Journal Article

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

Mega, Jessica L, Simon, Tabassome, Antman, Elliott M, Sabatine, Marc S, Close, Sandra L, Walker, Joseph R, Wiviott, Stephen D, Shen, Lei, Braunwald, Eugene

2010

Overview

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. 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. 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. 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. Daiichi Sankyo Company Ltd and Eli Lilly and Company.

• Publisher: Elsevier Ltd,Elsevier,Elsevier Limited
• Subject: Acute Coronary Syndrome - drug therapy / Acute Coronary Syndrome - genetics / Acute coronary syndromes / Angioplasty, Balloon, Coronary / Aryl Hydrocarbon Hydroxylases - genetics / ATP Binding Cassette Transporter, Sub-Family B / ATP-Binding Cassette, Sub-Family B, Member 1 - genetics / Biological and medical sciences / Cardiovascular Diseases - etiology / Clinical trials / Clopidogrel / Cytochrome P-450 CYP2C19 / Drug therapy / Drugs / Fees & charges / Female / General aspects / Genetic variance / Genetic Variation / Genotype / Genotypes / Health risks / Heart attacks / Humans / Internal Medicine / Male / Mass spectrometry / Medical sciences / Metabolites / Middle Aged / Myocardial infarction / P-Glycoprotein / Pharmacodynamics / Pharmacogenetics / Pharmacokinetics / Piperazines - adverse effects / Piperazines - therapeutic use / Platelet Aggregation - drug effects / Platelet Aggregation Inhibitors - adverse effects / Platelet Aggregation Inhibitors - therapeutic use / Polymorphism, Single Nucleotide / Prasugrel Hydrochloride / Randomized Controlled Trials as Topic / Stock options / Studies / Thiophenes - adverse effects / Thiophenes - therapeutic use / Ticlopidine - adverse effects / Ticlopidine - analogs & derivatives / Ticlopidine - therapeutic use