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Original Investigation
February 11, 2019

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

Author Affiliations
  • 1Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
  • 2China National Clinical Research Center for Neurological Diseases, Beijing, China
  • 3Center of Stroke, Beijing Institute for Brain Disorders, Beijing, China
  • 4Beijing Key Laboratory of Translational Medicine for Cerebrovascular Disease, Beijing, China
  • 5Dean’s Office, Dell Medical School, University of Texas at Austin, Austin, Texas
  • 6Department of Clinical Pharmacology and Clinical Research Platform of East of Paris (URCEST-CRC-CRB), Assistance Publique–Hôpitaux de Paris, Paris, France
  • 7Department of Clinical Pharmacology, Sorbonne Université, Paris, France
  • 8FACT (French Alliance for Cardiovascular Clinical Trials), Paris, France
  • 9Illinois Neurological Institute Stroke Network, OSF Healthcare System, Peoria, Illinois
  • 10Department of Neurology, University of Illinois College of Medicine at Peoria, Peoria, Illinois
JAMA Neurol. 2019;76(5):552-560. doi:10.1001/jamaneurol.2018.4775
Key Points

Question  Are ABCB1 genetic variants associated with the efficacy of clopidogrel bisulfate for minor stroke or transient ischemic attack?

Findings  In this secondary analysis of a randomized clinical trial that included 2836 adults, clopidogrel plus aspirin was associated with a significant reduction in the risk of new stroke in patients with ABCB1 –154 TT and 3435 CC genotype but not in those with ABCB1 -154 TC/CC or 3435 CT/TT genotype compared with aspirin alone.

Meaning  ABCB1 genetic variants may be associated with the efficacy of clopidogrel for treatment of minor stroke or transient ischemic attack.

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

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