Pretreatment with Prasugrel Associated with Increase in Major Bleeding Complications

P2Y₁₂ receptor antagonists are effective in patients with non–ST-segment elevation (NSTE) acute coronary syndromes. A loading dose of clopidogrel is required in patients undergoing percutaneous coronary intervention (PCI); however, clopidogrel does not become biologically and clinically effective until several hours after administration.

Prasugrel and ticagrelor, P2Y₁₂ receptor antagonists, are more potent agents and have a more rapid onset of action compared with clopidogrel. These drugs have been shown to be more effective than clopidogrel in patients with acute coronary syndromes, but were associated with an increase in bleeding complications.

The effect of the timing of administration—before or after coronary angiography—is unknown. In 1 previous study, pretreatment was given before catheterization and in another study, P2Y₁₂ receptor antagonists were started after the coronary angiography was performed and the indication of PCI was confirmed.

Researchers recently conducted the ACCOAST (Comparison of Prasugrel at the Time of Percutaneous Coronary Intervention or as Pretreatment at the Time of Diagnosis in Patients with Non–ST-Segment Elevation Myocardial Infarction) trial to determine the effect of administering the P2Y₁₂ antagonist prasugrel at the time of diagnosis versus administering it after the coronary angiography if PCI was indicated. They reported trial results online in the New England Journal of Medicine [doi:10.1056/NEJMoa1308075].

ACCOAST was a phase 3, randomized, double-blind, event-driven study sponsored by Daiichi Sankyo and Eli Lilly. The primary composite end point was the first occurrence of death from cardiovascular causes, myocardial infarction, stroke, urgent revascularization, or the need for rescue therapy with glycoprotein IIb/IIIa inhibitors through day 7 after randomization. Secondary efficacy end points included a composite of death from cardiovascular causes, myocardial infarction, or stroke; death from any cause; and stent thrombosis. Safety end points of major and minor bleeding according to Thrombolysis in Myocardial Infarction (TIMI) criteria were evaluated for all bleeding episodes and according to whether the bleeding was related or not related to coronary-artery bypass grafting (CABG).

The researchers randomly assigned 4033 patients to pretreatment with prasugrel (n=2037) or to no pretreatment with prasugrel (control group) (n=1996) from December 6, 2009, through November 16, 2012. The 2 groups were well balanced in baseline characteristics. Three patients were lost to follow-up through day 30.

PCI was performed in 68.7% of the patients (2770/4033), at a median time of 4.3 hours after the initial loading dose. Through day 7, the strategy chosen was CABG in 6.2% of the patients (249/4033) and medical management in 25.1% (1014/4033).

There was no significant difference in the incidence of the primary end point through day 7 after randomization between the 2 groups (10.0% in the pretreatment group and 9.8% in the control group; P=.81).

There was no significant between-group difference in any of the components of the primary end point, in total mortality, in the rate of stent thrombosis, or in prespecified composite secondary end points either at day 7 or at day 30.

The incidences of TIMI major bleeding and of TIMI major or minor bleeding through day 7 after the first loading dose were significantly higher in the pretreatment group than in the control group. 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.

Pretreatment did not reduce the rate of the primary outcome among patients undergoing PCI, but increased the rate of TIMI major bleeding at 7 days.

In summary, the researchers stated, “Among patients with NSTE acute coronary syndromes who were scheduled to undergo catheterization, pretreatment with prasugrel did not reduce the rate of major ischemic events up to 30 days, but increased the rate of major bleeding complications.”