CLOPIDOGREL IS THE MOST WIDELY PRESCRIBED PLATElet P2Y12 receptor inhibitor and is recommended, in addition to aspirin, for prevention of atherothrombotic recurrences inpatientswithacutecoronary syndromes (ACS) and for those undergoing percutaneous coronary interventions (PCI). Despite the proven efficacy of clopidogrel for patients in these high-risk settings, studies of platelet function testing (PFT) have shown broad variability in interindividual response to this pivotal antiplatelet agent. Importantly, PFT has prognostic implications because patients with high residual platelet reactivity (HRPR) vs low residual platelet reactivity (LRPR) have increased risks of ischemic and bleeding complications, respectively. These observations have led to investigations aimed at defining the best platelet function test and cutoff values to predict adverse outcomes as well as treatment strategies associated with optimized levels of platelet inhibitory effects; the ultimate goal is to minimize ischemic and bleeding complications. In this issue of JAMA, Parodi et al report the results of the RECLOSE 2–ACS (Responsiveness to Clopidogrel and Stent Thrombosis 2–ACS) study, in which they evaluated the prognostic implications of HRPR after clopidogrel loading in a large cohort of patients with ACS (n=1789) undergoing PCI and assessed effects of adjusting antiplatelet treatment regimens based on the results of PFT. The incidence of HRPR was 14% (248/1789). Despite intensification of antiplatelet treatment by means of increasing clopidogrel maintenance dosing or switching to ticlopidine, HRPR persisted in nearly 40% of patients. The authors observed that the primary end point (a composite of cardiac death, myocardial infarction, stroke, and any urgent coronary revascularization) at 2 years was significantly higher (an approximately 6% absolute increase) in patients with HRPR compared with patients with LRPR. The prognostic value of HRPR was confirmed in multivariable and propensity-scored analyses. The primary end point outcomes were driven by cardiac mortality, which increased more than 2-fold in patients with HRPR. Similarly, a doubling of stent thrombosis rates occurred in patients with HRPR. There were no significant differences in outcomes between patients whose platelet reactivity was lower than the HRPR threshold after antiplatelet treatment adjustment and those whose HRPR status persisted. The major strengths of this investigation are the inclusion of a large population of ACS patients and the long-term follow-up. In addition, the study confirms the prognostic value of HRPR for ischemic outcomes and the limited ability of earlier-generation P2Y12 inhibitors to influence HRPR status. However, several issues and uncertainties surround the field of PFT. In the study by Parodi et al, PFT was assessed using light transmittance aggregometry. Although the authors applied the gold standard PFT assay in a large population, this technology is not user-friendly and is limited only to experienced research laboratories. Indeed, using a more broadly applicable test, such as a point-of-care assay, would have been of greater practical value. In addition, even though the authors considered a previously defined cutoff level to define HRPR, such a threshold has been derived primarily from studies conducted by the same investigators and identified in patients with a different risk profile vs that of the current investigation. It is somewhat surprising that rates of HRPR in this ACS study population, an established predictor of HRPR, were similar to those in more stable patients defined in prior reports from the same investigators. These rates are markedly lower than those reported in other studies, including the GRAVITAS trial (41% HRPR rate), which was composed primarily of stable patients. Differences in type of PFT, cutoff values, and timing of testing could have affected these findings. Although this does not argue against the prognostic implications of HRPR as defined in RECLOSE 2–ACS, a different threshold may have had better predictive discrimination (the positive predictive value was only 15%). Thus, dedicated PFT studies may be warranted to define thresholds of platelet reactivity associated with adverse events specific to a given clinical setting. In the study by Parodi et al, HRPR status was defined based on a single measurement soon after PCI. However, studies of PFT have shown that platelet reactivity is subject to changes over time, particularly in the early weeks following PCI. Therefore, PFT early after PCI may not be the optimal time for testing, and serial PFT measurements has been suggested to better define levels of on-treatment