Diabetes and CYP2C19 Polymorphism Synergistically Impair the Antiplatelet Activity of Clopidogrel Compared to Ticagrelor in PCI-Treated ACS Patients.

Diabetes and CYP2C19 loss of function (LOF) alleles are associated with variable antiplatelet activity of the prodrug clopidogrel. We conducted a randomized trial (NCT03613857) to compare the combined and individualized effects of diabetes and CYP2C19 polymorphisms on the anti-platelet reactivity of clopidogrel vs ticagrelor in ACS patients undergoing percutaneous coronary intervention (PCI). Patients (948, 1 year follow-up 943) were randomly allocated in a 1:1 ratio to receive either clopidogrel or ticagrelor, following PCI; patients were sub-divided into eight subgroups according to the diabetes and/or CYP2C19 allele status. The study outcomes were recurrent ACS, maximum platelet aggregation (MPA),high platelet reactivity index (PRI),and incidence of major bleeding events. Diabetic patients with LOF alleles taking clopidogrel had the highest recurrent ACS rate (6 out of 33 patients) VS. all other study groups (p<0.05). However, both drugs had similar proportions of recurrent ACS in all other subgroups. Similarly, both PRI and MPA were significantly higher in the diabetic patients having LOF alleles and receiving clopidogrel VS. all other study groups (p<0.05). Nevertheless, ticagrelor caused higher rates of major bleeding VS. clopidogrel (p<0.001). PCI-treated ACS patients with diabetes and CYP2C19 LOF alleles are at a higher risk of recurrent ACS and high PRI/MPA, when treated with clopidogrel VS. ticagrelor, but almost comparable outcomes are recorded in the absence of one or the two risk factors. CLINICAL TRIAL REGISTRATION:: www.clinicaltrials.gov Identifier NCT03613857.