Higher rivaroxaban exposure (Cmax) was significantly associated with TIMI major bleeding (HR 1.08; 95% CI 1.06-1.11) but had little impact on efficacy outcomes in patients with ACS.
RCT (n=15,526)
randomized
Does therapeutic drug monitoring of rivaroxaban provide additional information regarding dose beyond patient characteristics in patients with acute coronary syndrome?
Therapeutic drug monitoring of rivaroxaban in patients with acute coronary syndrome is unlikely to provide additional dosing information beyond standard patient characteristics due to shallow exposure-response relationships.
Hazard Ratio: 1.08 (95% CI 1.06–1.11)
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 (C max ) 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 C max 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.
Zhang et al. (Tue,) conducted a rct in acute coronary syndrome (ACS) (n=15,526). Rivaroxaban vs. placebo was evaluated on TIMI major bleeding events (HR 1.08, 95% CI 1.06-1.11). Higher rivaroxaban exposure (Cmax) was significantly associated with TIMI major bleeding (HR 1.08; 95% CI 1.06-1.11) but had little impact on efficacy outcomes in patients with ACS.