Clinical Pharmacometrics, Bayer AG, Berlin, Germany.
Clinical Pharmacometrics, Bayer AG, Wuppertal, Germany.
J Thromb Thrombolysis. 2020 Jul;50(1):1-11. doi: 10.1007/s11239-020-02073-z.
Anticoagulant plasma concentrations and patient characteristics might affect the benefit-risk balance of therapy. This study assessed the impact of model-predicted rivaroxaban exposure and patient characteristics on outcomes in patients receiving rivaroxaban for venous thromboembolism treatment (VTE-T) using data from the phase 3 EINSTEIN-DVT and EINSTEIN-PE studies. In the absence of measured rivaroxaban exposure, exposure estimates were predicted based on individual increases in prothrombin time (PT) and the known correlation between rivaroxaban plasma concentrations and PT dynamics. The composite efficacy outcomes evaluated were recurrent deep-vein thrombosis (DVT) and pulmonary embolism (PE) and recurrent DVT, PE and all-cause death; safety outcomes were major bleeding and the composite of major or non-major clinically relevant (NMCR) bleeding. Exposure-response relationships were evaluated using multivariate logistic and Cox regression for the twice-daily (BID) and once-daily (OD) dosing periods, respectively. Predicted rivaroxaban exposure and CrCl were significantly associated with both efficacy outcomes in the BID period. In the OD period, exposure was significantly associated with recurrent DVT and PE but not recurrent DVT, PE and all-cause death. The statistically significant exposure-efficacy relationships were shallow. Exposure-safety relationships were absent within the investigated exposure range. During both dosing periods, low baseline hemoglobin and prior bleeding were associated with the composite of major or NMCR bleeding. In conclusion, based on the underlying data and analysis, no reliable target window for exposure with improved benefit-risk could be identified within the investigated exposure range. Therefore, monitoring rivaroxaban levels is unlikely to be beneficial in VTE-T.
抗凝血浆浓度和患者特征可能会影响治疗的获益风险平衡。本研究使用来自 3 期 EINSTEIN-DVT 和 EINSTEIN-PE 研究的数据，评估了模型预测的利伐沙班暴露量和患者特征对接受利伐沙班治疗静脉血栓栓塞症（VTE-T）患者结局的影响。在缺乏测量的利伐沙班暴露量的情况下，根据个体的凝血酶原时间（PT）增加和利伐沙班血浆浓度与 PT 动力学之间的已知相关性，预测暴露量估计值。评估的复合疗效结局包括复发性深静脉血栓形成（DVT）和肺栓塞（PE）以及复发性 DVT、PE 和全因死亡；安全性结局为大出血和大出血或非大出血具有临床意义（NMCR）复合事件。使用多变量逻辑回归和 Cox 回归分别评估了 BID 和 OD 给药期的暴露-反应关系。在 BID 期间，预测的利伐沙班暴露量和 CrCl 与疗效结局均显著相关。在 OD 期间，暴露量与复发性 DVT 和 PE 显著相关，但与复发性 DVT、PE 和全因死亡无关。暴露与疗效之间的统计学显著关系较浅。在研究的暴露范围内，未观察到暴露与安全性之间的关系。在两个给药期间，基线血红蛋白低和既往出血与大出血或 NMCR 复合事件相关。总之，基于基础数据和分析，在研究的暴露范围内，未确定可改善获益风险的暴露的可靠目标窗口。因此，监测利伐沙班水平在 VTE-T 中可能无益。
