Timing of Oral P2Y12 Inhibitor Administration in Patients With Non-ST-Segment Elevation Acute Coronary Syndrome

J Am Coll Cardiol. 2020 Nov 24;76(21):2450-2459. doi: 10.1016/j.jacc.2020.08.053. Epub 2020 Aug 31.


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).

Keywords: bleeding; ischemia; non–ST-segment elevation acute coronary syndrome; oral P2Y(12) inhibitors.

Publication types

  • Clinical Trial, Phase IV
  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acute Coronary Syndrome / complications
  • Acute Coronary Syndrome / diagnostic imaging
  • Acute Coronary Syndrome / therapy*
  • Aged
  • Coronary Angiography
  • Female
  • Humans
  • Male
  • Middle Aged
  • Non-ST Elevated Myocardial Infarction / etiology
  • Non-ST Elevated Myocardial Infarction / prevention & control*
  • Platelet Aggregation Inhibitors / administration & dosage*
  • Prasugrel Hydrochloride / administration & dosage*
  • Purinergic P2Y Receptor Antagonists / administration & dosage*
  • Ticagrelor / administration & dosage*


  • Platelet Aggregation Inhibitors
  • Purinergic P2Y Receptor Antagonists
  • Prasugrel Hydrochloride
  • Ticagrelor

Associated data

  • ClinicalTrials.gov/NCT02618837