Zhang Liping, Yan Xiaoyu, Nandy Partha, Willmann Stefan, Fox Keith A A, Berkowitz Scott D, Sharma Amarnath, Hermanowski-Vosatka Anne, Schmidt Stephan, Weitz Jeffrey I, Garmann Dirk, Peters Gary
Global Clinical Pharmacology, Janssen Research and Development, LLC, 5 Pauma Valley Ct, Raritan, NJ 08558, USA.
Janssen Research & Development, LLC, Raritan, NJ, USA.
Ther Adv Cardiovasc Dis. 2019 Jan-Dec;13:1753944719863641. doi: 10.1177/1753944719863641.
This analysis aimed to evaluate the impact of rivaroxaban exposure and patient characteristics on efficacy and safety outcomes in patients with acute coronary syndrome (ACS) and to determine whether therapeutic drug monitoring might provide additional information regarding rivaroxaban dose, beyond what patient characteristics provide.
A exposure-response analysis was conducted using data from the phase III ATLAS ACS 2 Thrombolysis in Myocardial Infarction (TIMI) 51 study, in which 15,526 randomized ACS patients received rivaroxaban (2.5 mg or 5 mg twice daily) or placebo for a mean of 13 months (maximum follow up: 31 months). A multivariate Cox model was used to correlate individual predicted rivaroxaban exposures and patient characteristics with time-to-event clinical outcomes.
For the incidence of myocardial infarction (MI), ischemic stroke, or nonhemorrhagic cardiovascular death, hazard ratios (HRs) for steady-state maximum plasma concentration (C) in the 5th and 95th percentiles the median were statistically significant but close to 1 for both rivaroxaban doses. For TIMI major bleeding events, a statistically significant association was observed with C [HR, 1.08; 95% CI, 1.06-1.11 (95th percentile median, 2.5 mg twice daily)], sex [HR, 0.56; 95% CI, 0.38-0.84 (female male)], and previous revascularization [HR, 0.62; 95% CI, 0.44-0.87 (no yes)].
The shallow slopes of the exposure-response relationships and the lack of a clear therapeutic window render it unlikely that therapeutic drug monitoring in patients with ACS would provide additional information regarding rivaroxaban dose beyond that provided by patient characteristics.
本分析旨在评估利伐沙班暴露量及患者特征对急性冠状动脉综合征（ACS）患者疗效和安全性结局的影响，并确定治疗药物监测是否能提供超出患者特征所提供的有关利伐沙班剂量的额外信息。
使用来自III期心肌梗死溶栓治疗（TIMI）51研究（即ATLAS ACS 2）的数据进行暴露-反应分析，其中15526例随机分组的ACS患者接受利伐沙班（2.5毫克或5毫克，每日两次）或安慰剂治疗，平均治疗13个月（最长随访：31个月）。采用多变量Cox模型将个体预测的利伐沙班暴露量和患者特征与事件发生时间的临床结局相关联。
对于心肌梗死（MI）、缺血性卒中或非出血性心血管死亡的发生率，利伐沙班两个剂量组第5百分位数和第95百分位数相对于中位数的稳态最大血浆浓度（C）的风险比（HR）具有统计学意义，但均接近1。对于TIMI大出血事件，观察到与C [HR，1.08；95% CI，1.06 - 1.11（第95百分位数相对于中位数，2.5毫克，每日两次）]、性别[HR，0.56；95% CI，0.38 - 0.84（女性相对于男性）]和既往血运重建[HR，0.62；95% CI，0.44 - 0.87（无相对于有）]存在统计学意义的关联。
暴露-反应关系的斜率较浅且缺乏明确的治疗窗，这使得对ACS患者进行治疗药物监测不太可能提供超出患者特征所提供的有关利伐沙班剂量的额外信息。
