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

Masafumi Ono; Yoshinobu Onuma; Hideyuki Kawashima; Hironori Hara; Chao Gao; Rutao Wang; Neil O'Leary; Edouard Benit; Luc Janssens; Maurizio Ferrario; Aleksander Żurakowski; Marcello Dominici; Kurt Huber; Paweł Buszman; Scot Garg; Joanna J Wykrzykowska; Jan J Piek; Peter Jüni; Christian Hamm; Stephan Windecker; Pascal Vranckx; Efthymios N Deliargyris; Deepak L Bhatt; Robert F Storey; Marco Valgimigli; Patrick W Serruys; GLOBAL LEADERS trial investigators

doi:10.1002/ccd.30217

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

Catheter Cardiovasc Interv. 2022 Jul;100(1):72-82. doi: 10.1002/ccd.30217. Epub 2022 May 2.

Authors

Masafumi Ono^{1

2}, Yoshinobu Onuma², Hideyuki Kawashima^{1

2}, Hironori Hara^{1

2}, Chao Gao^{3

4}, Rutao Wang^{3

4}, Neil O'Leary², Edouard Benit^{5

6}, Luc Janssens⁷, Maurizio Ferrario⁸, Aleksander Żurakowski⁹, Marcello Dominici¹⁰, Kurt Huber¹¹, Paweł Buszman¹², Scot Garg¹³, Joanna J Wykrzykowska^{1

14}, Jan J Piek¹, Peter Jüni¹⁵, Christian Hamm¹⁶, Stephan Windecker¹⁷, Pascal Vranckx¹⁸, Efthymios N Deliargyris¹⁹, Deepak L Bhatt²⁰, Robert F Storey²¹, Marco Valgimigli²², Patrick W Serruys^{2

23}; GLOBAL LEADERS trial investigators

Affiliations

¹ Department of Clinical and Experimental Cardiology, Amsterdam Cardiovascular Sciences, Amsterdam UMC, Heart Center, University of Amsterdam, Amsterdam, The Netherlands.
² Interventional Medicine and Innovation, National University of Ireland Galway (NUIG), Galway, Ireland.
³ Department of Cardiology, Radboud University Medical Center, Nijmegen, The Netherlands.
⁴ Department of Cardiology, Xijing Hospital, Xi'an, China.
⁵ Department of Cardiology and Critical Care Medicine, Hartcentrum Hasselt, Jessa Ziekenhuis, Hasselt, Belgium.
⁶ Faculty of Medicine and Life Sciences, University of Hasselt, Hasselt, Belgium.
⁷ Imelda Ziekenhuis, Bonheiden, Belgium.
⁸ Policlinico San Matteo, Pavia, Italy.
⁹ Frycz-Modrzewski Academy-Cracow, Cracow, Poland.
¹⁰ Azienda Ospedaliera S. Maria, Terni, Italy.
¹¹ Wilhelminenspital, Vienna, Austria.
¹² Department of Epidemiology, Silesian Medical School, Katowice, Poland.
¹³ Department of Cardiology, Royal Blackburn Hospital, Blackburn, UK.
¹⁴ University Medical Center Groningen, Groningen, The Netherlands.
¹⁵ Applied Health Research Centre, Li Ka Shing Knowledge Institute, St Michael's Hospital, University of Toronto, Toronto, Ontario, Canada.
¹⁶ University of Giessen and Kerckhoff Heartand Thorax Center, University of Giessen, Bad Nauheim, Germany.
¹⁷ Department of Cardiology, Inselspital, University of Bern, Bern, Switzerland.
¹⁸ Jessa Ziekenhuis, Faculty of Medicine and Life Sciences at the Hasselt University, Hasselt, Belgium.
¹⁹ Cytosorbents Corporation, Monmouth Junction, New Jersey, USA.
²⁰ Harvard Medical School, Brigham and Women's Hospital Heart & Vascular Center, Boston, Massachusetts, USA.
²¹ Cardiovascular Research Unit, Department of Infection, Immunity and Cardiovascular Disease, University of Sheffield, Sheffield, UK.
²² Cardiocentro Ticino Institute, Università della Svizzera Italiana (USI), Lugano, Switzerland.
²³ NHLI, Imperial College London, London, UK.

Abstract

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.

Keywords: drug interaction; dual antiplatelet therapy; percutaneous coronary intervention; proton pump inhibitor; ticagrelor monotherapy.

Publication types

Randomized Controlled Trial

MeSH terms

Aspirin
Humans
Myocardial Infarction*
Percutaneous Coronary Intervention*
Platelet Aggregation Inhibitors / adverse effects
Proton Pump Inhibitors
Ticagrelor
Treatment Outcome

Substances

Platelet Aggregation Inhibitors
Proton Pump Inhibitors
Ticagrelor
Aspirin