Key result
Higher predicted rivaroxaban exposure linked to ~8% higher TIMI major bleeding risk.
Why the study?
To evaluate the impact of rivaroxaban exposure and patient characteristics on ACS outcomes and determine if therapeutic drug monitoring adds value beyond patient characteristics.
Does model-predicted rivaroxaban exposure increase bleeding risk or improve efficacy outcomes in patients with acute coronary syndrome?
Cohort (n=15,526)
Double-blind
1:1:1 randomization to rivaroxaban 2.5 mg BID, 5 mg BID, or placebo in the original trial
Yes
Does model-predicted rivaroxaban exposure increase bleeding risk or improve efficacy outcomes in patients with acute coronary syndrome?
The shallow relationship between rivaroxaban exposure and clinical outcomes supports standard fixed dosing (2.5 mg twice daily) without routine therapeutic drug monitoring in ACS patients.
Shallow rivaroxaban exposure-response in ACS may support fixed dosing without monitoring; leaves open prospective validation beyond patient characteristics.
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.
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Zhang et al. (2019) conducted a cohort in Acute coronary syndrome (ACS) (n=15,526). Model-predicted rivaroxaban exposure (steady-state maximum plasma concentration, Cmax) vs. Median rivaroxaban exposure (or placebo zero exposure) was evaluated on TIMI major bleeding events (HR 1.08, 95% CI 1.06-1.11, p=<0.00001). Higher predicted rivaroxaban exposure (Cmax 95th percentile versus median) was associated with a small but statistically significant increase in TIMI major bleeding (HR 1.08, 95% CI 1.06-1.11) with very shallow exposure-response slopes.
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