Relative Effects of Two Different Enoxaparin Regimens as Comparators Against Newer Oral Anticoagulants Meta-analysis and Adjusted Indirect Comparison

Background: Two different regimens of enoxaparin (40 mg once daily or 30 mg bid) have been used as control arms in trials of new oral anticoagulants. The choice of enoxaparin comparator may influence the perceived relative efficacy and safety of the newer agents, and we aimed to identify any significant differences between the two enoxaparin regimens. Methods: We searched MEDLINE, EMBASE, and Cochrane Library for randomized controlled trials that compared enoxaparin to oral anticoagulant (apixaban, dabigatran, rivaroxaban) thromboprophylaxis in elective total knee or hip arthroplasty. Total VTE and bleeding events were pooled using fixed-effects meta-analysis and heterogeneity assessed with the 12 statistic. We conducted adjusted indirect comparisons of bid vs once-daily enoxaparin regimes based on new oral anticoagulants as common comparators. Results: Fourteen randomized controlled trials in hip and knee replacement surgery met the inclusion criteria. Adjusted indirect comparison showed that bid enoxaparin was significantly more effective in preventing VTE than enoxaparin once daily (relative risk [RR], 0.71; 95% CI, 0.61-0.83; P < .00001). For major and clinically relevant hemorrhage, adjusted indirect comparison showed that enoxaparin bid was nonsignificantly associated with increased risk of bleeding (RR 1.27; 95% CI, 0.97-1.65; P = .08) above that of enoxaparin once daily. Subgroup analysis limited to total knee arthroplasty trials showed similar results. Conclusions: The use of once-daily enoxaparin regimen as control in clinical trials will lead to more favorable estimates of relative efficacy for the new oral anticoagulants than if enoxaparin 30 mg bid had been chosen as a comparator.