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 | Cerebrovascular Disease | JAMA Neurology | JAMA Network
[Skip to Navigation]
Sign In
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
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
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.

Table 1.  Baseline Characteristics Between Carriers and Noncarriers of ABCB1 -154 TC/CC or 3435 CT/TT Genotype Stratified by Treatment Assignmenta
Baseline Characteristics Between Carriers and Noncarriers of ABCB1 -154 TC/CC or 3435 CT/TT Genotype Stratified by Treatment Assignmenta
Table 2.  Association of Clopidogrel Plus Aspirin vs Aspirin Alone With Clinical Outcome Stratified by ABCB1 Genotypes
Association of Clopidogrel Plus Aspirin vs Aspirin Alone With Clinical Outcome Stratified by ABCB1 Genotypes
Table 3.  Association of Clopidogrel Plus Aspirin vs Aspirin Alone With Clinical Outcome Stratified by ABCB1 –154T>C Genotypes
Association of Clopidogrel Plus Aspirin vs Aspirin Alone With Clinical Outcome Stratified by ABCB1 –154T>C Genotypes
Supplement 2.

eFigure 1. Flow Diagram of Participants in the Genetic Substudy for ABCB1

eFigure 2. Effect of Clopidogrel-Aspirin as Compared With Aspirin on New Stroke Stratified by ABCB1 Variants Status.

eFigure 3. Effect of Clopidogrel-Aspirin as Compared With Aspirin on New Stroke Stratified by Genotype for ABCB1 in Carriers of CYP2C19 Loss-of-Function Allele.

eFigure 4. Effect of Clopidogrel-Aspirin as Compared With Aspirin on New Stroke Stratified by Genotype for ABCB1 in Non-Carriers of CYP2C19 Loss-of-Function Allele.

eTable 1. Baseline Differences Between Individuals With and Without Genetic Data

eTable 2. Baseline Differences Between Clopidogrel-Aspirin and Aspirin Alone Groups in the Genetic Substudy

eTable 3. Effect of Clopidogrel-Aspirin as Compared With Aspirin on Clinical Outcome Stratified by ABCB1 -154T>C Genotype in Carriers of CYP2C19 Loss-of-Function Allele*

eTable 4. Effect of Clopidogrel-Aspirin as Compared With aspirin on Clinical Outcome Stratified by ABCB1 -154T>C Genotype in Non-Carriers of CYP2C19 Loss-of-Function Allele*

eTable 5. Effect of Clopidogrel-Aspirin as Compared With Aspirin on Clinical Outcome Stratified by ABCB1 3435C>T Genotype

eTable 6. Effect of Clopidogrel-Aspirin as Compared With Aspirin on Clinical Outcome Stratified by ABCB1 3435C>T Genotype in Carriers of CYP2C19 Loss-of-Function Allele*

eTable 7. Effect of Clopidogrel-Aspirin as Compared With Aspirin on Clinical Outcome Stratified by ABCB1 3435C>T Genotype in Non-Carriers of CYP2C19 Loss-of-Function Allele*

