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Review: New oral factor Xa inhibitors reduce DVT compared with standard thromboprophylaxis after THR or TKR

Question What are the effectiveness and safety of novel oral anticoagulants (NOACs) compared with standard thromboprophylaxis after total hip replacement (THR) or total knee replacement (TKR)? Review scope Included English-language systematic reviews comparing NOACs (direct thrombin inhibitors or factor Xa inhibitors) with standard thromboprophylaxis (warfarin, low-molecular-weight heparin [LMWH], unfractionated heparin, or aspirin) in randomized controlled trials (RCTs) of adults 18 years of age having elective THR or TKR. Primary outcomes were symptomatic deep venous thrombosis (DVT) and nonfatal pulmonary embolism (PE); secondary outcomes were mortality and major bleeding. Review methods MEDLINE, EMBASE/Excerpta Medica, Cochrane Database of Systematic Reviews (all 2009 to Mar 2013), and reference lists of reviews and guidelines were searched for systematic reviews. 6 reviews (5 to 43 included studies, mean age range 52 to 78 y, 45% to 84% women) met selection criteria; all were rated as good quality. A primary search found no additional RCTs published after the included reviews. Analyses focused on the 2 reviews with the most recent search dates, comprehensive analyses, and outcomes of interest. Main results The main results are in the Table. Conclusions After total hip or knee replacement surgery, factor Xa inhibitors reduce symptomatic deep venous thrombosis compared with low-molecular-weight heparin (LMWH); the direct thrombin inhibitor dabigatran does not differ from LMWH. Novel oral anticoagulants do not differ from standard thromboprophylaxis for mortality, nonfatal pulmonary embolism, or bleeding. New oral anticoagulants (factor Xa inhibitors and dabigatran) vs low-molecular-weight heparin (LMWH) after total hip or knee replacement* Outcomes Number of trials (n) Weighted event rates At 5 to 13 wk Factor Xa LMWH RRR/RRI (95% CI) NNT (CI) Symptomatic DVT 18 (22877) 0.27% 0.58% RRR 54% (30 to 70) 322 (249 to 581) Nonfatal PE 20 (26998) 0.26% 0.25% RRI 7% (35 to 73) NS Mortality 11 (23838) 0.24% 0.25% RRR 5% (63 to 45) NS Major bleeding 21 (31424) 0.83% 0.66% RRI 27% (2 to 64) NS Dabigatran LMWH Symptomatic DVT 4 (10264) 0.39% 0.48% RRR 18% (299 to 83) NS Nonfatal PE 4 (10264) 0.20% 0.29% RRR 31% (54 to 69) NS Mortality 4 (10264) 0.08% 0.05% RRI 54% (62 to 533) NS Major bleeding 4 (10264) 1.2% 1.3% RRR 6% (52 to 42) NS *DVT = deep venous thrombosis; NS = not significant; PE = pulmonary embolism; other abbreviations defined in Glossary. RRR, RRI, NNT, and CI calculated from control event rates and odds ratios or relative risks in article using a random-effects model. Based on a review of 22 randomized controlled trials comparing oral factor Xa inhibitors with LMWH. Based on a review of 4 randomized controlled trials comparing dabigatran with enoxaparin. Commentary Unfractionated heparin, LMWH, fondaparinux, aspirin, warfarin, and NOACs are recommended options for thromboprophylaxis after THR or TKR (1). The rigorous systematic review by Adam and colleagues compared NOACs and LMWH, the most widely used thromboprophylaxis options after THR and TKR. NOACs seem to be at least as effective and safe as LMWH for thromboprophylaxis, with a minimal benefit for the oral factor Xa inhibitors for prevention of symptomatic DVT (number needed to treat 322). Inferences about the relative efficacy or safety of individual NOACs cannot be made because there were no head-to-head trials and, in the existing RCTs, the timing of postoperative NOAC initiation (6 to 8 h for dabigatran and rivaroxaban, 12 to 24 h for apixaban) and definitions of bleeding outcomes differed. For practicing clinicians, although NOACs may be appealing based on their proven efficacy and safety and ease of use, LMWH remains a reasonable alternative for thromboprophylaxis. Specifically, a regimen of twice-daily enoxaparin, 30 mg, is as effective as NOACs for TKR and may be considered for THR (2). Relative costs will also be a factor in prescribing. Further research is needed to determine the optimal timing of postoperative NOAC initiation to minimize bleeding, since peak action occurs 1 to 3 hours after intake. Moreover, improvements in surgical and anesthesia techniques and early postoperative mobilization have reduced the perioperative thrombogenic milieu, and this will prompt the reevaluation of less intensive thromboprophylaxis options, such as aspirin, after THR and TKR (3).