Association Between ABCB1 Polymorphisms and Outcomes of Clopidogrel Treatment in Patients With Minor Stroke or Transient Ischemic Attack: Secondary Analysis of a Randomized Clinical Trial

Abstract

Importance: Genetic variants of ABCB1 may affect intestinal absorption of clopidogrel bisulfate. However, it is unclear whether ABCB1 polymorphisms are associated with clopidogrel efficacy for minor ischemic stroke or transient ischemic attack (TIA).

Objectives: To investigate the association between ABCB1 polymorphisms and clopidogrel efficacy for minor stroke or TIA.

Design, setting, and participants: In this prespecified secondary analysis of the Clopidogrel in High-Risk Patients With Acute Nondisabling Cerebrovascular Events (CHANCE) randomized clinical trial, 3010 patients with minor stroke or TIA at 73 sites in China with experience in conducting genetic studies were included from October 1, 2009, to July 30, 2012. The analysis was conducted on March 20, 2018. Four single-nucleotide polymorphisms (ABCB1 -154T>C [rs4148727], ABCB1 3435C>T [rs1045642], CYP2C19*2 [681G>A, rs4244285], and CYP2C19*3 [636G>A, rs4986893]) were genotyped among 2836 patients treated with clopidogrel plus aspirin (n = 1414) or aspirin alone (n = 1422). The association of ABCB1 genetic variants (-154 TC/CC and 3435 CT/TT) with clopidogrel efficacy was evaluated in the context of CYP2C19 status, another gene associated with clopidogrel efficacy.

Interventions: Patients in the CHANCE trial were randomized to treatment with clopidogrel combined with aspirin or to aspirin alone.

Main outcomes and measures: Primary efficacy outcome was stroke recurrence after 3 months. The safety outcome was any bleeding risk after 3 months.

Results: Among 2836 patients, the median age was 61.8 years (interquartile range, 54.4-71.1 years) and 1887 patients (66.5%) were male. A total of 2146 (75.7%) patients were carriers of ABCB1 -154 TC/CC (570 [20.1%]) or 3435 CT/TT (1851 [65.3%]) genotype. Clopidogrel plus aspirin treatment was associated with reduced risk of new stroke in patients with ABCB1 -154 TT and 3435 CC genotype (hazard ratio [HR], 0.43; 95% CI, 0.26-0.71) but not in those with ABCB1 -154 TC/CC or 3435 CT/TT genotype (HR, 0.78; 95% CI, 0.60-1.03) compared with aspirin (P = .04 for interaction). A combined association of ABCB1 and CYP2C19 polymorphisms with new stroke was observed. The risk of bleeding for clopidogrel plus aspirin treatment was not associated with the ABCB1 genotypes (2.3% and 1.3% vs 1.9% and 2.2%; P = .25 for interaction in patients with or without ABCB1 -154 TC/CC or 3435 CT/TT genotype).

Conclusions and relevance: The ABCB1 polymorphism was associated with the reduced efficacy of clopidogrel plus aspirin treatment compared with aspirin among patients with minor ischemic stroke or TIA. Genetic polymorphism of ABCB1 should be considered when prescribing clopidogrel for these patients.

Trial registration: ClinicalTrials.gov identifier: NCT00979589.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Johnston reported being the principal investigator of the Platelet-Oriented Inhibition in New TIA and Minor Ischemic Stroke (POINT) trial, a National Institutes of Health–sponsored trial, with clopidogrel and placebo donated by Sanofi. Dr Simon reported receiving personal fees from board membership, consultancy, or lecture from AstraZeneca, Astellas, Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis, Sanofi, and Pfizer.

Figures

Figure 1.. Risk of Stroke and Any Bleeding for Carriers and Noncarriers of ABCB1 –154 TC/CC or 3435 CT/TT Genotype by Treatment Assignment

A, Probability of new stroke from randomization throughout 90-day follow-up in carriers vs noncarriers treated with clopidogrel plus aspirin and aspirin alone. B, Probability of any bleeding from randomization throughout 90-day follow-up in carriers vs noncarriers treated with clopidogrel plus aspirin and aspirin alone.

Figure 2.. Risk of Stroke and Any Bleeding for Carriers and Noncarriers of ABCB1 –154 TC/CC or 3435 CT/TT Genotype by CYP2C19 Loss-of-Function (LOF) Allele Carrier Status and Treatment Assignment

Squares indicate point estimation and size of the squares indicate sample size. Error bars indicate 95% CIs.