Antiplatelet reduces cardiac events in PCI

November 7, 2007

Prasugrel, a new antiplatelet agent in Phase 3 clinical trials, is superior to clopidogrel in preventing major adverse cardiac events in patients undergoing percutaneous coronary intervention (pCI), but is associated with an increase in the risk of major bleeding.

Prasugrel, a new antiplatelet agent in Phase 3 clinical trials, is superior to clopidogrel inpreventing major adverse cardiac events in patients undergoing percutaneous coronary intervention(PCI), but is associated with an increase in the risk of major bleeding.

Despite the increased risk of major bleeding with prasugrel, the balance of efficacy and safetystrongly favored prasugrel over clopidogrel in the TRITON (Trial to Assess Improvement in TherapeuticOutcomes by Optimizing Platelet Inhibition with Prasugrel)-TIMI 38 trial, according to the study'sprincipal investigator Elliott M. Antman, MD.

Avoiding the drug in patients with a prior stroke or transient ischemic attack (TIA) and perhapsreducing the maintenance dose in older patients and those weighing less than 60 kg will improvefurther the net clinical benefit of prasugrel, Dr Antman said.

TRITON-TIMI 38 included 13,608 patients with acute coronary syndromes in whom PCI was scheduled. Theywere randomized to prasugrel, given as a 60-mg loading dose followed by a 10-mg/d maintenance dose,or clopidogrel, administered as a 300-mg loading dose followed by a 75-mg/d maintenance dose for 6 to15 months. The median duration of therapy was 12 months.

The incidence of the primary endpoint - a composite of cardiovascular death, nonfatal MI, and nonfatalstroke - occurred in 9.9% of patients randomized to prasugrel and 12.1% randomized to clopidogrel,corresponding to a 19% relative reduction in risk (P =.0004) in favor of prasugrel.

Major bleeding events occurred in 2.4% of patients assigned prasugrel compared with 1.8% assigned toclopidogrel, a 32% increase (P =0.03) associated with prasugrel.

There was also a favorable effect of prasugrel on stent thrombosis: 1.1% of the prasugrel-treatedpatients and 2.4% of the clopidogrel group had stent thrombosis - a 52% reduction (P

On a net clinical benefit endpoint that included all-cause mortality, nonfatal MI, nonfatal stroke,or nonfatal major bleed, prasugrel was associated with a 13% reduction in risk (P=.004).

The benefit with prasugrel was observed as early as 30 days and was maintained throughout thestudy.

Inhibition of platelet aggregation is superior with prasugrel compared with clopidogrel, Dr Antmansaid. Although a loading dose of 600 mg of clopidogrel is now common in patients undergoing PCI(TRITON used a 300-mg loading dose of clopidogrel), "prasugrel always had a higher inhibition ofplatelet aggregation even when compared with a 600-mg loading dose of clopidogrel," said Dr Antman,director, Samuel A. Levine Cardiac Unit, Brigham and Women's Hospital, Boston.

In a post-hoc subgroup analysis, patients with a prior stroke or TIA (approximately 4% of the study'spopulation) had an increase in major bleeding and worse outcomes with prasugrel than clopidogrel. Twoother subgroups - patients 75 years or older and patients weighing less than 60 kg - experienced anincrease in bleeding with prasugrel but had a tendency toward better outcomes.

Dr Antman postulated that a lower prasugrel maintenance dose may improve the benefit:risk ratio inolder patients and in those with low body weight; the results of a pharmacokinetic substudy of TRITONto be published in Circulation in December should add clarity to the potential benefit of dosemodifications in these subgroups.