A Pooled Analysis of Four Pivotal Studies of Rivaroxaban for the Prevention of Venous Thromboembolism after Orthopaedic Surgery: Effects of Specified Co-Medications.

Abstract RECORD is a pivotal clinical trial program investigating rivaroxaban – an oral, direct Factor Xa inhibitor – for the prevention of venous thromboembolism (VTE) following elective total hip and knee replacement (THR and TKR). The four multinational, randomized, double-blind, double-dummy phase III studies (RECORD1, 2, 3 and 4) in patients undergoing THR or TKR surgery, comparing rivaroxaban with enoxaparin 40 mg once daily (od) or 30 mg twice daily (bid), have been completed. Patients (N=12,729) were randomized to receive oral rivaroxaban 10 mg od starting 6–8 hours after surgery, or subcutaneous enoxaparin 40 mg od starting the evening before surgery (RECORD1–3) or 30 mg bid starting 12–24 hours after wound closure or adequate hemostasis (RECORD4). Those undergoing THR received rivaroxaban or enoxaparin for 31–39 days in RECORD1, and rivaroxaban for 31–39 days or enoxaparin for 10–14 days followed by placebo in RECORD2. In RECORD3 and 4 (TKR), prophylaxis was for 10–14 days. A pooled analysis of the results of all four RECORD studies evaluated the effect of rivaroxaban on the composite of symptomatic VTE and death, and bleeding. The aim of the present subgroup analysis was to investigate potential drug–drug interactions with specified co-medications, by describing the risk of on-treatment bleeding in the total study duration pool of all four RECORD studies. The co-medications investigated were non-steroidal anti-inflammatory drugs (NSAIDs) and acetylsalicylic acid (ASA), which are commonly used pain medications known to have a pharmacodynamic effect on bleeding. There was no restriction on the choice of specific drug or on the dose of ASA in the study protocols. These pre-specified analyses focused on on-treatment, adjudicated bleeding events – any bleeding, and the composite of major bleeding, and clinically relevant non-major bleeding – after the first tablet intake (rivaroxaban or matching placebo) and up to 2 days after the last dose of medication. Co-medication use was considered a time-dependent covariate, and relative bleeding rates with and without the co-medication were calculated for the rivaroxaban and enoxaparin/placebo groups separately. The time relative to surgery (day of surgery was day 1) was stratified into three time periods (days 1–3, days 4–7, and day 7 onwards), based on the consideration that the risk of a first bleeding event decreases over time after surgery, and because the prevalence of co-medication use can vary over time. Bleeding rates were recorded for each of these time periods over the at-risk period, which extended from the day of surgery until the last day of study medication intake +2 days or until event onset (recurrent bleeds were not included in the analyses). Rate ratios were derived using stratified Mantel–Haenszel methods. The ratios of the bleeding rate for exposed versus unexposed patient-days in the rivaroxaban group were compared with the corresponding rate ratio for the enoxaparin/placebo group for bleeding events. The concomitant use of ASA in the rivaroxaban groups showed rate ratios similar to those obtained in the enoxaparin/placebo group, for all bleeding endpoints. Rate ratios for bleeding endpoints were also similar between the rivaroxaban and the enoxaparin/placebo groups with concomitant use of NSAIDs. This RECORD1–4 subanalysis indicates that the use of these co-medications does not increase bleeding risk in patients taking rivaroxaban, compared with enoxaparin

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