Impact of proton pump inhibitors on efficacy of antiplatelet strategies with ticagrelor or aspirin after percutaneous coronary intervention: Insights from the GLOBAL LEADERS trial

Background: Several studies have suggested that proton pump inhibitors (PPIs) may reduce the antiplatelet effects of clopidogrel and/or aspirin, possibly leading to cardiovascular events. Aims: We aimed to investigate the association between PPI and clinical outcomes in patients treated with ticagrelor monotherapy or conventional antiplatelet therapy after percutaneous coronary intervention (PCI). Methods: This is a subanalysis of the randomized GLOBAL LEADERS trial, comparing the experimental antiplatelet arm (23-month ticagrelor monotherapy following 1-month dual antiplatelet therapy [DAPT]) with the reference arm (12-month aspirin monotherapy following 12-month DAPT) after PCI. Patient-oriented composite endpoints (POCEs: all-cause mortality, myocardial infarction, stroke, or repeat revascularization) and its components were assessed stratified by PPI use as a time-dependent covariate in patients with the experiment or reference antiplatelet arm. Results: Among 15,839 patients, 2115 patients (13.5%) experienced POCE at 2 years. In the reference arm, the use of PPIs was independently associated with POCE (hazard ratio [HR]: 1.27; 95% confidence interval [CI]: 1.12–1.44) and its individual components, whereas it was not in the experimental arm (HR: 1.04; 95% CI: 0.92–1.19; p_interaction = 0.035). During the second-year follow-up, patients taking aspirin with PPIs had a significantly higher risk of POCE compared to those on aspirin without PPIs (HR: 1.57; 95% CI: 1.27–1.94), whereas the risk did not differ significantly irrespective of PPI in ticagrelor monotherapy group (HR: 1.03; 95% CI: 0.83–1.28; p_interaction = 0.008). Conclusions: In contrast to conventional antiplatelet strategy, there were no evidence suggesting the interaction between ticagrelor monotherapy and PPIs on increased cardiovascular events, which should be confirmed in further studies. Clinical Trial Registration: URL: https://clinicaltrials.gov.