Selective Serotonin Reuptake Inhibitors and Bleeding Risk in Patients Undergoing PCI on Dual Antiplatelet Therapy: A Retrospective Cohort Study

Abstract Background Mood disorders are highly prevalent among patients with coronary artery disease, yet pharmacologic treatment with selective serotonin reuptake inhibitors (SSRIs) poses potential bleeding concerns, particularly in patients receiving dual antiplatelet therapy (DAPT) after percutaneous coronary intervention (PCI). Despite biologic plausibility and observational evidence linking SSRIs to impaired platelet aggregation, data specific to PCI populations remain limited. Methods Using the TriNetX Global Collaborative Network, we identified adults (≥18 years) who underwent PCI with 12 months of DAPT (aspirin plus a P2Y12 inhibitor) between January 2013 and August 2024. Patients were subdivided into SSRI users and non-users. SSRI users were those who had a prescription record within 12 months prior to PCI and refilled records in both the 0–6 month and 6–12 month periods following index PCI. SSRI non-users were those who had no SSRI prescriptions within 12 months before and after index PCI. Individuals on anticoagulants, serotonin–norepinephrine reuptake inhibitors, or with recent major bleeding were excluded. Propensity-score matching (1:1) was used to balance baseline characteristics between SSRI users and non-users, and time-to-event outcomes were assessed using Kaplan-Meier and Cox proportional-hazards analyses. The primary endpoint was any major bleeding (intracranial hemorrhage ICH, gastrointestinal bleeding GIB, requirement for blood transfusion, or other major bleeding) over one year; secondary outcomes included ICH, GIB, transfusion, acute myocardial infarction, stroke/TIA, and all-cause mortality Results Of 29,973 PCI patients on DAPT, 3,847 used SSRIs. After matching, 3,023 SSRI users were compared with 3,023 non-users. Over one year, major bleeding occurred in 14.0% of SSRI users versus 11.3% of non-users (HR 1.28; 95% CI 1.11–1.48; p0.001). SSRI use was associated with significantly higher risk of ICH (1.2% vs 0.7%; HR 1.73; 95% CI 1.01–2.97; p=0.043) and GIB (7.4% vs 5.6%; HR 1.34; 95% CI 1.10–1.63; p=0.004). Red blood cell transfusion (4.6% vs 4.1%; HR 1.15; 95% CI 0.90–1.46; p=0.267), all-cause mortality (4.1% vs 3.8%; HR 1.08; 95% CI 0.83–1.39; p=0.573), and ischemic outcomes were comparable between groups. The association was strongest in patients aged ≥65 years, with hypertension, chronic kidney disease, or concomitant NSAID use, and was consistent across ACS and non-ACS presentations. Conclusion In this large, retrospective, real-world cohort, concomitant SSRI therapy during DAPT was associated with an increased bleeding risk, primarily driven by intracranial and gastrointestinal events, without a corresponding increase in ischemic outcomes, highlighting the importance of clinical awareness of this pharmacodynamic interaction, particularly in higher-risk subgroups, and underscoring the value of established bleeding prevention strategies in this population.