Objective: In closely monitored randomized controlled trials, newer P2Y12 agents (ticagrelor and prasugrel) reduced cardiovascular outcomes compared to clopidogrel following percutaneous coronary intervention (PCI) in acute coronary syndrome (ACS). However, the bleeding risk associated with the use of these newer agents in real-world practice is not well understood. This study aimed to evaluate the comparative safety of each P2Y12 inhibitor on hospitalizations due to major bleeding in a real-world population.

Methods: This retrospective, propensity score-matched (PSM) cohort study utilized the IBM MarketScan® database (2013-2018) to identify incident users of P2Y12 inhibitors with age ≥ 18 years. The primary safety outcome was hospitalization due to any major bleeding event including gastrointestinal, intracranial, and other serious forms of bleeding. In pair-wise comparisons using cox-proportional hazards models, ticagrelor, prasugrel, and clopidogrel users were compared for the primary safety outcome at 30, 90, and 180 days following the first prescription of P2Y12 inhibitor after PCI.

Results: There were 21,719 (ticagrelor vs clopidogrel), 11,513 (prasugrel vs clopidogrel), and 11,065 (ticagrelor vs prasugrel) PSM pairs. Overall the risk of major bleeding was similar for all P2Y12 agents. Hospitalization for major bleeding was generally lower among ticagrelor users vs clopidogrel and higher among prasugrel users compared to clopidogrel. However, the only comparison to reach statistical significance was a 66% higher risk of major bleeding at 90 days with prasugrel use compared to clopidogrel (HR 1.66; 95% CI, 1.11-2.48).

Conclusion: The risk of hospitalization due to major bleeding was similar between the comparisons made with a few exceptions at 90-day outcomes, wherein prasugrel appeared to be associated with safety issues compared to clopidogrel. These results provide guidance for clinical practice that is often not available during the drug approval process. This study has important clinical implications for the safe management of ACS with P2Y12 inhibitors.