New versus established drugs in venous thromboprophylaxis - Efficacy and safety considerations related to timing of administration

European surgeons generally administer thromboprophylaxis with low-molecular-weight heparins (LMW-Hs) at high doses 12 hours preoperatively in response to findings that surgery-related deep-vein thrombosis typically originates at the time of major orthopedic surgery or shortly afterwards. North American surgeons, in contrast, generally administer LMWHs at an almost 50% higher dose than that given in Europe 12-24 hours postoperatively, even though both pre- and postoperative administration are considered suitable in current guidelines. This review therefore examines how close to major orthopedic surgery thromboprophylaxis is administered, and the subsequent effect of timing on clinically relevant efficacy and safety parameters. The trials examined involve fondaparinux sodium (fondaparinux) and (xi)melagatran, in comparison with the established LMWHs enoxaparin sodium (enoxaparin) and dalteparin. In key trials, fondaparinux reduced the risk of asymptomatic and clinical venous thromboembolism (VTE) by 55% compared with enoxaparin, at the expense of a 1.6-fold higher risk of bleeding. While the studies were not designed to compare efficacy endpoints based on clinical outcomes, no significant difference was demonstrated for symptomatic VTE. The fact that the enoxaparin regimen was started at the upper limits of its recommended initiation timeframe may have significantly influenced the results of comparative studies, given that several meta-analyses found that the timing of LMWH initiation significantly influenced its effectiveness on asymptomatic VTE and major bleedings. Compared with once-daily LMWH in European trials, early postoperative doses/regimens of twice-daily (xi)melagatran did not increase severe bleeding and was significantly less effective at preventing asymptornatic total VTE in patients who had undergone total hip-replacernent surgery. When used according to the 'knife-to-skin' protocol, the melagatran regimen was superior to enoxaparin in preventing major asymptornatic VTE, but at the cost of a higher rate of major bleeding. In North America, the delayed postoperative administration of (xi)melagatran (oral only) was less effective than the postoperative twice-daily enoxaparin regimen with regard to asymptomatic total and major VTE. Our analysis highlights the fact that differences in efficacy and safety data in clinical trials of thromboprophyaxis might also be linked to differences in the timing of initiation. However, it is not possible to assess the importance of this 'time effect' among other factors considered as drug-specific properties (pharmacokinetics, mode of action, dosage) and evaluate their respective contribution in the observed differences. To avoid unbiased comparison in further studies, the possible effect of timing should be taken into account and, when feasible, both therapies started at the same time. For instance, harmonizing the initiation of thromboprophylaxis 6-8 or 12 hours postoperatively could be two acceptable harmonized options for scheduling in clinical trials.