Extended‐duration new oral anticoagulants for venous thromboprophylaxis in patients undergoing total hip arthroplasty: a meta‐analysis of the randomized controlled trials

Extended-duration thromboprophylaxis with low-molecular-weight heparin (LMWH) reduces the frequency of symptomatic venous thromboembolism (VTE) among patients undergoing total hip or knee arthroplasty [1]. Recent trials have evaluated the efficacy and safety of the new oral anticoagulants (NOACs), dabigatran etexilate, rivaroxaban and apixaban, for VTE prevention in patients undergoing total hip arthroplasty (THA) [2–5]. We performed a meta-analysis to obtain the best estimates of the effects of NOACs compared with LMWH for extended prophylaxis against symptomatic VTE in this patient population [2–5]. We report the relative risk reductions for symptomatic VTE and for the primary composite outcome in trials that included both symptomatic and asymptomatic VTE events and all-cause mortality. We searched electronic databases (PubMed and CENTRAL) up to April 2013 to identify randomized controlled trials of extended-duration thromboprophylaxis (> 4 weeks) in patients undergoing THA that compared an NOAC with an LMWH. Pooled estimates were obtained using a random effects model (DerSimonian and Laird method) and the results are presented as odd ratios with their respective 95% confidence intervals (Cls) and absolute risk reductions [6]. Heterogeneity assessment was performed using the I index and v test. Calculations were performed using RevMan version 5.1. We identified four trials (15 497 patients) that contributed to the analysis of one or more of the following outcomes: (i) symptomatic VTE (11 799 patients); (ii) combined total VTE and all-cause mortality (11 247 patients); (iii) major bleeding (15 241 patients); (iv) clinically relevant non-major bleeding (15 241 patients); (v) all-cause mortality during treatment (13 988 patients); and (vi) all-cause mortality during follow-up (10 221 patients). All these four trials were double-blind and double-dummy with a treatment period of 28–39 days. Enoxaparin was started preoperatively in studies performed in Europe and postoperatively in studies performed outside of Europe according to local practice. Mandatory bilateral venography was performed within 2 days of the end of the treatment period. In comparison with enoxaparin, extended-duration thromboprophylaxis with NOAC reduced the risk of symptomatic VTE (0.19% vs. 0.46%; RR, 0.42; 95% CI, 0.21–0.86; P = 0.02; ARR, 0.27%; NNT = 370) with no statistical evidence of heterogeneity (Fig. 1a; Table 1 and Table S1). A similar relative odds reduction was evident for combined VTE and all-cause mortality (3.84% vs. 5.06%; RR, 0.57; 95% CI, 0.31–1.07; P = 0.08; ARR, 1.22%; NNT = 82) but there was substantial heterogeneity among the trials for this outcome (P < 0.00001) (Fig. 1b). The heterogeneity was not significant when trials of factor Xa inhibitor (RECORD-1 and ADVANCE-3; I = 0%; v = 0.23; P = 0.63) and direct thrombin inhibitors (RENOVATE 1 and 2; I = 0%; v = 0.94; P = 0.33) were combined separately. Major bleeding rates were not significantly higher with NOACs compared with enoxaparin (0.98% vs. 0.67%; RR, 1.26; 95% CI, 0.87–1.81; P = 0.22) (Fig. 1c). There was also no difference in clinically relevant non-major bleeding rates (3.66% vs. 3.32%; RR, 1.08; 95% CI, 0.90–1.30; P = 0.42), all-cause mortality during the treatment period Correspondence: Aaron Liew, Department of Medicine, National University of Ireland Galway (NUIG), University Road, Galway, Ireland. Tel. : +353 91 544206: fax: +353 91 494540 E-mail: liew.aaron@gmail.com