Timing of Oral P2Y 12 Inhibitor Administration in Patients With Non-ST-Segment Elevation Acute Coronary Syndrome.

Background: Although oral P2Y ₁₂ 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 P2Y ₁₂ 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 P2Y ₁₂ 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 P2Y ₁₂ 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 P2Y ₁₂ Receptor Blockers In Non-ST Elevated Acute Coronary Syndromes With Initial Invasive Indication [DUBIUS]; NCT02618837).
Competing Interests: Author Relationship With Industry This work was funded by the Italian Society of Interventional Cardiology (SICI-GISE). Dr. Tarantini has received Speakers Bureau fees from AstraZeneca, Daiichi-Sankyo, and Eli Lilly. Dr. Mojoli has received individual payments for participating on the Advisory Boards of The Medicines Company and Abbott Vascular; and has been a speaker at scientific congresses from AstraZeneca, Daiichi-Sankyo, Chiesi Farmaceutici, and Servier; and his institution has received an unconditioned research grant from Chiesi Farmaceutici. Dr. Varbella has received consulting fees/honoraria from AstraZeneca, Daiichi-Sankyo, Bayer, Pfizer, Boehringer Ingelheim, Servier, Amgen, Sanofi, Piam, Alvi Medica, Teleflex, and Stenty. Dr. Caporale has received an Advisory Board fee from AstraZeneca. Dr. Rigattieri has received a consulting fee from AstraZeneca; and has received a Speakers Bureau fee from Eli Lilly. Dr. Andò has received individual payments as a consultant, for serving on the Advisory Board, or as a speaker at scientific congresses from AstraZeneca, Daiichi-Sankyo, Chiesi Farmaceutici, Pfizer–Bristol Myers Squibb, Boehringer Ingelheim, and Biosensors. Dr. Saia has received Speakers Bureau fees from AstraZeneca and Daiichi-Sankyo. Dr. Ferlini has received individual payment as a consultant, for serving on the Advisory Board, or as a speaker at scientific congresses from AstraZeneca, Chiesi Farmaceutici, Bayer, Biosensors, Sanofi, and Boehringer Ingelheim. Dr. Angiolillo has received consulting fees or honoraria as an individual from Abbott, Amgen, Aralez, AstraZeneca, Bayer, Biosensors, Boehringer Ingelheim, Bristol Myers Squibb, Chiesi, Daiichi-Sankyo, Eli Lilly, Haemonetics, Janssen, Merck, PhaseBio, PLx Pharma, Pfizer, Sanofi, and The Medicines Company; has received payment as an individual for participation in review activities from CeloNova and St. Jude Medical; and has received institutional payments for grants from Amgen, AstraZeneca, Bayer, Biosensors, CeloNova, CSL Behring, Daiichi-Sankyo, Eisai, Eli-Lilly, Gilead, Idorsia, Janssen, Matsutani Chemical Industry Co., Merck, Novartis, Osprey Medical, Renal Guard Solutions, and the Scott R. MacKenzie Foundation. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
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