Antiplatelet agents remain a cornerstone of treatment for acute coronary syndrome. More than 15 years after the introduction of ticlopidine in coronary artery disease, the combination of aspirin with P2Y ₁₂ inhibitors has became a standard of care. However, the optimal timing of the introduction of P2Y ₁₂ inhibitors remains controversial. Clopidogrel is a prodrug that needs hepatic biotransformation in two important steps to irreversibly block the P2 ₁₂ receptor. New P2Y ₁₂ inhibitors – namely, prasugrel and ticagrelor – have a simpler hepatic metabolization and induce a rapid and intense level of platelet inhibition . These agents are proposed as first-line treatment for non–ST-segment elevation acute coronary syndromes (NSTE-ACS); however, the question of timing of administration has never been addressed in a dedicated randomized study. European and American guidelines recommend giving P2Y ₁₂ inhibitors as soon as possible; however, the evidence to support this statement is weak. A recent meta-analysis did not show a survival benefit for clopidogrel pretreatment in 37,000 patients undergoing percutaneous coronary intervention (PCI), while there was an excess of major bleeding and little impact on ischemic outcomes.

The ACCOAST study has addressed the question of optimal timing of P2Y ₁₂ inhibition in patients with non–ST-segment elevation myocardial infarction (NSTEMI) managed invasively within 48 hours of admission. In this study, 4033 patients were randomized to receive prasugrel as pretreatment or to selectively receive prasugrel at the time of PCI. Despite effective platelet inhibition at the time of PCI, pretreatment with prasugrel did not reduce the occurrence of the primary endpoint (a composite of cardiovascular death, myocardial infarction, stroke, urgent revascularization or glycoprotein IIb/IIIa inhibitor rescue therapy) ( Fig. 1 ). Moreover, pretreatment was associated with a twofold increase in major bleeding complications at 7 days. Interestingly, among the 69% of patients who underwent PCI, no evidence of reduction in ischemic complications was observed and pretreatment was associated with a threefold increased risk of major bleeding complications. Finally, there were significantly more major and life-threatening bleeding complications not related to coronary artery bypass graft (CABG) surgery in the pretreatment group than in the control group. These results were consistent across all the subgroups, including in patients in whom radial access was used for PCI.

Primary efficacy and safety endpoints at 30 days in the total and percutaneous coronary intervention (PCI) populations. TIMI: Thrombolysis in Myocardial Infarction Study Group.

The results of the ACCOAST study offer new insights into pretreatment with P2Y ₁₂ inhibitors in NSTEMI. The use of new P2Y ₁₂ inhibitors in NSTE-ACS may be postponed to the time of the decision about PCI, to avoid overtreatment in patients who may need CABG surgery or medical treatment . Can the ACCOAST results be applied to other P2Y ₁₂ inhibitors, such as clopidogrel and ticagrelor? For clopidogrel, the oldest studies suggest a potential benefit for pretreatment when there is a very long delay between randomization and PCI . More recent studies have not confirmed the benefit of pretreatment with shorter delays and higher doses of clopidogrel . For ticagrelor, in the PLATO trial , all patients were pretreated with clopidogrel, ticagrelor or both before PCI; the question of pretreatment has not been addressed for ticagrelor.

The potential risk/benefit ratio for pretreatment with new P2Y ₁₂ inhibitors must now be reconsidered for these agents in NSTE-ACS. Practical implications may be as follows: in patients with a short delay (< 24–48 hours) from admission to angiography, pretreatment should be avoided; in patients with a delay from admission to angiography of > 48 hours, pretreatment with either clopidogrel (on the basis of old data) or ticagrelor (without data) may be considered.