Fast track — ArticlesEffect of CYP2C19 and ABCB1 single nucleotide polymorphisms on outcomes of treatment with ticagrelor versus clopidogrel for acute coronary syndromes: a genetic substudy of the PLATO trial
Introduction
Dual antiplatelet treatment with aspirin and a thienopyridine is recommended treatment for acute coronary syndromes to reduce the rate of recurrent ischaemic events and stent thrombosis.1, 2, 3, 4, 5 Thienopyridines (clopidogrel and prasugrel) are oral prodrugs that need to be converted to active metabolites to irreversibly bind to the P2Y12 receptor. About 85% of clopidogrel is hydrolysed to an inactive metabolite, with the remainder converted to the active metabolite by two sequential steps dependent on cytochrome P450 (CYP), with contributions from the isoenzymes CYP2C19, CYP3A4 or CYP3A5, CYP2C9, CYP1A2, and CYP2B6.6, 7, 8 The CYP2C19 genotype affects both metabolic steps and is the most important determinant of the pharmacokinetic and pharmacodynamic response to clopidogrel, although it only explains about 12% of reported variability.9, 10, 11, 12 In patients treated with clopidogrel after an acute coronary syndrome event or stenting, or both, the presence of any loss-of-function CYP2C19 allele (*2, *3, *4, *5, *6, *7, and *8) is associated with an increased risk of ischaemic events and stent thrombosis,9, 10, 13, 14 whereas the presence of any gain-of-function CYP2C19 allele (*17) is associated with a raised risk of bleeding.15 Variations in the genes regulating clopidogrel absorption and efflux, such as the gene encoding the P-glycoprotein multidrug resistant-1 efflux transporter, ABCB1,16 might also affect the rate of clinical events during treatment.17
Ticagrelor is an oral, reversible platelet inhibitor that binds directly to the P2Y12 receptor and does not need metabolic activation for pharmacodynamic activity.18 Compared with clopidogrel, ticagrelor provides more pronounced and consistent platelet inhibition with a faster onset and offset of the effect of treatment.18, 19 At present, no genetic determinants of the ticagrelor response are known, although ticagrelor absorption might be affected by ABCB1 polymorphisms.20 In the PLATelet inhibition and patient Outcomes (PLATO) trial,21 ticagrelor reduced events of the primary composite endpoint of cardiovascular death, myocardial infarction, or stroke by 16% (95% CI 8–21), without any difference in overall major bleeding, but increased events of major bleeding related to non-coronary artery bypass graft (CABG) by 19% (95% CI 2–38). In this first substudy from the PLATO genetics programme, we aimed to investigate the role of CYP2C19 and ABCB1 polymorphisms on efficacy and safety outcomes both between and within the ticagrelor and clopidogrel arms of the PLATO study.
Section snippets
Study design
The detailed design and outcomes of the PLATO study have previously been reported.21, 22 In brief, PLATO was a prospective, randomised, double-blind, double-dummy, parallel-group, international, multicentre phase 3 study of 18 624 patients with or without ST-elevation acute coronary syndrome. The study assessed the efficacy and safety of up to 12 months' treatment with either 90 mg ticagrelor twice daily (180 mg loading dose) or 75 mg clopidogrel once daily (300–600 mg loading dose) for the
Results
10 285 patients consented to give a blood sample for genetic analysis. Demographic indicators and drug use were well balanced between the treatment groups at baseline (table 1 and webappendix). These characteristics and study outcomes did not differ from that of the total PLATO population, apart from ethnic group: 98% (n=10 115 patients) of the genetics cohort compared with 92% (n=17 077) of the total cohort were white. Predicted phenotypes and allele frequencies were representative of a white
Discussion
Treatment with ticagrelor versus clopidogrel in a large population with acute coronary syndromes was associated with lower rates of cardiovascular death and myocardial infarction, similar rates of total major bleeding, and higher rates of major bleeding related to non-CABG, irrespective of CYP2C19 and ABCB1 polymorphisms. These findings are from the large, double-blind randomised PLATO trial, so they should provide reliable information about pharmacogenomic interactions of these genetic
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