Influence of model-predicted rivaroxaban exposure and patient characteristics on efficacy and safety outcomes in patients with acute coronary syndrome. (July 2019)

• Record Type: Journal Article
• Authors: 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
• Is Part Of: Therapeutic advances in cardiovascular disease. Volume 13(2019)
• Publication Date: 2019-07
• Subjects: acute coronary syndromes -- bleeding -- exposure–response analysis -- monitoring -- population pharmacokinetics -- rivaroxaban; Cardiovascular system -- Diseases -- Periodicals; Cardiovascular system -- Diseases -- Treatment -- Periodicals; Cardiovascular pharmacology -- Periodicals; Cardiovascular Diseases -- diagnosis -- Periodicals; Cardiovascular Diseases -- therapy -- Periodicals; Cardiovascular Agents -- therapeutic use -- Periodicals; Cardiovascular Diseases -- drug therapy -- Periodicals; Cardiovascular System -- drug effects -- Periodicals; Cardiologie; Hart- en vaatziekten; Appareil cardiovasculaire -- Maladies -- Périodiques; Appareil cardiovasculaire -- Maladies -- Traitement -- Périodiques; Pharmacologie cardiovasculaire -- Périodiques; 616.10605
• DOI: 10.1177/1753944719863641
• Languages: English
• ISSNs: 1753-9447

Abstract

Background: 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. Methods: A post hoc 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. Results: For the incidence of myocardial infarction (MI), ischemic stroke, or nonhemorrhagic cardiovascular death, hazard ratios (HRs) for steady-state maximum plasma concentration (Cmax ) in the 5th and 95th percentiles versus 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 Cmax [HR, 1.08; 95% CI, 1.06–1.11 (95th percentile versus median, 2.5 mg twice daily)], sex [HR, 0.56; 95% CI, 0.38–0.84 (female versus male)], and previous revascularization [HR, 0.62; 95% CI, 0.44–0.87 (no versus yes)]. Conclusions: 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.