Anna Franzone1, Eugène McFadden2, Sergio Leonardi3, Raffaele Piccolo1, Pascal Vranckx4, Patrick W Serruys5, Edouard Benit6, Christoph Liebetrau7, Luc Janssens8, Maurizio Ferrario3, Aleksander Zurakowski9, Roberto Diletti10, Marcello Dominici11, Kurt Huber12, Ton Slagboom13, Paweł Buszman14, Leonardo Bolognese15, Carlo Tumscitz16, Krzysztof Bryniarski17, Adel Aminian18, Mathias Vrolix19, Ivo Petrov20, Scot Garg21, Christoph Naber22, Janusz Prokopczuk23, Christian Hamm24, Philippe Gabriel Steg25, Dik Heg26, Peter Jüni27, Stephan Windecker28, Marco Valgimigli29. 1. Department of Advanced Biomedical Sciences, Federico II University of Naples, Naples, Italy. 2. Cardialysis Core Laboratories and Clinical Trial Management, Rotterdam, the Netherlands; Department of Cardiology, Cork University Hospital, Cork, Ireland. 3. University of Pavia and Fondazione IRCCS Policlinico S. Matteo, Pavia, Italy. 4. Department of Cardiology and Critical Care Medicine, Hartcentrum Hasselt, Jessa Ziekenhuis, Belgium. 5. Department of Cardiology, Imperial College of London, London, United Kingdom. 6. Department of Cardiology, Jessa Hospital, Hasselt, Belgium. 7. Department of Cardiology, Kerckhoff Heart and Thorax Center, Bad Nauheim, Germany; German Center for Cardiovascular Research (DZHK), partner site RheinMain, Frankfurt am Main, Germany. 8. Imelda Hospital, Bonheiden, Belgium. 9. Department of Interventional Cardiology, American Heart of Poland SA, Chrzanów, Poland. 10. Thoraxcenter, Erasmus Medical Center, Rotterdam, the Netherlands. 11. S. Maria University-Hospital, Terni, Italy. 12. 3rd Medical Department, Cardiology, Wilhelminenhospital, and Sigmund Freud University Medical School, Vienna, Austria. 13. Onze Lieve Vrouwe Gasthuis Amsterdam, Amsterdam, the Netherlands. 14. Center for Cardiovascular Research and Development, American Heart of Poland, Sanatoryjna 1, Ustroń, Poland; Department of Epidemiology and Statistics, Medical University of Silesia, Poniatowskiego 15, Katowice. 15. Azienda Toscana Usl Sudest, Arezzo, Italy. 16. Cardiology Unit Sant'Anna Hospital, Ferrara, Italy. 17. Jagiellonian University Medical College, The John Paul II Hospital, Krakow, Poland. 18. Department of Cardiology, Centre Hospitalier Universitaire de Charleroi, Charleroi, Belgium. 19. Ziekenhuis Oost Limburg, Genk, Belgium. 20. Acibadem City Clinic Cardiovascular Center, Sofia, Bulgaria. 21. East Lancashire Hospitals NHS Trust, Blackburn, United Kingdom. 22. Contilia Heart and Vascular Centre, Stadtspital Triemli, Zürich, Switzerland. 23. Polsko-Amerykańskie Kliniki Serca Kozle, Kozle, Poland. 24. German Center for Cardiovascular Research (DZHK), partner site RheinMain, Frankfurt am Main, Germany; Department of Cardiology, Kerckhoff Heart and Thorax Center, Bad Nauheim, Germany. 25. Hôpital Bichat, AP-HP, Université Paris-Diderot, Paris, France. 26. Institute of Social and Preventive Medicine and Clinical Trials Unit, University of Bern, Bern, Switzerland. 27. Applied Health Research Centre, Li Ka Shing Knowledge Institute of St. Michael's Hospital, Department of Medicine, University of Toronto, Toronto, Ontario, Canada. 28. Department of Cardiology, Inselspital, University of Bern, Bern, Switzerland. 29. Department of Cardiology, Inselspital, University of Bern, Bern, Switzerland. Electronic address: marco.valgimigli@insel.ch.
