ESC 2013 Report – ACCOAST – Pretreatment with prasugrel before angiography did not improve outcomes and worsened bleeding

Among patients with non-ST-segment elevation acute coronary syndrome (ACS), pretreatment with prasugrel before angiography did not improve outcomes and worsened bleeding, a randomized trial showed.

The rate of cardiovascular death, MI, stroke, urgent revascularization, or glycoprotein IIb/IIIa inhibitor rescue therapy through day 7 was 10% with pretreatment of all patients and 9.8% when prasugrel was given only after angiography resulted in planned use of percutaneous coronary intervention (HR 1.02, 95% CI 0.84-1.25), according to Gilles Montalescot, MD, PhD, of Pitié-Salpêtrière University Hospital in Paris.

That lack of efficacy was accompanied by a significant increase in all TIMI major bleeding — regardless of whether it was related to CABG — through day 7 (2.6% versus 1.4%; HR 1.90, 95% CI 1.19-3.02), Montalescot reported at the European Society of Cardiology meeting here. The findings were published simultaneously online in the New England Journal of Medicine.

“It’s probably time for a reappraisal of routine pretreatment strategies in non-ST-elevation ACS,” Montalescot said at a press briefing.

“Overall, these results indicate that patients with [non-ST-segment elevation MI] who are selected for an early invasive strategy will be best served by administration of prasugrel only after angiographic definition of their coronary anatomy,” John Keaney Jr., MD, of the University of Massachusetts Medical School in Worcester, wrote in an editorial accompanying the NEJM paper. “It remains to be seen whether a similar strategy could be applied to ticagrelor, the other high-potency P2Y₁₂ antagonist currently available.”

Montalescot noted that a strategy of pretreatment versus treatment in the cath lab has not been tested using ticagrelor because all of the patients in the pivotal PLATO trial were pretreated.

Two previous trials evaluating pretreatment with clopidogrel — one in patients with non-ST-segment elevation ACS and one in patients undergoing elective PCI — have suggested that the strategy reduces ischemic events at the cost of increased major bleeding. Those findings have formed the basis of a class I recommendation to pretreat patients with non-ST-segment elevation ACS who are scheduled to undergo an invasive procedure.

Recent observational studies and a meta-analysis have disputed the benefit of routine pretreatment with clopidogrel. But other P2Y₁₂ inhibitors — prasugrel and ticagrelor — are more potent and faster acting.

ACCOAST, which was conducted at 171 centers in 19 countries, was designed to compare pretreatment with prasugrel at the time of diagnosis of non-ST-segment elevation ACS before angiography with administration after angiography only if PCI was indicated.

Patients in the pretreatment group received a 30-mg loading dose of prasugrel before angiography and another 30-dose if PCI was indicated after angiography. Patients in the control group received prasugrel (60 mg) only if they underwent PCI.

The trial was stopped early after 4,033 of a planned 4,100 patients were enrolled because of a lack of efficacy and an increase in bleeding associated with pretreatment. All of the included patients (mean age 64) had a positive troponin level and were scheduled to undergo angiography within 48 hours after randomization.

After angiography, 68.7% of the patients underwent PCI, 25.1% received medical therapy alone, and 6.2% underwent CABG.

There were no differences between the pretreatment and control groups in the rate of the primary composite endpoint or any of the individual components either at 7 days or 1 month.

At 7 days, the rate of TIMI major bleeding not related CABG was nearly three times higher in the pretreatment group (1.3% versus 0.5%; HR 2.95, 95% CI 1.39-6.28) and the rate of life-threatening bleeding was more than five times higher (0.8% versus 0.2%; HR 5.56, 95% CI 1.63-19.0).

Rates of fatal bleeding and intracranial hemorrhage were similar in the two groups.

The findings were consistent in the patients who ultimately underwent PCI.

Reference: New England Journal of Medicine
Source reference: Montalescot G, et al “Pretreatment with prasugrel in non-ST-segment elevation acute coronary syndromes” N Engl J Med 2013; DOI: 10.1056/NEJM1308075.

Additional source: New England Journal of Medicine
Source reference:Keaney J Jr. “P2Y₁₂ inhibition in patients with NSTEMI — Can later be better?” N Engl J Med 2013; DOI: 10.1056/NEJMe1308820.

 

Disclosure:

Montalescot reported receiving consulting fees from Bayer, Boehringer Ingelheim, Europa, GlaxoSmithKline, Iroko Cardio International, Lead-Up, Novartis, Springer, TIMI Group, WebMD, and Wolters, consulting fees and grant support from Bristol-Myers Squibb, AstraZeneca, Biotronik, Eli Lilly, The Medicines Company, Medtronic, Menarini, Roche, sanofi-aventis, Pfizer, and Accumetrics, and grant support from Abbott Vascular, Daiichi Sankyo, Nanospheres, and Stentys. His co-authors reported relationships with Daiichi Sankyo, Eli Lilly, Menarini, Abbott, AstraZeneca, Iroko Cardio International, Adamed, Adyton Medical Polska, Abiomed Europe, Biotronik, Balton, Bayer, Braun, BioMatrix, Boston Scientific, Boehringer Ingelheim, Bracco, Bristol-Myers Squibb, Comesa Polska, Cordis, Cook, Covidien Polska, DRG MedTek, EuroCor, GE Healthcare, GlaxoSmithKline, HammerMed, Inspire MD, Medianet, Medtronic, The Medicines Company, Meril Life Sciences, Merck Sharp & Dohme, Orbus-Neich, Pfizer, Possis, ProCardia Medical, Promed, REVA Medical, sanofi-aventis, Siemens, Solvay, Stentys, St. Jude Medical, Terumo, Tyco, Volcano, Abbott Vascular, Correvio, Roche Diagnostics, Merck, Rome, Brahms, CSL Behring, Novartis, CERC, LFB, Fresenius, and Hexacath. Four of the authors are employees of and hold stock in Eli Lilly.

Keaney is an associate editor of the New England Journal of Medicine.

King reported relationships with Contact Surgical, the Harvard Clinical Research Institute, Duke University, Capricor Inc., Celonova Biosciences Inc., Wyeth Pharmaceuticals, and Merck.