Effects of Age, Weight, Gender and Renal Function in a Pooled Analysis of Four Phase III Studies of Rivaroxaban for Prevention of Venous Thromboembolism after Major Orthopedic Surgery

Abstract

Abstract The RECORD program comprised four pivotal phase III trials comparing the oral direct Factor Xa inhibitor, rivaroxaban, with subcutaneous enoxaparin for the prevention of venous thromboembolism (VTE) after total hip and knee replacement (THR and TKR). A total of 12,729 patients were randomized to receive rivaroxaban 10 mg once daily (od) starting 6–8 hours after surgery, or enoxaparin 40 mg od (RECORD1–3) starting the evening before surgery, or 30 mg every 12 hours (RECORD4) starting 12–24 hours after surgery. In RECORD1, patients undergoing THR received extended prophylaxis for 31–39 days. In RECORD2, patients undergoing THR received rivaroxaban for 31–39 days, or enoxaparin for 12±2 days followed by placebo up to 35 days. Patients undergoing TKR in RECORD3 and 4 received prophylaxis for 12±2 days. In all four trials the rivaroxaban regimens showed superior efficacy to the enoxaparin regimens with no significant increase in bleeding. The RECORD1–4 pooled analysis showed that rivaroxaban was significantly superior to enoxaparin for the primary endpoint, symptomatic VTE and all-cause mortality (0.8% vs 1.6%, respectively; p<0.001), with similar bleeding rates in both groups. Pooled subgroup analyses were performed to determine the influence of age, weight, gender, or renal function (calculated creatinine clearance [CrCl] at baseline) on the studies primary and main secondary efficacy outcomes, and any adjudicated bleeding events in RECORD1–4. Treatment effect (rivaroxaban vs enoxaparin regimens) was expressed on the odds-ratio (OR) scale for total VTE (the composite of any deep vein thrombosis, non-fatal pulmonary embolism and all-cause mortality, modified-intention-to-treat [mITT] population) and major VTE (the composite of proximal deep vein thrombosis, non-fatal pulmonary embolism and VTE-related death, mITT population for major VTE) at the end of the planned medication period. For any bleeding (major and non-major bleeding after the start of study medication up to 2 days after the last dose, safety population) the hazard ratio (HR) was used. Separate analyses were done for each subgroup. These pooled analyses show consistently superior efficacy to enoxaparin, irrespective of patients’ age (<65, 65–75, >75 yrs), weight (≤70, >70–90, >90kg), gender, or renal function (CrCl >80, 50–80, <50 ml/min). Interaction testing in logistic regression models provided no indication of treatment effect differences in these subgroups, except for total VTE and the CrCl subgroups, where treatment effect with rivaroxaban appeared to be larger for the >80 and <50 ml/min group compared with the 50–80 ml/min group. With respect to any bleeding, the risk on rivaroxaban relative to enoxaparin regimens was comparable across gender and the different age, body weight and renal function (>30 ml/min CrCl) groups studied. Similar trends were seen in the smaller subgroups of body weight extremes (>110 kg subgroup - total VTE: 5/100 [5.0%] vs 8/119 [6.7%], respectively; ≤50 kg subgroup - any bleeding: 12/147 [8.2%] vs 8/162 [4.9%], respectively). These results suggest that age, body weight, gender and renal function (>30 ml/min CrCl) have no clinically relevant effect on the efficacy or safety of rivaroxaban as thrombroprophylaxis following major orthopedic surgery. Subgroup Total VTE Odds ratio (rivaroxaban vs enoxaparin regimens) (95% CI Major VTE Odds ratio (rivaroxaban vs enoxaparin regimens) (95% CI) Any major or non-major bleeding Hazard ratio (rivaroxaban vs enoxaparin regimens) (95% CI) *Because of study exclusion criteria, few patients had CrCl <30 ml/min, CI = confidence interval Age <65 years 0.40 (0.28–0.55) 0.22 (0.10–0.44) 1.05 (0.86–1.29) 65–75 years 0.39 (0.29–0.52) 0.18 (0.08–0.34) 1.11 (0.90–1.38) >75 years 0.54 (0.36–0.81) 0.51 (0.21–1.15) 1.10 (0.79–1.52) Weight ≤70kg 0.43 (0.31–0.60) 0.25 (0.11–0.52) 1.17 (0.91–1.51) >70–90kg 0.45 (0.34–0.59) 0.21 (0.11–0.39) 0.95 (0.77–1.17) >90kg 0.38 (0.25–0.57) 0.32 (0.13–0.69) 1.22 (0.95–1.58) Gender Male 0.35 (0.25–0.48) 0.21 (0.10–0.40) 1.12 (0.93–1.36) Female 0.47 (0.37–0.59) 0.27 (0.16–0.45) 1.06 (0.87–1.28) CrCl (ml/min) >80 0.35 (0.27–0.46) 0.22 (0.12–0.38) 1.12 (0.94–1.35) 50–80 0.60 (0.45–0.81) 0.30 (0.15–0.56) 0.99 (0.79–1.24) <50* 0.32 (0.15–0.64) 0.23 (0.02–1.15) 1.07 (0.64 – 1.79)