Abstract
BACKGROUND: The GLOBAL LEADERS (GLOBAL LEADERS: A Clinical Study Comparing Two Forms of Anti-platelet Therapy After Stent Implantation) study randomly assigned 15,991 patients undergoingpercutaneous coronary intervention to 1-month dual antiplatelet therapy (DAPT) followed by 23-month ticagrelor monotherapy or conventional 12-month DAPT followed by 12-month aspirin. Apart from Q-wave myocardial infarction (MI), all study endpoints were analyzed as investigator reported. OBJECTIVES: This was a pre-specified ancillary study assessing whether experimental therapy is noninferior, and if met, superior, to conventional treatment for the coprimary efficacy endpoint of all-cause death, nonfatal MI, nonfatal stroke, or urgent target vessel revascularization and superior in preventing BARC 3 (Bleeding Academic Research Consortium) or 5 bleeding (coprimary safety endpoint) at 2 years with a 0.025 significance level to preserve nominal 5% alpha error. METHODS: An independent clinical event committee adjudicated investigator-reported and eventually unreported events of 7,585 patients from the 20 top-enrolling participating sites. RESULTS: The 2-year coprimary efficacy endpoint occurred in 271 (7.14%) and in 319 (8.41%) patients in the experimental and conventional groups, respectively (rate ratio [RR]: 0.85; 95% confidence interval [CI]: 0.72 to 0.99), fulfilling noninferiority (p noninferiority <0.001), but not superiority (p superiority = 0.0465). The rates of BARC 3 or 5 bleeding did not differ (RR: 1.00; 95% CI: 0.75 to 1.33; p = 0.986). A time-dependent treatment effect was observed with the experimental strategy being associated with a lower risk of MI (RR: 0.54; 95% CI: 0.33 to 0.88; p interaction = 0.062) and definite stent thrombosis (RR: 0.14; 95% CI: 0.03 to 0.63; p interaction = 0.007) after 1-year post-percutaneous coronary intervention. CONCLUSIONS:Ticagrelor monotherapy after 1-month DAPT was noninferior, but not superior, to conventional treatment in the prevention of ischemic events, and it did not decrease major bleeding risk as compared with conventional treatment. (GLOBAL LEADERS Adjudication Sub-Study [GLASSY]; NCT03231059).
RCT Entities:
BACKGROUND: The GLOBAL LEADERS (GLOBAL LEADERS: A Clinical Study Comparing Two Forms of Anti-platelet Therapy After Stent Implantation) study randomly assigned 15,991 patients undergoing percutaneous coronary intervention to 1-month dual antiplatelet therapy (DAPT) followed by 23-month ticagrelor monotherapy or conventional 12-month DAPT followed by 12-month aspirin. Apart from Q-wave myocardial infarction (MI), all study endpoints were analyzed as investigator reported. OBJECTIVES: This was a pre-specified ancillary study assessing whether experimental therapy is noninferior, and if met, superior, to conventional treatment for the coprimary efficacy endpoint of all-cause death, nonfatal MI, nonfatal stroke, or urgent target vessel revascularization and superior in preventing BARC 3 (Bleeding Academic Research Consortium) or 5 bleeding (coprimary safety endpoint) at 2 years with a 0.025 significance level to preserve nominal 5% alpha error. METHODS: An independent clinical event committee adjudicated investigator-reported and eventually unreported events of 7,585 patients from the 20 top-enrolling participating sites. RESULTS: The 2-year coprimary efficacy endpoint occurred in 271 (7.14%) and in 319 (8.41%) patients in the experimental and conventional groups, respectively (rate ratio [RR]: 0.85; 95% confidence interval [CI]: 0.72 to 0.99), fulfilling noninferiority (p noninferiority <0.001), but not superiority (p superiority = 0.0465). The rates of BARC 3 or 5 bleeding did not differ (RR: 1.00; 95% CI: 0.75 to 1.33; p = 0.986). A time-dependent treatment effect was observed with the experimental strategy being associated with a lower risk of MI (RR: 0.54; 95% CI: 0.33 to 0.88; p interaction = 0.062) and definite stent thrombosis (RR: 0.14; 95% CI: 0.03 to 0.63; p interaction = 0.007) after 1-year post-percutaneous coronary intervention. CONCLUSIONS:Ticagrelor monotherapy after 1-month DAPT was noninferior, but not superior, to conventional treatment in the prevention of ischemic events, and it did not decrease major bleeding risk as compared with conventional treatment. (GLOBAL LEADERS Adjudication Sub-Study [GLASSY]; NCT03231059).
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