Therapeutic index of anticoagulants for prevention of venous thromboembolism following orthopedic surgery: a dose-response meta-analysis.

Information on the comparative effectiveness of drugs is crucial for drug development decisions, in addition to being needed by regulators, prescribers, and payers. We have carried out a dose-response meta-analysis of three end points each for efficacy and bleeding for various anticoagulants evaluated for the prevention of venous thromboembolism (VTE) following orthopedic surgery to assess the comparative efficacy and safety of various classes of agents. Data obtained from 89 randomized controlled trials of 23 anticoagulants representing seven drug classes were analyzed. The analysis showed significant differences in the therapeutic index (TI), the ratio of the dose with an acceptable bleeding risk to the dose with a relevant risk reduction for VTE, across the drug classes but not for drugs within a class. The direct inhibitors of FXa, the activated form of factor X--also known as prothrombinase--were found to have a significantly higher TI than that of any other class of anticoagulants, including enoxaparin, suggesting that this mechanism of action provides the best safety-to-efficacy margin.