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Prevention of venous thromboembolism after major orthopedic surgery: summing up evidence about old and new antithrombotic agents

Orthopedic surgery is still a major indication for the clinical use of old and new anticoagulant drugs, being both a useful experimental setting for the clinical investigator and a major challenge for the caring physician. Low-molecular-weight heparins (LMWH) have progressively shown over time and trials a more favourable efficacy and safety profile than unfractioned heparin and are probably the most commonly used prophylactic agent in Europe after hip and knee surgery. On the other side of the ocean, vitaminK antagonists (VKAs) still have the preference of roughly half of the prescribing surgeons in North America for knee replacement [1,2].Most likely, this is probably due to the higher rate of bleeding at the surgical site for LMWH than for warfarin, particularly if heparin therapy is started soon after surgery or even before, and in spite of the high rate of venous thromboembolic events occurring with the use of warfarin as prophylactic agent [3,4]. In this issue of the Journal, Mismetti et al. [5] present an interesting meta-analysis on the use of VKAs in orthopedic surgery and review newly published trials not previously included in ameta-analytic evaluation and accounting formore than 6000 patients, i.e. a half of all the LMWH-treated patients studied for this indication [4,6–8]. A general rule of the evidence-based medicine applies: that as new relevant trials are concluded, a newmeta-analysis is worthwhile or even required. Actually, one of the basic assumptions underlying the metaanalytic process is to include all relevant trials available on that specific topic. This is the reason why meta-analysis papers are often short-living papers, and for the same reason theCochrane Collaboration (an international organization of healthcare professionals, practising physicians, researchers and consumers interested in optimizing decisions about healthcare) aims not only at preparing and promoting the accessibility to systematic reviews but also at maintaining them, and it requires that the reviewers undertake to publish timely updates of their work [9]. Moreover, all systematic reviews are retrospective and observational, and therefore subject to systematic and random error [10]. One other major concern aboutmeta-analysis is the risk of incomplete literature search and, in particular, the publication bias, with the obvious consequence of overestimating the efficacy of the treatment under study [11]. This is why registers of ongoing trials should be favoured by institutional agencies and strongly requested by regulatory agencies to avoid omission of negative results. More easy to handle, but not always well managed in published papers, is the issue of study selection and/or quality assessment: as Mismetty et al. briefly discuss in their paper [5], previous meta-analysis of thromboembolism prevention in orthopedic surgery came to discordant results considering different subsets of trials. The rule of thumb for the clinician is to rely on data coming from meta-analysis that include homogeneous populations and treatments and provide detailed description of their characteristics. Very recently and certainly beyond the time boundaries of the literature search of Mismetti et al. [5], three studies have been published comparing warfarin with a new direct thrombin inhibitor, ximelagatran, in the prevention of venous thromboembolism after major knee surgery [12–14]. After oral administration, ximelagatran is rapidly absorbed and converted to its active form, melagatran [15], which directly inhibits free and clot bound thrombin [16]. The pharmacokinetic properties of ximelagatran guarantee safe and effective administration of fixed doses without monitoring. The extremely high interest of clinicians and scientists in ximelagatran is demonstrated, as a home-made example for the readers of the Journal of Thrombosis and Haemostasis, by the five trials and three Correspondence: Alfonso Iorio, Sezione di Medicina Interna e Cardiovascolare, Dipartimento di Medicina Interna, Università degli Studi di Perugia, Perugia, Italy. Tel.: +39 07 5578 3607, +39 34 9120 4919; fax: +39 07 5572 2011; e-mail: iorioa@unipg.it