Genetic variants in ABCB1 and CYP2C19 and cardiovascular outcomes after treatment with clopidogrel and prasugrel in the TRITON–TIMI 38 trial: a pharmacogenetic analysis

Summary

Background

Clopidogrel and prasugrel are subject to efflux via P-glycoprotein (encoded by ABCB1, also known as MDR1). ABCB1 polymorphisms, particularly 3435C→T, may affect drug transport and efficacy. We aimed to assess the effect of this polymorphism by itself and alongside variants in CYP2C19 on cardiovascular outcomes in patients treated with clopidogrel or prasugrel in TRITON–TIMI 38. We also assessed the effect of genotype on the pharmacodynamic and pharmacokinetic properties of these drugs in healthy individuals.

Methods

We genotyped ABCB1 in 2932 patients with acute coronary syndromes undergoing percutaneous intervention who were treated with clopidogrel (n=1471) or prasugrel (n=1461) in the TRITON–TIMI 38 trial. We evaluated the association between ABCB1 3435C→T and rates of the primary efficacy endpoint (cardiovascular death, myocardial infarction, or stroke) until 15 months. We then assessed the combined effect of ABCB1 3435C→T genotype and reduced-function alleles of CYP2C19. 321 healthy individuals were also genotyped, and we tested the association of genetic variants with reduction in maximum platelet aggregation and plasma concentrations of active drug metabolites.

Findings

In patients treated with clopidogrel, ABCB1 3435C→T genotype was significantly associated with the risk of cardiovascular death, myocardial infarction, or stroke (p=0·0064). TT homozygotes had a 72% increased risk of the primary endpoint compared with CT/CC individuals (Kaplan-Meier event rates 12·9% [52 of 414] vs 7·8% [80 of 1057 participants]; HR 1·72, 95% CI 1·22–2·44, p=0·002). ABCB1 3435C→T and CYP2C19 genotypes were significant, independent predictors of the primary endpoint, and 681 (47%) of the 1454 genotyped patients taking clopidogrel who were either CYP2C19 reduced-function allele carriers, ABCB1 3435 TT homozygotes, or both were at increased risk of the primary endpoint (HR 1·97, 95% CI 1·38–2·82, p=0·0002). In healthy participants, 3435 TT homozygotes had an absolute reduction in maximum platelet aggregation with clopidogrel that was 7·3 percentage points less than for CT/CC individuals (p=0·0127). ABCB1 genotypes were not significantly associated with clinical or pharmacological outcomes in patients with an acute coronary syndrome or healthy individuals treated with prasugrel, respectively.

Interpretation

Individuals with the ABCB1 3435 TT genotype have reduced platelet inhibition and are at increased risk of recurrent ischaemic events during clopidogrel treatment. In patients with acute coronary syndromes who have undergone percutaneous intervention, when both ABCB1 and CYP2C19 are taken into account, nearly half of the population carries a genotype associated with increased risk of major adverse cardiovascular events while on standard doses of clopidogrel.

Funding

Daiichi Sankyo Company Ltd and Eli Lilly and Company.

Introduction

In patients presenting with acute coronary syndromes and in those undergoing percutaneous coronary interventions with stenting, dual antiplatelet treatment with aspirin and the thienopyridine clopidogrel is the guideline-approved standard of care.1, 2 As such, clopidogrel is one of the most frequently prescribed drugs worldwide. However, the pharmacodynamic response to clopidogrel varies substantially between patients,³ and individuals with low platelet inhibition during treatment with clopidogrel are at increased risk of cardiovascular events.⁴ Prasugrel is a third-generation thienopyridine that achieves greater platelet inhibition with less variability between patients than does clopidogrel.⁵ In the Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel–Thrombolysis in Myocardial Infarction (TRITON–TIMI) 38, treatment with prasugrel compared with clopidogrel resulted in a significantly lower rate of ischaemic events and more bleeding.⁶

Both clopidogrel and prasugrel are prodrugs that need intestinal absorption and subsequent biotransformation to active metabolites by cytochrome P450 enzymes. In several studies, reduced-function genetic variants in CYP2C19 (located on chromosome 10) have been associated with reduced concentrations of active drug metabolite, diminished platelet inhibition, and higher rates of adverse cardiovascular events in the setting of treatment with clopidogrel, but not prasugrel.7, 8, 9, 10, 11, 12, 13, 14, 15 To that end, the US Food and Drug Administration has incorporated CYP2C19 genetic information into the updated clopidogrel label in the form of a boxed warning noting that carriers of two reduced-function CYP2C19 alleles have a diminished response to standard doses of clopidogrel.

Additionally, a key protein involved in thienopyridine absorption is the efflux pump P-glycoprotein, which is encoded by ABCB1 (also known as MDR1, located on chromosome 7). P-glycoprotein is an ATP-dependent efflux pump that transports various molecules across extracellular and intracellular membranes. It is expressed, among other places, on intestinal epithelial cells, where increased expression or function can affect bioavailability of drugs that are substrates. Previous research suggests that when treated with clopidogrel, individuals with genetic variants in ABCB1 (specifically those who are TT homozygotes for the 3435C→T variant) have reduced concentrations of the active drug metabolite¹⁶ and increased rates of adverse clinical outcomes.¹⁰ Further investigation into the effect of this polymorphism on outcomes in patients treated with clopidogrel, the effect in relation to CYP2C19 reduced-function variants, and the effect in those treated with the third-generation thienopyridine prasugrel is needed.

We genotyped a subset of patients in the TRITON–TIMI 38 trial who provided samples for genetic analysis with the aim of assessing the association between the ABCB1 3435C→T polymorphism and adverse cardiovascular outcomes during treatment with clopidogrel or prasugrel. To obtain supporting pharmacological data, ABCB1 genotyping was also done in healthy individuals in whom platelet inhibition and drug concentrations were measured in response to clopidogrel or prasugrel. We also assessed the contribution of the ABCB1 3435C→T polymorphism in the context of CYP2C19 status to elucidate the independent contribution of variants in these two genes.