AHA: Platelet reactivity is not predictive of ischemic outcomes

No significant differences existed between prasugrel vs. clopidogrel in the occurrence of the primary efficacy endpoint through 30 months, and there is no significant association between platelet reactivity and occurrence of ischemic outcomes, according to a platelet function substudy of TRILOGY ACS, presented Nov. 4 as a late breaker at the American Heart Association’s (AHA) scientific sessions in Los Angeles.

However, among patients with acute coronary syndrome (ACS) without ST-segment elevation and initially managed without revascularization, prasugrel was associated with lower platelet reactivity than clopidogrel, irrespective of age, weight and dose, wrote the study authors in the Journal of the American Medical Association, where the substudy was simultaneously published.

Lead investigator Paul A. Gurbel, MD, director of cardiovascular research at the Sinai Center for Thrombosis Research in Baltimore, when presenting the study at AHA, said that few studies have evaluated time-dependent relationships of platelet reactivity with ischemic event occurrence, nor is there information available on platelet function and ischemic event occurrence in ACS patients managed medically without revascularization.

Researchers enrolled patients with medically managed unstable angina or non–STEMI in the original TRILOGY ACS trial (2008 to 2011), comparing clopidogrel vs. prasugrel. Of 9,326 participants, 27.5 percent were included in the platelet function substudy, with 1,286 treated with prasugrel and 1,278 treated with clopidogrel.

Patients received aspirin with either prasugrel (10 or 5 mg/d) or clopidogrel (75 mg/d), and those 75 years or older and those younger than 75 years who weighed less than 60 kg received a 5 mg prasugrel maintenance dose. Also, platelet reactivity, measured in P2Y12 reaction units (PRUs), was performed at baseline, at two hours, and at one, three, six, 12, 18, 24 and 30 months after randomization. The primary efficacy endpoint was a composite of cardiovascular death, MI or stroke through 30 months.

Among participants younger than 75 years and weighing 60 kg or more, the median PRU values at 30 days were 64 in the prasugrel group vs. 200 in the clopidogrel group, “a difference that persisted through all subsequent time points,” wrote the study authors. For participants younger than 75 years and weighing less than 60 kg, the median 30-day PRU values were 139 for the prasugrel group vs. 209 for the clopidogrel group, and for participants 75 years or older, the median PRU values were 164 for the prasugrel group vs. 222 for the clopidogrel group.

At 30 months, the rate of the primary efficacy endpoint was 17.2 percent (160 events) in the prasugrel group vs. 18.9 percent (180 events) in the clopidogrel group. “There were no significant differences in the continuous distributions of 30-day PRU values for participants with a primary efficacy endpoint event after 30 days (214 patients) compared with participants without an event (1,794 patients) and no significant relationship between the occurrence of the primary efficacy endpoint and continuous PRU values,” they wrote. Gurbel et al observed similar findings with 30-day PRU cut points used to define high on-treatment platelet reactivity—PRU more than 208 and PRU more than 230.

The lack of significant independent association between platelet reactivity and ischemic outcomes may explain comparable clinical outcomes in the main TRILOGY ACS, Gurbel said at AHA.12.

“Where does this leave the hypothesis that platelet function testing can identify patients at high risk of cardiovascular events and in turn guide the intensification of antiplatelet therapy?” questioned Matthew J. Price, MD, of Scripps Clinic and the Scripps Translational Science Institute in La Jolla, Calif., in the accompanying JAMA editorial.

The findings provide “important insights” about the limitations of platelet function testing and intensified P2Y12 inhibition in clinical practice, wrote Price. “First, the association between P2Y12-mediated platelet reactivity and outcomes appears to depend critically on the context within which it is measured.”

However, extrapolating the findings of the TRILOGY ACS platelet function substudy to all patients with ACS managed noninvasively “may be problematic,” cautioned Price. “In addition, the TRILOGY ACS substudy does not address the potential clinical efficacy of platelet function testing to guide therapy in patients with ACS treated with PCI.”

He recommended that systematic blood sample collection should be considered in randomized clinical trials designed to evaluate novel therapeutics or to expand product labeling. “This might permit pharmacodynamic or exploratory pharmacogenomic analyses by independent groups that might be useful in identifying individuals who may safely derive the greatest treatment benefit,” Price concluded.