Background Clopidogrel is a prodrug, which is metabolised to its active metabolite especially by the CYP2C19 enzyme. Carrying some polymorphisms, contained in the DNA region encoding the CYP2C19 expression, have shown a significant association with a lack of clopidogrel efficacy among coronary patients. This association had been widely researched and the clopidogrel label recommends testing the CYP2C19 loss of function alleles before the start of the treatment, even DPWG and CPIC pharmacogenetic dosing guidelines, and recommend switching clopidogrel in case of carrying the CYP2C19 loss of function alleles in coronary patients with stent. This remains unstudied in cerebrovascular-disease patients.

Purpose Explore the influence of CYP2C19 genetic polymorphisms on clopidogrel response in cerebrovascular disease patients.

Material and methods Patients after stroke or transient ischaemic event (TIA) treated with clopidogrel after hospitalisation were recruited. These were tested for carrying the CYP2C19*2, *3 (loss of function (LOF)) and *17 (gain of function (GOF)) alleles. As primary endpoint we considered the combined occurrence of stroke, TIA, cardiovascular death and acute coronary syndrome (ACS). Furthermore, we collected data about clinical parameters (age, sex, ethnicity), co-medication during follow-up and vascular risk factors.

We tested the association between carrying LOF or GOF alleles and the primary endpoint in a univariate analysis, and multivariate analysis including those clinical parameters previously related to clopidogrel response. OR and HR were calculated and P-values<0.05 were considered statistically significant.

Results Sixty-seven patients were recruited, 53 (79.1%) because of stroke, mean age 68.2±9.83 years, 35.8% females and 100% caucasians. Carrying CYP2C19 LOF alleles was significantly associated with the primary endpoint in the single analysis (OR=3.82; 95% CI: 1.1 to 13.2; p=0.028), in the multivariate analysis (OR=5.07; 95% CI: 1.2 to 21.45; p=0.023). This association remains significant if we perform a survival analysis (HR=3.01; 95% CI: 1.01 to 9.0; p=0.048). Carrying CYP2C19 GOF alleles was not related to the primary endpoint in the univariate analysis but, in the multivariate analysis, it was significantly associated with a protection against the primary endpoint.

Conclusion CYP2C19 LOF polymorphisms may be used as genetic markers of clopidogrel response in cerebrovascular disease patients. Among these patients, CYP2C19 GOF allele may be considered as a protector against the primary endpoint.

References and/or acknowledgements Agradecimientos: Thanks to all the patients participating.

No conflict of interest.