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

Yuesong Pan, Weiqi Chen, Yilong Wang, Hao Li, S. Claiborne Johnston, Tabassome Simon, Xingquan Zhao, Liping Liu, David Wang, Xia Meng, Yongjun Wang

Research output: Contribution to journalArticle

2 Citations (Scopus)

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], CYP2C192 [681G>A, rs4244285], and CYP2C193 [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.

Original languageEnglish (US)
Pages (from-to)552-560
Number of pages9
JournalJAMA Neurology
Volume76
Issue number5
DOIs
StatePublished - May 2019

Fingerprint

clopidogrel
Transient Ischemic Attack
Randomized Controlled Trials
Stroke
Aspirin
Genotype

ASJC Scopus subject areas

  • Clinical Neurology

Cite this

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. / Pan, Yuesong; Chen, Weiqi; Wang, Yilong; Li, Hao; Johnston, S. Claiborne; Simon, Tabassome; Zhao, Xingquan; Liu, Liping; Wang, David; Meng, Xia; Wang, Yongjun.

In: JAMA Neurology, Vol. 76, No. 5, 05.2019, p. 552-560.

Research output: Contribution to journalArticle

Pan, Yuesong ; Chen, Weiqi ; Wang, Yilong ; Li, Hao ; Johnston, S. Claiborne ; Simon, Tabassome ; Zhao, Xingquan ; Liu, Liping ; Wang, David ; Meng, Xia ; Wang, Yongjun. / 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. In: JAMA Neurology. 2019 ; Vol. 76, No. 5. pp. 552-560.
@article{668d9e62f1534c1a8c5c38a1d6cf9c98,
title = "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], CYP2C192 [681G>A, rs4244285], and CYP2C193 [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.",
author = "Yuesong Pan and Weiqi Chen and Yilong Wang and Hao Li and Johnston, {S. Claiborne} and Tabassome Simon and Xingquan Zhao and Liping Liu and David Wang and Xia Meng and Yongjun Wang",
year = "2019",
month = "5",
doi = "10.1001/jamaneurol.2018.4775",
language = "English (US)",
volume = "76",
pages = "552--560",
journal = "JAMA Neurology",
issn = "2168-6149",
publisher = "American Medical Association",
number = "5",

}

TY - JOUR

T1 - Association between ABCB1 Polymorphisms and Outcomes of Clopidogrel Treatment in Patients with Minor Stroke or Transient Ischemic Attack

T2 - Secondary Analysis of a Randomized Clinical Trial

AU - Pan, Yuesong

AU - Chen, Weiqi

AU - Wang, Yilong

AU - Li, Hao

AU - Johnston, S. Claiborne

AU - Simon, Tabassome

AU - Zhao, Xingquan

AU - Liu, Liping

AU - Wang, David

AU - Meng, Xia

AU - Wang, Yongjun

PY - 2019/5

Y1 - 2019/5

N2 - 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], CYP2C192 [681G>A, rs4244285], and CYP2C193 [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.

AB - 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], CYP2C192 [681G>A, rs4244285], and CYP2C193 [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.

UR - http://www.scopus.com/inward/record.url?scp=85061322784&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85061322784&partnerID=8YFLogxK

U2 - 10.1001/jamaneurol.2018.4775

DO - 10.1001/jamaneurol.2018.4775

M3 - Article

C2 - 30742211

AN - SCOPUS:85061322784

VL - 76

SP - 552

EP - 560

JO - JAMA Neurology

JF - JAMA Neurology

SN - 2168-6149

IS - 5

ER -