The Effects of Rivaroxaban Exposure and Clinical Risk Factors on Efficacy and Safety Outcomes in Patients Treated for Venous Thromboembolism

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 the need for 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 treatment of deep vein thrombosis (DVT) or pulmonary embolism (PE) 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 (15 mg twice daily [BID] for 21 days followed by 20 mg once daily [OD] for up to 12 months) in the phase 3 EINSTEIN-DVT (NCT00440193) and EINSTEIN-PE (NCT00439777) trials (BID period, N = 4130; OD period, N = 3953). Due to a lack of measured PK data in the phase 3 trials, individual rivaroxaban exposure metrics (area under the concentration-time curve, maximum concentration [C_max] and trough concentration [C_trough]) were estimated using an integrated population PK model based on clinical risk factors, regimen and (where available) PT measurements. Exposure estimates were improved by application of an adjustment function based on a linear relationship between PK and prothrombin time measurements (measured centrally using a rivaroxaban-sensitive thromboplastin reagent) obtained in phase 2/3 rivaroxaban studies. Composite efficacy outcomes were: (1) objectively-documented recurrent DVT, or fatal or non-fatal PE; and (2) recurrent DVT, fatal or non-fatal PE, or death from any cause. Safety outcomes were major bleeding, and a composite of major and non-major clinically relevant (NMCR) bleeding. Relationships between exposure/clinical risk factors and outcomes were evaluated using logistic regression for the 21-day BID dosing period and Cox regression for the subsequent OD dosing period.

Results: Of the estimated exposure parameters, C_trough displayed the strongest associations for efficacy and safety during both dosing periods. The first and second composite efficacy outcomes occurred in 1.0% and 1.1% of patients, respectively, in the BID period, and 1.0% and 1.6% of patients, respectively, in the OD period. Individual predicted C_trough was significantly associated with the first efficacy outcome in both dosing periods (Table 1), and with recurrent DVT, fatal or non-fatal PE, or death from any cause in the BID period only (Figure 1, Table 1). Patients with reduced creatinine clearance (CrCL; < 50 mL/min) were more likely than patients with CrCL > 80 mL/min to develop one of the composite efficacy outcomes during the BID and OD dosing periods (Figure 1, Table 1). Active malignancy at randomization was significant for the second efficacy endpoint in the OD period (hazard ratio 5.31 [95% CI: 2.97-9.51]). Major bleeding and major and NMCR bleeding occurred in 0.4% and 4.3% of patients, respectively, in the BID period and in 0.6% and 6.0% of patients, respectively, in the OD period. None of the investigated exposure metrics was a significant predictor of major bleeding or major and NMCR bleeding in either dosing period. Clinical variables including a history of bleeding, low baseline hemoglobin and non-steroidal anti-inflammatory drug use were, however, significant predictors of bleeding events (Table 2). CrCL was not a significant predictor of bleeding events.

Conclusions: Estimated rivaroxaban exposure was significantly associated with efficacy outcomes but not with bleeding outcomes in patients with DVT or PE enrolled in the EINSTEIN-DVT and EINSTEIN-PE trials. Clinical risk factors had a substantial impact on outcomes. Based on these findings, it is unlikely that TDM would further improve the benefit-risk profile of rivaroxaban treatment in patients with venous thromboembolism.

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