1.
Wang  Y, Wang  Y, Zhao  X,  et al; CHANCE Investigators.  Clopidogrel with aspirin in acute minor stroke or transient ischemic attack.  N Engl J Med. 2013;369(1):11-19. doi:10.1056/NEJMoa1215340PubMedGoogle ScholarCrossref
2.
Kernan  WN, Ovbiagele  B, Black  HR,  et al; American Heart Association Stroke Council, Council on Cardiovascular and Stroke Nursing, Council on Clinical Cardiology, and Council on Peripheral Vascular Disease.  Guidelines for the prevention of stroke in patients with stroke and transient ischemic attack: a guideline for healthcare professionals from the American Heart Association/American Stroke Association.  Stroke. 2014;45(7):2160-2236. doi:10.1161/STR.0000000000000024PubMedGoogle ScholarCrossref
3.
Powers  WJ, Rabinstein  AA, Ackerson  T,  et al; American Heart Association Stroke Council.  2018 Guidelines for the early management of patients with acute ischemic stroke: a guideline for healthcare professionals from the American Heart Association/American Stroke Association.  Stroke. 2018;49(3):e46-e110. doi:10.1161/STR.0000000000000158PubMedGoogle ScholarCrossref
4.
Topçuoglu  MA, Arsava  EM, Ay  H.  Antiplatelet resistance in stroke.  Expert Rev Neurother. 2011;11(2):251-263. doi:10.1586/ern.10.203PubMedGoogle ScholarCrossref
5.
Mijajlovic  MD, Shulga  O, Bloch  S, Covickovic-Sternic  N, Aleksic  V, Bornstein  NM.  Clinical consequences of aspirin and clopidogrel resistance: an overview.  Acta Neurol Scand. 2013;128(4):213-219. doi:10.1111/ane.12111PubMedGoogle ScholarCrossref
6.
Zabalza  M, Subirana  I, Sala  J,  et al.  Meta-analyses of the association between cytochrome CYP2C19 loss- and gain-of-function polymorphisms and cardiovascular outcomes in patients with coronary artery disease treated with clopidogrel.  Heart. 2012;98(2):100-108. doi:10.1136/hrt.2011.227652PubMedGoogle ScholarCrossref
7.
Simon  T, Verstuyft  C, Mary-Krause  M,  et al; French Registry of Acute ST-Elevation and Non-ST-Elevation Myocardial Infarction (FAST-MI) Investigators.  Genetic determinants of response to clopidogrel and cardiovascular events.  N Engl J Med. 2009;360(4):363-375. doi:10.1056/NEJMoa0808227PubMedGoogle ScholarCrossref
8.
Jia  DM, Chen  ZB, Zhang  MJ,  et al.  CYP2C19 polymorphisms and antiplatelet effects of clopidogrel in acute ischemic stroke in China.  Stroke. 2013;44(6):1717-1719. doi:10.1161/STROKEAHA.113.000823PubMedGoogle ScholarCrossref
9.
Pan  Y, Chen  W, Xu  Y,  et al.  Genetic polymorphisms and clopidogrel efficacy for acute ischemic stroke or transient ischemic attack: a systematic review and meta-analysis.  Circulation. 2017;135(1):21-33. doi:10.1161/CIRCULATIONAHA.116.024913PubMedGoogle ScholarCrossref
10.
Wang  Y, Zhao  X, Lin  J,  et al; CHANCE investigators.  Association between CYP2C19 loss-of-function allele status and efficacy of clopidogrel for risk reduction among patients with minor stroke or transient ischemic attack.  JAMA. 2016;316(1):70-78. doi:10.1001/jama.2016.8662PubMedGoogle ScholarCrossref
11.
Momary  KM, Dorsch  MP, Bates  ER.  Genetic causes of clopidogrel nonresponsiveness: which ones really count?  Pharmacotherapy. 2010;30(3):265-274. doi:10.1592/phco.30.3.265PubMedGoogle ScholarCrossref
12.
Mega  JL, Close  SL, Wiviott  SD,  et al.  Genetic variants in ABCB1 and CYP2C19 and cardiovascular outcomes after treatment with clopidogrel and prasugrel in the TRITON-TIMI 38 trial: a pharmacogenetic analysis.  Lancet. 2010;376(9749):1312-1319. doi:10.1016/S0140-6736(10)61273-1PubMedGoogle ScholarCrossref
13.
Cayla  G, Hulot  JS, O’Connor  SA,  et al.  Clinical, angiographic, and genetic factors associated with early coronary stent thrombosis.  JAMA. 2011;306(16):1765-1774. doi:10.1001/jama.2011.1529PubMedGoogle ScholarCrossref
14.
Jeong  YH, Tantry  US, Kim  IS,  et al.  Effect of CYP2C19*2 and *3 loss-of-function alleles on platelet reactivity and adverse clinical events in East Asian acute myocardial infarction survivors treated with clopidogrel and aspirin.  Circ Cardiovasc Interv. 2011;4(6):585-594. doi:10.1161/CIRCINTERVENTIONS.111.962555PubMedGoogle ScholarCrossref
15.
Wallentin  L, James  S, Storey  RF,  et al; PLATO investigators.  Effect of CYP2C19 and ABCB1 single nucleotide polymorphisms on outcomes of treatment with ticagrelor versus clopidogrel for acute coronary syndromes: a genetic substudy of the PLATO trial.  Lancet. 2010;376(9749):1320-1328. doi:10.1016/S0140-6736(10)61274-3PubMedGoogle ScholarCrossref
16.
Su  JF, Hu  XH, Li  CY.  Risk factors for clopidogrel resistance in patients with ischemic cerebral infarction and the correlation with ABCB1 gene rs1045642 polymorphism.  Exp Ther Med. 2015;9(1):267-271. doi:10.3892/etm.2014.2058PubMedGoogle ScholarCrossref
17.
Li  XQ, Ma  N, Li  XG,  et al.  Association of PON1, P2Y12 and COX1 with recurrent ischemic events in patients with extracranial or intracranial stenting.  PLoS One. 2016;11(2):e0148891. doi:10.1371/journal.pone.0148891PubMedGoogle ScholarCrossref
18.
Wang  Y, Pan  Y, Zhao  X,  et al; CHANCE Investigators.  Clopidogrel with aspirin in acute minor stroke or transient ischemic attack (CHANCE) trial: one-year outcomes.  Circulation. 2015;132(1):40-46. doi:10.1161/CIRCULATIONAHA.114.014791PubMedGoogle ScholarCrossref
19.
Wang  Y, Johnston  SC; CHANCE Investigators.  Rationale and design of a randomized, double-blind trial comparing the effects of a 3-month clopidogrel-aspirin regimen versus aspirin alone for the treatment of high-risk patients with acute nondisabling cerebrovascular event.  Am Heart J. 2010;160(3):380-386.e1. doi:10.1016/j.ahj.2010.05.017PubMedGoogle ScholarCrossref
20.
GUSTO investigators.  An international randomized trial comparing four thrombolytic strategies for acute myocardial infarction.  N Engl J Med. 1993;329(10):673-682. doi:10.1056/NEJM199309023291001PubMedGoogle ScholarCrossref
21.
Kim  YO, Kim  SY, Yun  DH, Lee  SW.  Association between ABCB1 polymorphisms and ischemic stroke in Korean population.  Exp Neurobiol. 2012;21(4):164-171. doi:10.5607/en.2012.21.4.164PubMedGoogle ScholarCrossref
22.
Park  MW, Her  SH, Kim  CJ,  et al.  Evaluation of the incremental prognostic value of the combination of CYP2C19 poor metabolizer status and ABCB1 3435 TT polymorphism over conventional risk factors for cardiovascular events after drug-eluting stent implantation in East Asians.  Genet Med. 2016;18(8):833-841. doi:10.1038/gim.2015.171PubMedGoogle ScholarCrossref
23.
Paré  G, Mehta  SR, Yusuf  S,  et al.  Effects of CYP2C19 genotype on outcomes of clopidogrel treatment.  N Engl J Med. 2010;363(18):1704-1714. doi:10.1056/NEJMoa1008410PubMedGoogle ScholarCrossref
24.
Vargas-Alarcón  G, Ramírez-Bello  J, de la Peña  A,  et al.  Distribution of ABCB1, CYP3A5, CYP2C19, and P2RY12 gene polymorphisms in a Mexican Mestizos population.  Mol Biol Rep. 2014;41(10):7023-7029. doi:10.1007/s11033-014-3590-yPubMedGoogle ScholarCrossref
25.
Santos  PC, Soares  RA, Santos  DB,  et al.  CYP2C19 and ABCB1 gene polymorphisms are differently distributed according to ethnicity in the Brazilian general population.  BMC Med Genet. 2011;12:13. doi:10.1186/1471-2350-12-13PubMedGoogle ScholarCrossref
26.
Johnston  SC, Easton  JD, Farrant  M,  et al; Clinical Research Collaboration, Neurological Emergencies Treatment Trials Network, and the POINT Investigators.  Clopidogrel and aspirin in acute ischemic stroke and high-risk TIA.  N Engl J Med. 2018;379(3):215-225. doi:10.1056/NEJMoa1800410PubMedGoogle ScholarCrossref
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

