Association Between ABCB1 Polymorphisms and Outcomes of Clopidogrel Treatment in Patients With Minor Stroke or Transient Ischemic Attack

Importance

Genetic variants ofABCB1may affect intestinal absorption of clopidogrel bisulfate. However, it is unclear whetherABCB1polymorphisms are associated with clopidogrel efficacy for minor ischemic stroke or transient ischemic attack (TIA).

Objectives

To investigate the association betweenABCB1polymorphisms 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],ABCB13435C>T [rs1045642],CYP2C19*2[681G>A,rs4244285], andCYP2C19*3[636G>A,rs4986893]) were genotyped among 2836 patients treated with clopidogrel plus aspirin (n = 1414) or aspirin alone (n = 1422). The association ofABCB1genetic variants (–154 TC/CC and 3435 CT/TT) with clopidogrel efficacy was evaluated in the context ofCYP2C19status, 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 ofABCB1–154 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 withABCB1–154 TT and 3435 CC genotype (hazard ratio [HR], 0.43; 95% CI, 0.26-0.71) but not in those withABCB1–154 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 ofABCB1andCYP2C19polymorphisms with new stroke was observed. The risk of bleeding for clopidogrel plus aspirin treatment was not associated with theABCB1genotypes (2.3% and 1.3% vs 1.9% and 2.2%;P = .25 for interaction in patients with or withoutABCB1–154 TC/CC or 3435 CT/TT genotype)

Conclusions and Relevance

TheABCB1polymorphism was associated with the reduced efficacy of clopidogrel plus aspirin treatment compared with aspirin among patients with minor ischemic stroke or TIA. Genetic polymorphism ofABCB1should be considered when prescribing clopidogrel for these patients.

Trial Registration

ClinicalTrials.gov identifier:NCT00979589