(164) Genetic Polymorphisms of CYP2C19 Gene, Clopidogrel Use, and Risk of Mortality: The Rotterdam Study

Friday, August 26, 2022

8:00 AM – 6:00 PM CEST

Location: Hall C

Publication Number: 495

Presenting Author(s)

Negin Soroush, PharmD
– PhD Candidate, Erasmus MC, Rotterdam, Zuid-Holland, Netherlands

Co-Author(s)

M.Kamran Ikram
– Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands, Netherlands
Bruno H. Stricker
– Professor of Pharmacoepidemiology, Epidemiology department, Erasmus Medical Center, Rotterdam, The Netherlands, Rotterdam, Netherlands
Fariba Ahmadizar
– Assistant Professor, Molecular (Pharmaco) Epidemiology, Julius Center, UMC Utrecht, the Netherlands, Netherlands

Background: The genetic variations of cytochrome P450 (CYP) 2C19 are associated with the antiplatelet efficacy of clopidogrel. However, guidelines do not recommend routine genetic testing prior to antiplatelet therapy. Also, most studies consist of cardiac indications, but relatively few studies have focused on clopidogrel use in stroke patients in real-life conditions.

Objectives: To determine the association between CYP2C19 loss of function (LoF) alleles and the outcome of three-year mortality in a population of clopidogrel users and a subgroup of patients with a history of ischemic stroke and transient ischemic attack (TIA). In a secondary analysis, we investigated the event risk only in subjects who were still current users of clopidogrel at the event date.

Methods: This inception cohort study included 983 participants from the population-based cohort of the Rotterdam Study who had started clopidogrel during the study period and for whom genetic data were available. The date of the first clopidogrel prescription was the day of entry to the study. The cumulative survival was compared between CYP2C19*2 LoF allele carriers and non-carriers using Kaplan-Meier (K-M) estimate. We performed a time-to-event analysis of the main outcome of mortality in three years of follow-up. A Cox regression analysis was used to estimate the associations between LoF allele status and mortality in the total population and a non-fatal stroke/TIA subgroup. In a secondary analysis, we investigated this association among the current clopidogrel users.

Results: The outcome of 3-years mortality occurred in 139 patients (14.1%) of the total population with a median (IQR) age of 75(67-82) years during follow-up. 30.6% (n=301) of subjects were CYP2C19*2 LoF allele carriers and the cumulative incidence of 3 years mortality was 17.3% (52 events). The K-M estimate showed significantly lower cumulative survival in the LoF allele carriers than non-carriers (log-rank test p=0.04) during follow-up. The CYP2C19*2 LoF allele carriers had an increased 3-years mortality risk with a Hazard ratio (HR) of 1.65 (95% CI: 1.16, 2.35) in the fully adjusted model. In the stroke subgroup (292 patients) the risk estimate was greater [HR= 2.28 (1.26, 4.12)]. However, in the current users’ analysis, this association was not statistically significant [HR: 1.13 (95% CI: 0.74, 1.72)].

Conclusions: Our findings support the role of CYP2C19 variations in the effectiveness of clopidogrel and suggest that in a real-life setting of a European population, LoF CYP2C19*2 allele carriers treated with clopidogrel have a higher risk of mortality in three years of follow-up. We observed a higher estimation of event risk in the subset of people with stroke/TIA.