6 to 9 days. These trials showed no advantage of melagatran-ximelagatran in terms of clinical endpoints such as symptomatic deep venous thrombosis, pulmonary embolism, and death from all causes. (4) Three randomised double-blind trials have compared ximelagatran with warfarin in more than 5000 patients. Treatment lasted 7 to 12 days. Ximelagatran was no better than warfarin when assessed using clinical endpoints. (5) In these trials melagatran-ximelagatran did not increase the risk of bleeding compared with LMWH or warfarin. (6) Melagatran-ximelagatran can cause an increase in serum transaminase activity, and is contraindicated if pretreatment serum transaminase activity is more than twice the upper limit of normal. (7) Trials versus warfarin showed a higher risk of myocardial infarction in patients taking ximelagatran (0.7% versus 0.16%). (8) There are few data on the patient subgroups most likely to receive melagatran-ximelagatran, namely patients over 75, underweight and overweight patients, and patients with renal failure. (9) There is currently no clotting test that allows the melagatran-ximelagatran dose regimen to be adjusted in patients who have an increased risk of adverse effects due to overdosing. There is no available antidote if overdose occurs. (10) Erythromycin increases melagatran bioavailability, thereby increasing the bleeding risk. Melagatran and ximelagatran must not be combined with other anticoagulants, thrombolytic agents or antiplatelet drugs because of a increased bleeding risk. (11) In practice, low-molecular-weight heparin remains the reference prophylactic treatment for venous thromboembolism after hip or knee replacement surgery.
mesh_terms: D000925:Anticoagulants / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D019644:Arthroplasty, Replacement, Hip / Q000534:rehabilitation; D019645:Arthroplasty, Replacement, Knee / Q000534:rehabilitation; D001384:Azetidines / Q000627:therapeutic use*; D005343:Fibrinolytic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use; D005998:Glycine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives / Q000627:therapeutic use*; D006495:Heparin, Low-Molecular-Weight / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use; D006801:Humans; D016032:Randomized Controlled Trials as Topic; D016896:Treatment Outcome; D020246:Venous Thrombosis / Q000188:drug therapy / Q000517:prevention & control*
chemical_list: D000925:Anticoagulants; D001384:Azetidines; D005343:Fibrinolytic Agents; D006495:Heparin, Low-Molecular-Weight; D005998:Glycine