Abstract WP173: Interaction Between CYP2C19 Allele Status And Outcome Following Ischemic Stroke In Patients Treated With Clopidogrel: A TARDIS Trial Substudy

Background: Clopidogrel is routinely prescribed following ischaemic stroke (IS), or transient ischaemic attack (TIA), as secondary prevention. Conversion of clopidogrel to its active form involves several hepatic cytochrome P450 enzymes (CYP450), including P450-2C19 (CYP2C19). Previous evidence suggests that CYP2C19 loss of function (LoF) carriers prescribed clopidogrel are at increased risk of vascular events in comparison with non-carriers. We sought to test for interaction between CYP2C19 LoF status and treatment effects in the TARDIS trial. Methods: TARDIS was an international, randomised trial recruiting participants with acute IS/TIA. Participants were assigned to receive intensive antiplatelet therapy (aspirin, clopidogrel, and dipyridamole) or guideline therapy (clopidogrel alone or aspirin and dipyridamole). Blood samples for genotyping were taken from consented participants at a 70 of the 106 recruiting centres. Results: Of 3096 participants, 1361 (44%) had samples available for genotyping. Median age was 69.0 years and 65.1% were male. Of the 1361 with samples, 1071 (78.7%) were randomised to clopidogrel and 290 (21.3%) to aspirin plus dipyridamole. 387 (28.4%) participants were CYP2C19 LoF allele carriers. At 35 days, 64 participants (4.7%) had a further IS/TIA and the rate of major adverse cardiovascular events was 6.8%. In participants randomised to clopidogrel (monotherapy or intensive) the rates of further IS/TIA were 4.9% in LoF allele carriers and 4.2% in non-carriers. As for those taking clopidogrel monotherapy, the rates of further IS/TIA were 7.4% in LoF allele carriers compared to 3.8% in non-carriers, though this difference was non-significant (p=0.14). There were no significant differences, in outcome or bleeding risk, by treatment group and LoF carrier status. Conclusions: No significant interaction was found between CYP2C19 genotype and outcome following IS/TIA when prescribed clopidogrel, either as monotherapy or in combination with aspirin and dipyridamole. There was no observed interaction between LoF status, clinical outcome, and bleeding rates. A caveat is that this analysis was undertaken on a subgroup of TARDIS participants and so was underpowered to detect a difference in the monotherapy group.