Both the European Society of Cardiology and the European Association for Cardio-Thoracic Surgery myocardial revascularization guidelines [Wijns W et al. Eur Heart J 2010] and American College of Cardiology Foundation, American Heart Association, and Society for Cardiovascular Angiography and Interventions percutaneous coronary intervention (PCI) guidelines [Levine GN et al. J Am Coll Cardiol 2011] recommend (with a Class I recommendation) the use of a loading dose of a P2Y₁₂ receptor inhibitor before PCI with stenting. David J. Cohen, MD, MSc, University of Missouri at Kansas City, Kansas City, Missouri, USA, suggested that despite the Class I recommendation, data supporting P2Y₁₂ inhibitor preloading before PCI are uncertain, as they are based predominantly on older trials that used conservative management strategies with prolonged treatment delays and with a substantial proportion of benefit occurring before the PCI.

The data for the current preloading guidelines come from 3 early trials: Percutaneous Coronary Intervention–Clopidogrel in Unstable Angina to Prevent Recurrent Events [PCI-CURE; Mehta SR et al. Lancet 2001], Clopidogrel for the Reduction of Events During Observation [CREDO; Steinhubl SR et al. JAMA 2002], and Clopidogrel as Adjunctive Reperfusion Therapy–Percutaneous Coronary Intervention [CLARITY-PCI; Sabatine MS et al. JAMA 2005], only 2 of which (PCI-CURE and CLARITY-PCI) showed significant reductions in end points with preloading. Of note, 2 of these trials (PCI-CURE and CLARITY-PCI) were subgroup analyses of larger trials based on postrandomization management and therefore were not truly randomized comparisons. CREDO, the only true randomized controlled trial of the 3, failed to show a benefit with preloading. The major concern with all 3 trials is the length of time between preload and PCI (median, 6 days in PCI-CURE; 3–24 hours in CREDO; and 2–8 days in CLARITY-PCI).

Upstream use of P2Y₁₂ loading prior to PCI with ticagrelor was superior to clopidogrel in the Platelet Inhibition and Patient Outcomes trial. However, there has been no study evaluating the potential benefit of pretreatment versus treatment at the time of PCI with ticagrelor.

A Comparison of Prasugrel at PCI or Time of Diagnosis of Non-ST-Elevation Myocardial Infarction [ACCOAST; Montalescot G et al. N Engl J Med 2013] was a Phase 3 trial designed to compare 2 prasugrel loading-dose regimens in patients with non–ST-segment elevation myocardial infarctions (NSTEMIs) with elevated troponin (≥ 1.5 times the upper limit of normal) who were intended to undergo an early (within 24 hours) invasive management strategy [Montalescot G et al. Am Heart J 2011]. Participants were randomized to either placebo (n = 1996) or prasugrel 30 mg (n = 2037) [Montalescot G et al. N Engl J Med 2013]. Following coronary angiography, subjects in the placebo group intended for PCI received the full loading dose of prasugrel 60 mg, while those in the prasugrel 30 mg group who were intended for PCI received an additional 30 mg of prasugrel. After PCI, all subjects received 5 or 10 mg of prasugrel daily (based on age and weight) for 30 days. The primary end point was a composite of cardiovascular (CV) death, MI, stroke, urgent revascularization, or glycoprotein (GP) IIb/IIIa bailout, at 7 days. Key safety end points include Thrombolysis In Myocardial Infarction (TIMI) major and minor bleeding risks [Montalescot G et al. Am Heart J 2011]. ACCOAST was stopped early because of an increase in major and life-threatening bleeding and no reduction in CV events.

Subjects were aged 64 years (mean) and mostly men; about one-quarter were high risk according to the Global Registry of Acute Coronary Events risk score. The median time from first loading dose to coronary angiography was 4.4 hours in the pretreated group and 4.2 hours in the placebo group.

At Day 30, preloading was not associated with an incremental benefit on the composite primary end point of CV death, MI, stroke, urgent revascularization, or GP IIb/IIIa bailout (HR, 0.997; 95% CI, 0.83 to 1.20; p = .98). The absence of additional benefit was consistent for each of the individual end points and among the subgroup of participants who underwent PCI (the majority but not all trial subjects).

Although relatively infrequent, there was a doubling of TIMI major bleeding among subjects who received the 30-mg prasugrel preload (HR, 2.0; 95% CI, 1.3 to 3.1; p = .002).

Dr. Cohen concluded that in patients with NSTEMIs undergoing invasive management within 48 hours of admission, pretreatment with prasugrel (compared with treatment started only at the time of PCI) does not decrease major ischemic events but increases major bleeding complications. It is unknown whether these findings apply to patients with longer waiting times or to those treated with other agents (eg, clopidogrel, ticagrelor). Thus, the results showed no benefit of pretreatment, and reexamination of the current guidelines may be warranted.