Introduction

Clopidogrel bisulfate combined with aspirin is a recommended treatment for patients with acute minor ischemic stroke or transient ischemic attack (TIA).1-3 However, despite clopidogrel use, a substantial number of patients experience recurrent stroke, which may be explained at least in part by inadequate platelet inhibition.4,5

Quiz Ref IDClopidogrel is a prodrug that requires intestinal absorption and biotransformation to active metabolites by hepatic cytochrome P450 enzymes (CYP450). Previous studies showed that reduced function of CYP2C19 (OMIM 124020), a gene encoding CYP450, was associated with increased adverse cardiovascular events in patients with coronary artery disease6,7 or stroke8-10 treated with clopidogrel. In addition, polymorphisms of the genes regulating intestinal absorption of clopidogrel, such as the gene ABCB1 (OMIM 171050) encoding the P-glycoprotein multidrug-resistant–1 efflux transporter, might also affect clinical outcomes.11 Several,7,12,13 but not all,14,15 previous studies showed an association of ABCB1 3435C>T polymorphisms with reduced efficacy of clopidogrel treatment in coronary artery disease. Recent studies did not detect this association in patients with ischemic stroke.16,17 However, the sample sizes of these studies were relatively small. Therefore, the association between ABCB1 polymorphisms and the efficacy of clopidogrel treatment in patients with stroke or TIA remains unclear.

The previous genetic secondary analysis of the Clopidogrel in High-Risk Patients With Acute Nondisabling Cerebrovascular Events (CHANCE) trial showed reduced efficacy of dual therapy of clopidogrel and aspirin in carriers of the CYP2C19 loss-of-function alleles.10 In the present study, we further estimate the efficacy and safety of dual therapy of clopidogrel and aspirin compared with aspirin alone according to ABCB1 genotypes in the context of CYP2C19 status among patients in the trial.

