Abstract Body (Do not enter title and authors here): Background:
Polypharmacy is increasingly prevalent among patients with acute coronary syndrome (ACS) due to the burden of multimorbidity and guideline-recommended therapies. However, the impact of polypharmacy on cardiovascular (CV) outcomes in ACS remains uncertain.

Aims:
To determine the relationship between polypharmacy and major adverse CV events (MACE, defined as the composite of CV death, myocardial infarction [MI], or stroke) among patients with ACS.

Methods:
The ATLAS ACS 2-TIMI 51 trial randomized patients with recent ACS to receive twice-daily doses of either 2.5 mg or 5 mg of rivaroxaban or placebo. Patients were categorized into three groups based on the number of baseline concomitant medications: non-polypharmacy (0–4), polypharmacy (5–9), and hyper-polypharmacy (≥10). Cumulative incidence of events over 720 days was estimated using the Kaplan-Meier method. The association between polypharmacy status and MACE was assessed using the log-rank test and Cox proportional hazards models.

Results:
Among 15,342 ACS patients, 6,804 (44.3%) were in the polypharmacy group and 3,575 (23.3%) in the hyper-polypharmacy group. Hyper-polypharmacy was associated with a greater risk of MACE compared to both polypharmacy and non-polypharmacy groups (11.8% vs. 9.3% vs. 8.1%; p = 0.0001; HR = 1.25 [95% CI: 1.07–1.45] and HR = 1.42 [95% CI: 1.21–1.68], respectively). A similar pattern was observed for MI (7.1% vs. 5.7% vs. 5.1%; p = 0.0015; HR = 1.24 [95% CI: 1.03–1.50] and HR = 1.47 [95% CI: 1.19–1.82]). There were no significant differences in the incidence of CV death or stroke across polypharmacy categories. The efficacy of rivaroxaban was not significantly modified by polypharmacy status (p for interaction = 0.93).

Conclusions:
Among patients with ACS, hyper-polypharmacy was common and associated with an increased risk of MACE, primarily driven by a higher incidence of MI. These findings underscore the need for future research to investigate how medication burden, treatment appropriateness, and potential drug–drug interactions influence CV outcomes in this population.