Giuseppe Tarantini1, Marco Mojoli2, Ferdinando Varbella3, Roberto Caporale4, Stefano Rigattieri5, Giuseppe Andò6, Plinio Cirillo7, Simona Pierini8, Andrea Santarelli9, Paolo Sganzerla10, Luisa Cacciavillani11, Luciano Babuin11, Nicoletta De Cesare12, Ugo Limbruno13, Alberto Massoni14, Andrea Rognoni15, Daniela Pavan2, Flavia Belloni15, Carlo Cernetti16, Luca Favero16, Francesco Saia17, Luca Nai Fovino11, Giulia Masiero11, Loris Roncon18, Valeria Gasparetto19, Marco Ferlini20, Federico Ronco21, Roberta Rossini22, Paolo Canova23, Daniela Trabattoni24, Alessandra Russo25, Vincenzo Guiducci26, Carlo Penzo27, Fabio Tarantino28, Ciro Mauro29, Elena Corrada30, Giovanni Esposito7, Alfredo Marchese31, Sergio Berti32, Matteo Martinato11, Danila Azzolina11, Dario Gregori11, Dominick J Angiolillo33, Giuseppe Musumeci34. 1. Department of Cardiac, Thoracic, and Vascular Sciences and Public Health, University of Padova, Padova, Italy. Electronic address: giuseppe.tarantini.1@gmail.com. 2. Azienda Sanitaria Friuli Occidentale, Ospedale Santa Maria degli Angeli, Pordenone, Italy. 3. Ospedali Riuniti, Rivoli, Italy. 4. Ospedale Civile dell'Annunziata, Cosenza, Italy. 5. Sandro Pertini Hospital, Rome, Italy. 6. Azienda Ospedaliera Universitaria Policlinico "Gaetano Martino," Messina, Italy. 7. Department of Advanced Biomedical Sciences, Federico II University of Naples, Naples, Italy. 8. Ospedale Bassini, Cinisello Balsamo, Italy. 9. Cardiovascular Department, Infermi Hospital, Rimini, Italy. 10. ASST Bergamo Ovest, Ospedale di Treviglio, Italy. 11. Department of Cardiac, Thoracic, and Vascular Sciences and Public Health, University of Padova, Padova, Italy. 12. Policlinico San Marco, Zingonia, Italy. 13. Azienda Ospedaliera Grosseto, Grosseto, Italy. 14. Ospedale Universitario "Maggiore della Carità," Novara, Italy. 15. Ospedale S. Spirito, Rome, Italy. 16. Ospedale di Treviso ULSS 2, Treviso, Italy. 17. University Hospital of Bologna Sant'Orsola-Malpighi, Bologna, Italy. 18. Hospital Santa Maria della Misericordia, Rovigo, Italy. 19. Ca Ospedale P.Pederzoli, Peschiera del Garda, Italy. 20. Fondazione IRCCS Policlinico San Matteo, Pavia, Italy. 21. Ospedale dell'Angelo, Mestre, Italy. 22. SS. Croce e Carle Hospital, Cuneo, Italy. 23. Dipartimento Cardiovascolare, ASST Papa Giovanni XXIII, Bergamo, Italy. 24. Centro Cardiologico Monzino, IRCCS, Milano, Italy. 25. ASST Valle Olona, Presidio Ospedaliero San Antonio Abate, Gallarate, Italy. 26. Azienda Unità Sanitaria Locale-IRCCS di Reggio Emilia, Reggio Emilia, Italy. 27. Azienda Ospedaliero Universitaria di Ferrara Arcispedale Sant'Anna, Ferrara, Italy. 28. Morgagni-Pierantoni Hospital, Forlì, Italy. 29. Antonio Cardarelli Hospital, Naples, Italy. 30. Humanitas Clinical and Research Center IRCCS, Rozzano, Milan, Italy. 31. Anthea Hospital, GVM Care & Research, Bari, Italy. 32. Fondazione Toscana G. Monasterio, Ospedale del Cuore G. Pasquinucci, Massa, Italy. 33. Division of Cardiology, University of Florida College of Medicine, Jacksonville, Florida. 34. Division of Cardiology, Azienda Sanitaria Ospedaliera Ordine Mauriziano, Torino, Italy.
