Pretreatment with the P2Y₁₂ antagonist prasugrel in patients with non-ST–segment elevation acute coronary syndromes did not reduce the rate of major ischemic events, but did increase the rate of major bleeding complications within 30 days of coronary angiography in the randomized, controlled, phase III ACCOAST trial.

The incidence of the primary efficacy endpoint – a composite of death from cardiovascular causes, myocardial infarction, stroke, urgent revascularization, or glycoprotein IIb/IIIa inhibitor rescue therapy through day 7 – was similar in 2,037 patients who were randomized to receive prasugrel before and after angiography, and in 1,996 patients who were randomized to receive treatment only after angiography (10.0% and 9.8%; respectively; hazard ratio, 1.02), Dr. Gilles Montalescot of Institut de Cardiologie, Centre Hospitalier Universitaire Pitié-Salpêtrière, Paris, and colleagues found.

The findings were similar, with no significant differences noted between the pretreatment and control groups with respect to the primary efficacy endpoint, among the 2,770 patients managed by percutaneous coronary intervention (PCI), compared with the entire cohort ultimately managed by PCI, coronary artery bypass grafting (CABG), or medical treatment alone.

However, the rate of a key safety endpoint – thrombolysis in myocardial infarction (TIMI) major bleeding episodes through day 7 – was increased in those in the pretreatment group, compared with the control group (2.6% vs. 1.4%; hazard ratio, 1.90), the investigators said, noting that the findings, which were reported at the annual congress of the European Society of Cardiology and simultaneously published online Sept. 1 in the New England Journal of Medicine, were confirmed at 30 days.

"There was an increase by a factor of 3 in all major bleeding not related to CABG and an increase by a factor of 6 in life-threatening bleeding not related to CABG. TIMI minor bleeding events were also increased with pretreatment compared with no pretreatment (hazard ratio, 2.50)," they wrote (N. Engl. J. Med. 2013 Sept. 1 [doi:10.1056/NEJM1308075]).

Patients in the trial were adults with a mean age of 63 years who had non-ST–segment elevation (NSTE) acute coronary syndromes and a positive troponin level. They were enrolled between Dec. 6, 2009, and Nov. 16, 2012. All were scheduled to undergo coronary angiography within 2-48 hours following randomization.

Those randomized to the pretreatment group received a 30-mg loading dose with prasugrel before angiography, and an additional 30 mg at the time of PCI. Those randomized to the control group received a placebo before the angiography, and 60 mg of prasugrel at the time of PCI.

In a pharmacodynamic substudy involving 23 patients, the investigators noted that "at the time of arterial access, a median of 4.8 hours after the first loading dose, there was greater platelet inhibition in the pretreatment group than in the control group, which may have contributed to the increased rate of bleeding complications in the pretreatment group."

Of note, the lack of protection afforded by prasugrel against ischemic events was demonstrated consistently across all prespecified subgroups, including high-risk groups such as the elderly, those with diabetes, and those with a Global Registry of Acute Coronary Events (GRACE) risk score of 140 or higher.

"This suggests that stronger [than clopidogrel] antiplatelet therapy does not prevent the occurrence of a myocardial infarction before catheterization or after PCI," the investigators wrote. Nonetheless, the lack of P2Y₁₂ inhibition in the control group did notresult in an excess of ischemic events in patients who underwent CABG or medical therapy. In fact, other studies have shown that currently, the risk of ischemic events is "extremely low" because of the short time between admission to the hospital and catheterization.

The benefit of adding clopidogrel to aspirin in patients with NSTE acute coronary syndromes was demonstrated in the Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE) study, in which a small subgroup of patients received the drug prior to undergoing PCI; the significant reduction in ischemic events set a precedent for clopidogrel treatment before catheterization, although subsequent studies have not supported the finding. The pretreatment use of clopidogrel and aspirin in patients with NSTE acute coronary syndrome to help reduce ischemic events following an invasive procedure is commonplace, and is included as a class I recommendation in guidelines from the American College of Cardiology Foundation–American Heart Association. This is despite a lack of rigorous studies supporting the practice, which has often been extended to new oral P2Y₁₂ antagonists like prasugrel as well, they explained.

However, prasugrel is more potent and has a more rapid onset of action than clopidogrel. "Our results support the administration of prasugrel when the coronary anatomy is known and after PCI is selected as the treatment strategy," they concluded.

This study was supported by Daiichi Sankyo and Eli Lilly. Multiple study authors, including Dr. Montalescot, reported having disclosures.

Prasugrel pretreatment ups bleeding risk in NSTE ACS