Clopidogrel is a prodrug that needs to be converted into an active metabolite in order to be active, however wide interindividual variability has been noted both in the concentration of active metabolite and also platelet responsiveness. The GRAVITAS (Gauging Responsiveness with A VerifyNow assay – Impact on Thrombosis and Safety) aimed to investigate the effect of high-dose vs standard-dose clopidogrel in patients with high on-treatment platelet reactivity after PCI.
The study was a randomised, double-blind, active-control trial assessing patients who underwent drug-eluting stent implantation. Those with high platelet reactivity using the VerifyNow assay – despite clopidogrel therapy – were randomised to either high-dose (600mg followed by daily 150mg) or standard-dose (75mg daily) clopidogrel. The primary endpoint was the six-month incidence of death from cardiovascular causes, nonfatal myocardial infarction, or stent thrombosis. Bleeding and platelet reactivity outcomes were also analysed.
At six-month follow-up, the primary end point had occurred in 2.3% of patients receiving high-dose and 2.3% of patients receiving standard-dose clopidogrel (p=.97). Of note, severe or moderate bleeding was not increased with the high-dose regimen (1.4% vs 2.3%; P=.10), however high-dose clopidogrel caused a 22% absolute reduction in the rate of high on-treatment platelet reactivity at thirty days (P<.001).
The use of high-dose clopidogrel in patients with high on-treatment platelet reactivity after PCI was not associated with any improvement in clinical outcomes, despite an overall lowering in platelet reactivity.
- Price MJ, Berger PB, Teirstein PS et al. Standard- vs High-Does Clopidogrel Based on Platelet Function Testing After Percutaneous Coronary Intervention. JAMA 2011;305:1097-1105.