LOS ANGELES, CA—Among medically managed patients with acute coronary syndromes (ACS) but no ST-segment elevation, prasugrel is associated with lower platelet reactivity than clopidogrel, irrespective of age, weight, and dose. However, according to results of the TRILOGY ACS substudy presented Sunday, November 4, 2012, at the American Heart Association Scientific Sessions, platelet reactivity showed no association with the occurrence of ischemic outcomes.

The findings were published simultaneously online in the Journal of the American Medical Association.

For the main TRILOGY ACS (Targeted Platelet Inhibition to Clarify the Optimal Strategy to Medically Manage Acute Coronary Syndromes) trial, 9,326 patients with unstable angina or NSTEMI already taking aspirin were randomized to either prasugrel or clopidogrel. Patients were enrolled in 52 countries from June 2008 to September 2011; the results, presented in August at the European Society of Cardiology Congress, showed that prasugrel did not reduce the frequency of ischemic events compared with clopidogrel.

In the platelet function substudy, Paul A. Gurbel, MD, of Sinai Hospital of Baltimore (Baltimore, MD), and colleagues included 2,564 patients from 25 countries who had at least 1 valid P2Y12 reaction unit (PRU) measurement with the VerifyNow assay (Accumetrics, San Diego, CA). All patients were treated with aspirin and either prasugrel (n = 1,286; 5 mg/day for patients 75 years and older and younger than 75 years but weighing less than 60 kg; 10 mg/day for all other patients) or clopidogrel (n = 1,278; 75 mg/day). Platelet reactivity was measured at baseline and 2 hours and 1,3,6,12,18, 24, and 30 months after randomization.

Platelet Function Not an Independent Predictor

Approximately 20% of the substudy participants were 75 years or older (n = 515) and approximately 16% (n = 399) weighed less than 60 kg.

After randomization, prasugrel treatment was associated with lower median PRU values than clopidogrel treatment starting at 2 hours after the first dose, with pronounced differences at all time points from 30 days through 30 months in the subgroup of participants receiving prasugrel 10 mg/day. Within this group, median

30-day PRU values were 64 for the prasugrel group compared with 200 for the clopidogrel group (P < 0.001). Among participants who received the 5-mg/day maintenance dose of prasugrel, differences were observed in median PRU values through 18 months compared with those taking clopidogrel, but these differences were less pronounced than for participants who received prasugrel 10-mg/day.

At 30 days, prasugrel 5 mg was associated with a lower median 30-day PRU response than clopidogrel for participants younger than 75 years who weighed less than 60 kg (139 vs. 209; P < 0.001). Patients 75 years or older had a median PRU of 164 vs. 222 in the clopidogrel group (P < 0.001). The 30-day median PRU values for participants treated with prasugrel 10 mg were lower than those observed in patients taking prasugrel 5 mg for participants younger than 75 years and weighing less than 60 kg and for participants aged 75 years or older (both P < 0.001).

The Kaplan-Meier estimates for the primary efficacy endpoint (composite of cardiovascular death, MI, or stroke through 30 months) were similar for patients included in the platelet function substudy compared with those who were not (18.1% vs. 19.3%; P = 0.48) and—despite the differences achieved in high-treatment platelet reactivity—were also no different between the clopidogrel and prasugrel substudy treatment cohorts (17.2% vs. 18.9%; P = 0.29). Likewise, estimates of all-cause death and all MI through 30 months were similar based on inclusion in the substudy (all-cause death 11.0% vs. 11.9%; P = 0.74; MI 10.2% vs. 11.5%; P = 0.45) and by treatment among substudy participants (all-cause death 10.5% vs. 11.5%; P = 0.39; MI 10.5% vs. 10.0%; P = 0.83).

A ‘Precedent for Future Trials’

“The lack of significant independent association between platelet reactivity and ischemic outcomes may explain the comparable clinical outcomes in TRILOGY ACS,” Dr. Gurbel concluded.

In an accompanying editorial, Matthew J. Price, MD, of the Scripps Clinic (La Jolla, CA), questioned the hypothesis that platelet function testing can identify patients at high risk of cardiovascular events and in turn guide the intensification of antiplatelet therapy. “The findings provide important insights about the limitations of platelet function testing and intensified P2Y12 inhibition in clinical practice,” he wrote, adding that the association between platelet reactivity and outcomes depends “critically on the context within which it was measured.”

The study, Dr. Price continued, demonstrates that “P2Y12-mediated platelet reactivity during the subacute and chronic phases of therapy is not strongly associated with outcomes among medically treated patients with ACS.”

However, the findings may not apply to all ACS patients managed noninvasively, he noted. “Survival or other types of bias introduced by the delayed randomization design of the TRILOGY ACS trial may have attenuated the pathophysiologic importance of platelet P2Y12 receptor inhibition,” Dr. Price wrote.

Going forward, “the TRILOGY ACS platelet function substudy establishes an important precedent for future trials,” he concluded. “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.”

Time for a New Approach

Commenting on the study, Lars C. Wallentin, MD, PhD, of the Uppsala Clinical Research Center (Uppsala, Sweden), praised the study for providing “an opportunity for us to understand the mechanism both for success and for failure.”

However, he noted, the results leave “many more questions than answers.”

Dr. Wallentin suggested trying something new instead of repeatedly rehashing the same methodology. “We have many other options and maybe this is a learning experience,” he said. “We are only measuring 1 receptor on the platelet and there are so many other mechanisms we are not aware of whether or not they might be further activated. Let’s try something different.”

Study Details

Compared with those not included, participants in the substudy analysis were less likely to be 75 years or older, to present with NSTEMI, and to have prior peripheral arterial disease and prior CABG, but were more likely to have prior heart failure and to be treated with a daily aspirin dose of less than 100 mg. Within the substudy, baseline characteristics were well balanced between the treatment groups.

2. Price MJ. Measured drug effect and cardiovascular outcomes in patients receiving platelet P2Y12 receptor antagonists: Clarifying the time and place for intensive inhibition. JAMA. 2012.Epub ahead of print.

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