Subanalysis of PLATO Study

Chicago—A genetic substudy of a phase 3 trial found that the benefit of ticagrelor compared with clopidogrel in patients with acute coronary syndrome (ACS) was not based on the presence of poor metabolizers of clopidogrel in the overall population. Results were presented at the ACC meeting in a poster titled Greater Efficacy of Ticagrelor Compared to Clopidogrel in Acute Coronary Syndrome Is Not Driven by Outcomes in Poor Metabolizers of Clopidogrel. The US Food and Drug Administration approved ticagrelor in July 2011 based on results of the PLATO (Platelet Inhibition and Patient Outcomes) study that demonstrated patients with ACS who took ticagrelor had a significant reduction in the primary end point (rate of cardiovascular death, myocardial infarction, or stroke) compared with those taking clopidogrel. There was no difference between the groups in the rate of overall major bleeding. The results were similar regardless of whether the patients had ST-segment elevation. In the prospective, randomized, double-blind, international, multicenter PLATO study, the authors enrolled 18,624 patients who were assessed for ≤12 months. They took ticagrelor (180-mg loading dose and 90 mg twice daily afterward) or clopidogrel (300-mg to 600-mg loading dose and 75-mg daily dose afterward). Ticagrelor is an oral, reversibly-binding P2Y12 receptor antagonist, and clopidogrel is an oral P2Y12 platelet inhibitor. Approximately 2.4% of patients in each group were classified as poor metabolizers of clopidogrel, defined as having 2 loss-of-function alleles at the CYP2C19 isoenzyme, the main genetic factor affecting the pharmacokinetic and pharmacodynamic response to clopidogrel. The substudy examined 5137 patients in the ticagrelor group and 5148 patients in the clopidogrel group, each of whom consented to give blood samples for genetic analysis. Baseline characteristics were similar between the groups. The mean age was 62.5 years, 69% of the patients were male, and 98% were white. Among the ticagrelor patients, 121 were classified as poor metabolizers compared with 125 in the clopidogrel cohort. Excluding the poor metabolizers, patients in the ticagrelor group had a significant reduction in the primary end point compared with the clopidogrel group (8.8% vs 10.4% per year; hazard ratio [HR], 0.85; 95% confidence interval [CI], 0.74-0.96; P=.01). When including only the poor metabolizers, there was a similar difference in the reduction rates (8.8% vs 9.7% per year; HR, 0.87; 95% CI, 0.38-2.02). Each group had a 10.7% rate per year of major bleeding (HR, 0.99; 95% CI, 0.88-1.33), whereas non–coronary artery bypass graft major bleeding occurred in 4.0% of the ticagrelor patients per year compared with 3.3% of the clopidogrel group (HR, 1.19; 95% CI, 0.95-1.47). The authors indicated that the results of the subanalysis were consistent with the entire PLATO population.