Abstract
BACKGROUND: Although oral P2Y12 inhibitors are key in the management of patients with non-ST-segment elevation acute coronary syndrome, the optimal timing of their administration is not well defined. OBJECTIVES: The purpose of this study was to compare downstream and upstream oral P2Y12 inhibitors administration strategies in patients with non-ST-segment elevation acute coronary syndrome undergoing invasive treatment. METHODS: We performed a randomized, adaptive, open-label, multicenter clinical trial. Patients were randomly assigned to receive pre-treatment with ticagrelor before angiography (upstream group) or no pre-treatment (downstream group). Patients in the downstream group undergoing percutaneous coronary intervention were further randomized to receive ticagrelor or prasugrel. The primary hypothesis was the superiority of the downstream versus the upstream strategy on the combination of efficacy and safety events (net clinical benefit). RESULTS: We randomized 1,449 patients to downstream or upstream oral P2Y12 inhibitor administration. A pre-specified stopping rule for futility at interim analysis led the trial to be stopped. The rate of the primary endpoint, a composite of death due to vascular causes; nonfatal myocardial infarction or nonfatal stroke; and Bleeding Academic Research Consortium type 3, 4, and 5 bleeding through day 30, did not differ significantly between the downstream and upstream groups (percent absolute risk reduction: -0.46; 95% repeated confidence interval: -2.90 to 1.90). These results were confirmed among patients undergoing percutaneous coronary intervention (72% of population) and regardless of the timing of coronary angiography (within or after 24 h from enrollment). CONCLUSIONS: Downstream and upstream oral P2Y12 inhibitor administration strategies were associated with low incidence of ischemic and bleeding events and minimal numeric difference of event rates between treatment groups. These findings led to premature interruption of the trial and suggest the unlikelihood of enhanced efficacy of 1 strategy over the other. (Downstream Versus Upstream Strategy for the Administration of P2Y12Receptor Blockers In Non-ST Elevated Acute Coronary Syndromes With Initial Invasive Indication [DUBIUS]; NCT02618837).
RCT Entities:
BACKGROUND: Although oral P2Y12 inhibitors are key in the management of patients with non-ST-segment elevation acute coronary syndrome, the optimal timing of their administration is not well defined. OBJECTIVES: The purpose of this study was to compare downstream and upstream oral P2Y12 inhibitors administration strategies in patients with non-ST-segment elevation acute coronary syndrome undergoing invasive treatment. METHODS: We performed a randomized, adaptive, open-label, multicenter clinical trial. Patients were randomly assigned to receive pre-treatment with ticagrelor before angiography (upstream group) or no pre-treatment (downstream group). Patients in the downstream group undergoing percutaneous coronary intervention were further randomized to receive ticagrelor or prasugrel. The primary hypothesis was the superiority of the downstream versus the upstream strategy on the combination of efficacy and safety events (net clinical benefit). RESULTS: We randomized 1,449 patients to downstream or upstream oral P2Y12 inhibitor administration. A pre-specified stopping rule for futility at interim analysis led the trial to be stopped. The rate of the primary endpoint, a composite of death due to vascular causes; nonfatal myocardial infarction or nonfatal stroke; and Bleeding Academic Research Consortium type 3, 4, and 5 bleeding through day 30, did not differ significantly between the downstream and upstream groups (percent absolute risk reduction: -0.46; 95% repeated confidence interval: -2.90 to 1.90). These results were confirmed among patients undergoing percutaneous coronary intervention (72% of population) and regardless of the timing of coronary angiography (within or after 24 h from enrollment). CONCLUSIONS: Downstream and upstream oral P2Y12 inhibitor administration strategies were associated with low incidence of ischemic and bleeding events and minimal numeric difference of event rates between treatment groups. These findings led to premature interruption of the trial and suggest the unlikelihood of enhanced efficacy of 1 strategy over the other. (Downstream Versus Upstream Strategy for the Administration of P2Y12 Receptor Blockers In Non-ST Elevated Acute Coronary Syndromes With Initial Invasive Indication [DUBIUS]; NCT02618837).
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