Downstream or upstream administration of P2Y12 receptor blockers in non-ST elevated acute coronary syndromes: study protocol for a randomized controlled trial

Giuseppe Tarantini, Marco Mojoli, Ferdinando Varbella, Roberto Caporale, Stefano Rigattieri, Giuseppe Andò, Plinio Cirillo, Simona Pierini, Andrea Santarelli, Paolo Sganzerla, Nicoletta De Cesare, Ugo Limbruno, Alessandro Lupi, Roberto Ricci, Carlo Cernetti, Luca Favero, Francesco Saia, Loris Roncon, Valeria Gasparetto, Marco FerliniFederico Ronco, Luca Ferri, Daniela Trabattoni, Alessandra Russo, Vincenzo Guiducci, Carlo Penzo, Fabio Tarantino, Ciro Mauro, Alfredo Marchese, Battistina Castiglioni, Alessio La Manna, Matteo Martinato, Dario Gregori, Dominick J. Angiolillo, Giuseppe Musumeci

Research output: Contribution to journalArticlepeer-review


Background: The optimal timing to administer a P2Y12 inhibitor in patients presenting with a non-ST elevation acute coronary syndrome remains a topic of debate. Pretreatment with ticagrelor before coronary anatomy is known as a widely adopted strategy. However, there is poor evidence on how this compares with administration of a P2Y12 inhibitor after defining coronary anatomy (i.e., downstream administration). Moreover, there are limited head-to-head comparisons of the two P2Y12 inhibitors—ticagrelor and prasugrel—currently recommended by the guidelines. Study design: DUBIUS is a phase 4, multicenter, parallel-group, double randomized study conducted in NSTE-ACS patients designed to compare a pretreatment strategy (including only ticagrelor) versus a downstream strategy (including prasugrel or ticagrelor) and to compare downstream prasugrel with downstream ticagrelor. A total of 2520 patients will be randomly assigned to pretreatment with ticagrelor or to no pretreatment. The PCI group of the downstream arm will be further randomized to receive prasugrel or ticagrelor. The two primary hypotheses are that the downstream strategy is superior to the upstream strategy and that downstream ticagrelor is non-inferior to downstream prasugrel, both measured by the incidence of a composite efficacy and safety endpoint of death from vascular causes, non-fatal MI, or non-fatal stroke, and Bleeding Academic Research Consortium (BARC) type 3, 4, and 5 bleedings. Conclusions: The DUBIUS study will provide important evidence related to the benefits and risks of pretreatment with ticagrelor compared with a strategy of no pretreatment. Moreover, the clinical impact of using downstream ticagrelor compared with downstream prasugrel will be assessed. Trial registration: NCT02618837. Registered on 1 December 2015.

Original languageEnglish
Article number966
Issue number1
Publication statusPublished - Dec 2020


  • Bleeding
  • Ischemia
  • Non-ST elevation acute coronary syndrome
  • Oral P2Y inhibitors
  • Randomized clinical trial

ASJC Scopus subject areas

  • Medicine (miscellaneous)
  • Pharmacology (medical)


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