"Prasugrel versus Clopidogrel in Patients with Acute Coronary Syndromes". The New England Journal of Medicine. 2007. 357:2001-2015. PubMed•Full text•PDF

## Clinical Question
Does prasugrel provide better cardiovascular outcomes compared to clopidogrel in patients with moderate-to-high-risk acute coronary syndromes and scheduled percutaneous coronary intervention?

## Bottom Line
In patients with acute coronary syndromes scheduled for percutaneous coronary intervention, prasugrel therapy was associated with significantly reduced rates of ischemic events, including stent thrombosis, but increased risk of major bleeding, including fatal bleeding.

## Major Points
Dual-antiplatelet therapy with aspirin and a thienopyridine is essential in the management of acute coronary syndromes and percutaneous coronary intervention. Despite the improvement in cardiovascular outcomes with clopidogrel, concerns regarding variability in responsiveness and delayed antiplatelet effects prompted research into more potent alternatives. Prasugrel, a novel thienopyridine, provides more consistent and stronger platelet inhibition compared to clopidogrel.

In this trial, prasugrel showed a relative reduction rate of 19% in the primary efficacy endpoint of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke. It also achieved significant reductions in myocardial infarction, urgent target-vessel revascularization, and stent thrombosis. Nevertheless, prasugrel use led to an increased incidence of major bleeding events, including a higher rate of fatal hemorrhages.

## Guidelines
Following the results of this study, guidelines may recommend prasugrel for patients with acute coronary syndromes who are undergoing percutaneous coronary intervention, considering the balance between its benefits and bleeding risks.

## Design
- Multicenter, double-blind, randomized, placebo-controlled trial
- N=13,608 patients with moderate-to-high-risk acute coronary syndromes with scheduled percutaneous coronary intervention
- Interventions: prasugrel (60 mg loading dose, 10 mg maintenance daily) vs. clopidogrel (300 mg loading dose, 75 mg maintenance daily) for 6 to 15 months
- Primary efficacy outcome: composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke
- Key safety endpoint: major bleeding

## Population
- Inclusion criteria: Moderate-to-high-risk acute coronary syndromes with scheduled percutaneous coronary intervention, including unstable angina, non-ST or ST-elevation myocardial infarction.
- Exclusion criteria: Increased risk of bleeding, current use of thienopyridine, history of stroke or TIA, etc.

## Interventions
- Prasugrel: 60 mg loading dose, followed by 10 mg maintenance dose daily, or
- Clopidogrel: 300 mg loading dose, followed by 75 mg maintenance dose daily

## Outcomes
- Primary efficacy outcome: 12.1% in clopidogrel group vs. 9.9% in prasugrel group (P<0.001)
- Secondary efficacy outcomes: Significant reductions in myocardial infarction, urgent target-vessel revascularization, and stent thrombosis with prasugrel
- Major bleeding events: Observed in 2.4% on prasugrel vs. 1.8% on clopidogrel (P=0.03)
- Life-threatening bleeding: Higher in prasugrel group (1.4% vs. 0.9%; P=0.01)

## Criticisms
- Increased risk of fatal bleeding with prasugrel raises concerns, particularly in high-risk subgroups such as the elderly, those with prior stroke, and patients weighing less than 60kg
- Post hoc analyses identified subgroups that may not have derived net clinical benefit or experienced harm from prasugrel

## Funding
The study was funded by research grants from Daiichi Sankyo and Eli Lilly.

## Further Reading
Full details of the study available at NEJM.org and ClinicalTrials.gov number, NCT00097591.