The Effects of Rivaroxaban Exposure and Clinical Risk Factors on Efficacy and Safety Outcomes in the Prevention of Venous Thromboembolism after Elective Hip or Knee Replacement Surgery

Abstract Introduction: The oral factor Xa inhibitor rivaroxaban has previously demonstrated a predictable pharmacokinetic (PK) and pharmacodynamic profile, and has been developed for fixed dose administration without routine coagulation or therapeutic drug monitoring (TDM). The objectives of this study were to investigate the relationship between rivaroxaban exposure and efficacy/safety outcomes, and to evaluate the relative influence of relevant clinical risk factors in patients receiving rivaroxaban for venous thromboembolism prevention (VTE-P) after elective total hip replacement (THR) or total knee replacement (TKR) surgery to assess whether TDM might further improve the benefit-risk profile of rivaroxaban in this population. Methods: An exposure-response analysis was conducted using data from patients receiving rivaroxaban (10 mg once daily [OD] for ≤35 days after THR or ≤14 days after TKR) in the phase 3 REgulation of Coagulation in ORthopedic Surgery to prevent DVT and PE (RECORD) trials (efficacy population, n = 4246; safety population, n = 6097). Due to a lack of measured PK data in the phase 3 trials, individual rivaroxaban exposure metrics (area under the plasma concentration-time curve, maximum concentration and trough concentration [Ctrough]) were estimated using an integrated population PK model based on clinical risk factors, regimen and (where available) PT measurements. Exposure estimates were improved by applying an adjustment function based on the linear relationship between PK and prothrombin time measurements (measured centrally using a rivaroxaban-sensitive thromboplastin reagent) obtained in the phase 2/3 rivaroxaban studies. The composite efficacy outcome was total VTE (any objectively-documented asymptomatic or symptomatic deep vein thrombosis [proximal and/or distal], non-fatal pulmonary embolism and death). Safety endpoints were major bleeding, and a composite of major and non-major clinically relevant (NMCR) bleeding occurring (1) ≤3 days after surgery (days 1-4) and (2) >3 days after surgery (after day 4). The relationships between exposure/clinical risk factors and outcomes in terms of event rates were evaluated using logistic regression models. Results: The model-estimated rivaroxaban exposures are summarized in the Table. In the final model, age and creatinine clearance were included as forced variables for all endpoints. Exposure was not found to be a significant predictor of total VTE, major bleeding (days 1-4 and after day 4), or of the composite safety endpoint of major and NMCR bleeding during days 1-4. For major and NMCR bleeding after day 4, a statistically significant exposure-response relationship was observed, with Ctrough displaying the strongest association. The odds ratios (ORs) associated with Ctrough in the 5th and 95th percentiles versus the median were 0.82 (95% confidence interval [CI]: 0.77-0.87) and 1.68 (95% CI: 1.21-2.33), respectively. The relationship was shallow, with a predicted absolute increase in major and NMCR bleeding of ~1% at the 5th percentile of Ctrough to 2% at the 95th percentile (Figure). No clinical risk factors were predictors of total VTE or of major bleeding (days 1-4 and after day 4), or of major and NMCR bleeding after day 4. Male versus female sex (OR: 3.05; 95% CI: 1.92-4.93) and geographical region (OR: 1.63; 95% CI: 0.98-2.70, for the USA/Canada vs Western Europe) were significant predictors (p Conclusions: An exposure-response relationship for total VTE and major bleeding events was not observed in patients enrolled in the RECORD trials despite significant reductions in VTE with rivaroxaban versus the comparator enoxaparin, indicating a favorable benefit-risk ratio over the range of rivaroxaban concentrations observed with the 10 mg OD fixed dose. Exposure, and particularly Ctrough, was the predominant predictor of major and NMCR bleeding after day 4. These data are consistent with rivaroxaban phase 2 VTE-P studies, in which no significant dose-response relationship was observed for total VTE, but post-operative bleeding events increased dose dependently over the ranges of rivaroxaban doses of 5-40 mg OD and 2.5-30 mg twice daily. Based on these findings it is unlikely that TDM would further improve the benefit-risk profile of rivaroxaban for VTE prevention after THR and TKR. Download : Download high-res image (147KB) Download : Download full-size image Disclosures Berkowitz: Bayer US: Employment. Fox: Bayer HealthCare Pharmaceuticals: Consultancy, Honoraria; AstraZeneca: Research Funding; Janssen Biotech, Inc.: Consultancy, Honoraria. Schmidt: Bayer HealthCare Pharmaceuticals: Consultancy. Weitz: Bayer HealthCare Pharmaceuticals: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Portola Pharmaceuticals: Consultancy, Honoraria; Daiichi-Sankyo: Consultancy, Honoraria; Pfizer, Inc.: Consultancy, Honoraria; Janssen Biotech, Inc.: Consultancy, Honoraria; Ionis Pharmaceuticals: Consultancy, Honoraria; Boehringer Ingelheim: Consultancy, Honoraria; Novartis Pharmaceuticals: Consultancy, Honoraria; Merck & Co., Inc.: Consultancy, Honoraria. Garmann: Bayer AG: Employment. Kubitza: Bayer AG: Employment. Mueck: Bayer AG: Employment. Peters: Janssen Research & Development: Employment. Reinecke: Bayer AB: Employment; Bayer AG: Employment. Solms: Bayer AG: Employment. Spiro: Bayer US: Employment. Yan: Janssen Research & Development: Employment. Zhang: Janssen Research & Development: Employment. Willmann: Bayer AG: Employment.

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