Measured drug effect and cardiovascular outcomes in patients receiving platelet P2Y12 receptor antagonists: clarifying the time and place for intensive inhibition.

THE CLINICAL EFFICACY OF ORAL P2Y12 ANTAGOnists in reducing recurrent cardiovascular events in patients with acute coronary syndromes (ACS) treated with percutaneous coronary intervention (PCI) or with either a conservative or early invasive strategy is well established. However, the effect of clopidogrel on P2Y12-mediated platelet reactivity varies widely among individuals. Platelet function tests are now clinically available that can measure P2Y12-mediated platelet reactivity, thereby providing a measurement of drug effect in patients treated with a P2Y12-receptor antagonist. Platelet function testing has provided a measure of certainty to the understanding of cardiovascular diseases: agents that provide powerful and consistent inhibition of P2Y12-mediated reactivity reduce postprocedural myocardial infarction and stent thrombosis, confirming the mechanistic hypothesis that P2Y12-receptor signaling is a major component of pathophysiological thrombus formation in patients with ACS treated with PCI. In turn, however, platelet function testing has added uncertainty because if platelet reactivity among patients while receiving treatment (“on-treatment” reactivity) is a measure of the risk of future events, then the comparative benefit of the newer, more expensive P2Y12 antagonists may uniquely depend on the magnitude of the effect of clopidogrel in a particular individual (however, different drugs may differentially affect the P2Y12 site. This concept of selective intensive antiplatelet therapy based on a measured drug effect, which has not been proven in a definitive, randomized trial, has provoked intense debate in the cardiology community. Although substantial data indirectly support the validity of the platelet function testing hypothesis, randomized trials to date have been limited by insufficient power, insufficient pharmacodynamic intervention, and potential selection bias for low-risk patients. Platelet function testing was not systematically performed in the trial that demonstrated the superiority of prasugrel over clopidogrel in patients with ACS treated with PCI. It is therefore speculative whether the benefit of prasugrel could be greatest in patients who demonstrate the least drug effect while receiving clopidogrel or could be minimal in patients treated with clopidogrel who display a potent drug effect. In this issue of JAMA, Gurbel and colleagues report the results of the platelet function substudy of the Targeted Platelet Inhibition to Clarify the Optimal Strategy to Medically Manage Acute Coronary Syndromes (TRILOGY ACS) trial, which included 2564 patients, approximately 28% of those enrolled in the overall trial. In the overall trial, prasugrel was not superior to clopidogrel in reducing recurrent cardiovascular events in medically managed patients with ACS who were not intended to undergo revascularization. In the current study, the investigators measured on-treatment reactivity at several time points over the course of follow-up using the VerifyNow P2Y12 test, which has been previously shown to reliably measure the P2Y12 effect of clopidogrel and prasugrel as well as correlate with active metabolite exposure of both drugs. The goals of the platelet function substudy were 2-fold: to confirm that prasugrel at the doses used provided a greater drug effect (ie, lower on-treatment reactivity) than clopidogrel and to determine whether there was an association between the achieved level of reactivity over time and clinical outcomes, irrespective of study drug assignment. At all time points tested, patients randomly assigned to receive 10 mg of prasugrel (or 5-mg prasugrel if aged 75 years or weight 60 kg) displayed significantly lower levels of on-treatment reactivity than those