Mechanisms fo Clopidogrel Resistance in Older Adults (CEPAGE)

Overview

A clopidogrel resistance rate of 40-50% has been found in the population over 70 years of age, whereas biological resistance, associated with an increased risk of cardiovascular events, is observed in about 20-30% of younger patients. One hypothesis is that the active metabolite is less available in resistant patients. Indeed, 85% of the absorbed clopidogrel undergoes inactivation by esterases. Then the remaining fraction undergoes two steps of metabolisation to the active thiol metabolite by CYP450, essentially the isoform 2C19. In older adults, increased esterase activity and/or decreased CYP450 2C19 activity may lead to a decreased concentration of the active metabolite. Multiple chronic conditions and polypharmacy encountered in older individuals are associated with basal platelet hyperactivity, and may also contribute to a poor response to clopidogrel. No data on the relationship between platelet response and circulating metabolite levels, or on the determinants of response to clopidogrel, are currently available in the geriatric population. Therefore, we propose to analyse the relationship between age and platelet and extra-platelet mechanisms potentially involved in the variability of response to clopidogrel.

This study is a prospective observational multi-centre study. The main objective is assessing the pharmacokinetics (PK) and pharmacodynamics (PD) correlation of clopidogrel action in older adults, i.e. correlation between clopidogrel active metabolite concentration (PK) and platelet response phenotype (PD). The primary outcome is the correlation between the concentration of active metabolite of clopidogrel (PK) over the percentage of maximum aggregation at 10 μM ADP (PD) as a function of age. Inclusion criteria are: age 50-100 years old, hospitalization in one of the 4 participating centres, treatment with clopidogrel 75 milligrammes per day, for at least 10 days. The statistical analysis is a multiple linear regression model with the introduction of an interaction term. The first variable of interest (explanatory) is the concentration of the metabolite. A linear regression model will be used to estimate the proportion of variance explained. The analyses will be conducted with SAS version 9.4 (SAS Institute Inc., Cary, N.C., USA). Results will be published in an international scientific review.