Indirect Comparisons of Rivaroxaban Versus Alternative Prophylaxes for the Prevention of VTE in Patients Undergoing Total Knee Replacement.
Authors: Diamantopoulos Alexander , LeReun Corrine , Rasul Farhat , Lees Michael , Kubin Maria , Wells Philip 
Published: April 2020

Abstract
Introduction: Rivaroxaban is a novel, oral, direct Factor Xa inhibitor under regulatory review for the prevention of venous thromboembolism (VTE) after major orthopaedic surgery. Two large, randomized controlled trials compared 10 mg rivaroxaban once daily (od) with subcutaneous (sc) enoxaparin 40 mg od (RECORD3) and enoxaparin 30 mg twice daily (bid)(RECORD4) in patients undergoing total knee replacement (TKR). Rivaroxaban and enoxaparin were administered for 12 ± 2 days in both trials. In RECORD3, rivaroxaban was associated with a relative risk reduction (RRR) of 49% in total VTE (composite of any deep vein thrombosis, non-fatal pulmonary embolism and all-cause mortality) and 66% in symptomatic VTE versus enoxaparin (p=0.005). In RECORD4, rivaroxaban reduced total VTE versus enoxaparin (RRR 32%, p=0.012). There was no statistical difference in major bleeding between rivaroxaban and enoxaparin in either study. Although the comparison between rivaroxaban and enoxaparin is important, there are alternative VTE prophylaxes such as warfarin, fondaparinux and dabigatran (which received EU marketing approval in March 2008) for which there are no direct comparisons with rivaroxaban. This analysis was designed to assess the relative efficacy and safety of rivaroxaban versus warfarin, fondaparinux and dabigatran. This is important for clinical decision makers, but also provides important inputs for cost-effectiveness analyses of rivaroxaban versus these comparators.
Methods: The efficacy of rivaroxaban relative to warfarin, fondaparinux and dabigatran was assessed by comparing the occurrence of total VTE, total DVT (proximal and distal) and symptomatic DVT. Relative safety was assessed using rates of major bleeding. A systematic literature review identified randomised control trials (RCTs) comparing enoxaparin to warfarin, fondaparinux or dabigatran in TKR. Each of these publications was reviewed by independent analysts. Data for relevant efficacy and safety outcomes were taken from these studies, and from RECORD3 and 4 for rivaroxaban versus enoxaparin. If more than one set of RCTs were available for each comparator, a meta-analysis was undertaken to obtain the pooled results for efficacy and safety (Bucher et al., 1997). Indirect comparisons were conducted based on the summary statistics obtained in each meta-analysis. Results are presented for the indirect comparisons through enoxaparin 30 mg bid and enoxaparin 40 mg od separately. The results from such an analysis do not represent the same level of evidence as a comparative trial, but they provide a guide to potential relative efficacy and safety in the absence of a comparative trial and could be used by authorities to aid decision making (NICE, 2007).
Results: Rivaroxaban significantly reduced the incidence of key outcomes. When enoxaparin 30 mg bid was used as the common comparator, rivaroxaban was associated with reductions in total VTE of 56% versus warfarin (p&lt;0.001) and 29% versus dabigatran (p&lt;0.05). When enoxaparin 40 mg od was used as the common comparator, rivaroxaban was associated with reductions in total VTE of 67% versus warfarin (p&lt;0.001) and 47% versus dabigatran (p&lt;0.001). Similar reductions were shown in total DVT. No other statistically significant differences, including for the comparison with fondaparinux, were found. Importantly for a new anticoagulant, there were no increases in major bleeding with rivaroxaban, safety outcomes are therefore unlikely to influence cost-effectiveness.
Conclusions: An indirect statistical comparison showed that rivaroxaban reduced the incidence of overall or symptomatic VTE events relative to alternative prophylaxes without increasing major bleeding following TKR. In the absence of direct comparisons, this is the best evidence regarding the relative efficacy and safety of these options.