Elsevier

The Lancet

Volume 376, Issue 9749, 16–22 October 2010, Pages 1320-1328
The Lancet

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Effect 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

https://doi.org/10.1016/S0140-6736(10)61274-3Get rights and content

Summary

Background

In the PLATO trial of ticagrelor versus clopidogrel for treatment of acute coronary syndromes, ticagrelor reduced the composite outcome of cardiovascular death, myocardial infarction, and stroke, but increased events of major bleeding related to non-coronary artery bypass graft (CABG). CYP2C19 and ABCB1 genotypes are known to influence the effects of clopidogrel. In this substudy, we investigated the effects of these genotypes on outcomes between and within treatment groups.

Methods

DNA samples obtained from patients in the PLATO trial were genotyped for CYP2C19 loss-of-function alleles (*2, *3, *4, *5, *6, *7, and *8), the CYP2C19 gain-of-function allele *17, and the ABCB1 single nucleotide polymorphism 3435C→T. For the CYP2C19 genotype, patients were stratified by the presence or absence of any loss-of-function allele, and for the ABCB1 genotype, patients were stratified by predicted gene expression (high, intermediate, or low). The primary efficacy endpoint was the composite of cardiovascular death, myocardial infarction, or stroke after up to 12 months' treatment with ticagrelor or clopidogrel.

Findings

10 285 patients provided samples for genetic analysis. The primary outcome occurred less often with ticagrelor versus clopidogrel, irrespective of CYP2C19 genotype: 8·6% versus 11·2% (hazard ratio 0·77, 95% CI 0·60–0·99, p=0·0380) in patients with any loss-of-function allele; and 8·8% versus 10·0% (0·86, 0·74–1·01, p=0·0608) in those without any loss-of-function allele (interaction p=0·46). For the ABCB1 genotype, event rates for the primary outcome were also consistently lower in the ticagrelor than in the clopidogrel group for all genotype groups (interaction p=0·39; 8·8% vs 11·9%; 0·71, 0·55–0·92 for the high-expression genotype). In the clopidogrel group, the event rate at 30 days was higher in patients with than in those without any loss-of-function CYP2C19 alleles (5·7% vs 3·8%, p=0·028), leading to earlier separation of event rates between treatment groups in patients with loss-of-function alleles. Patients on clopidogrel who had any gain-of-function CYP2C19 allele had a higher frequency of major bleeding (11·9%) than did those without any gain-of-function or loss-of-function alleles (9·5%; p=0·022), but interaction between treatment and genotype groups was not significant for any type of major bleeding.

Interpretation

Ticagrelor is a more efficacious treatment for acute coronary syndromes than is clopidogrel, irrespective of CYP2C19 and ABCB1 polymorphisms. Use of ticagrelor instead of clopidogrel eliminates the need for presently recommended genetic testing before dual antiplatelet treatment.

Funding

AstraZeneca.

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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