Methods
Study Participants

Details on the rationale, design, and results of the CHANCE trial (NCT00979589) have been published previously.1,18,19 The trial protocol is given in Supplement 1. Quiz Ref IDIn brief, CHANCE was a randomized, double-blind, controlled clinical trial conducted at 114 hospitals in China between October 1, 2009, and July 30, 2012, that compared the efficacy of clopidogrel bisulfate (loading dose of 300 mg followed by 75 mg daily for 90 days) plus aspirin (loading dose of 75-300 mg followed by 75 mg daily for 21 days) with aspirin alone (loading dose of 75-300 mg followed by 75 mg daily for 90 days) among 5170 patients within 24 hours after onset of a minor ischemic stroke (National Institutes of Health Stroke Scale ≤3) or high-risk TIA (ABCD [age, blood pressure, clinical features, duration of TIA, and presence or absence of diabetes]2≥4). The protocol of the CHANCE trial was approved by the ethics committee of Beijing Tiantan Hospital and all participating centers. Each participant or his or her representative provided written informed consent before being entered into the study. Data were analyzed on March 20, 2018.

Seventy-three sites with experience collecting samples for genetic studies agreed to participate in the prespecified genetic secondary analysis. All patients at these sites for whom a separate written informed consent was obtained participated in this genetic secondary analysis.

Genotyping

Details on genotyping technology were published previously.10 Two single-nucleotide polymorphisms (SNPs) of the ABCB1 gene (–154T>C, rs4148727 and 3435C>T, rs1045642) were genotyped in 3010 participants. Participants were classified as homozygous for the T allele (TT), heterozygous (TC), or homozygous for the C allele (CC) for ABCB1 –154T>C SNP and homozygous for the C allele (CC), heterozygous (CT), or homozygous for the T allele (TT) for ABCB1 3435C>T SNP.

Because genetic variations in CYP2C19 (CYP2C19*2 [681G>A, rs4244285] and CYP2C19*3 [636G>A, rs4986893]) were associated with new stroke among clopidogrel-treated patients with minor stroke or TIA,10 we also evaluated the influence of ABCB1 polymorphism in the context of CYP2C19 status to understand the independent contribution of ABCB1 polymorphism. Patients with at least 1 loss-of-function allele (*2 or *3) were classified as CYP2C19 loss-of-function allele carriers.10

Genotyping of the 4 SNPs was centralized and performed using the Sequenom MassARRAY iPLEX platform (Sequenom). Genotyping success rate was greater than 94.3% among all samples genotyped for each of the 4 SNPs. The 2836 individuals with complete information for each of the 4 SNPs were included in the current analyses.

Clinical Outcomes

The definitions of the outcomes in the current analyses were identical to those in the trial.1Quiz Ref ID The primary outcome was a new stroke (ischemic or hemorrhagic) during the 90-day follow-up period. Secondary outcomes were new vascular events (composite of ischemic stroke, hemorrhagic stroke, myocardial infarction, or vascular death) and ischemic stroke at 90 days. The primary safety outcome was any bleeding. Safety outcome subtypes, including severe, moderate, and mild bleeding, defined according to the Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries (GUSTO) randomized trial criteria,20 were also examined. All reported efficacy and safety events were verified by a central adjudication committee that was blinded to the study group assignments.

Statistical Analysis

Continuous variables were presented as medians with interquartile ranges and categorical variables as percentages. Baseline characteristics between patients with and without genetic data were compared by Wilcoxon rank sum test for continuous variables and χ2 test for categorical variables. Baseline characteristics for patients with and without ABCB1 –154 TC/CC or 3435 CT/TT genotype stratified by treatment allocation were described separately. The linkage disequilibrium block and haplotype structure were measured by D′ among the 2 ABCB1 SNPs. Hardy-Weinberg equilibrium was evaluated with a χ2 test.

Differences in the outcome end points during the 90-day follow-up period were assessed using a Cox proportional hazards regression model, and hazard ratios (HRs) with 95% CIs were reported. When there were multiple events of the same type, the time to the first event was used in the model. Data from patients who had no event during the study were censored at termination of the trial or nonvascular death. For each model, the proportional hazards assumption was assessed by testing the interaction of treatment by time in the model. Whether the treatment effect differed in certain genotype categories was examined by testing the interactions of treatment by ABCB1 genotype and treatment by CYP2C19 loss-of-function allele carrier status in a multivariable Cox model. This model also included treatment group, ABCB1 genotype, CYP2C19 loss-of-function allele carrier status, and interaction of ABCB1 genotype by CYP2C19 loss-of-function allele carrier status. To exclude the influence of CYP2C19 polymorphism, we further assessed the association of ABCB1 polymorphism with the treatment effect among carriers and noncarriers of CYP2C19 loss-of-function allele.

All tests were 2-sided, and P < .05 was considered to be statistically significant. The linkage disequilibrium block and haplotype structure were estimated using the genetics package version 3.5.1 in R (R Development Core Team). All other analyses were conducted with SAS, version 9.4 (SAS Institute Inc).

Results
Study Patients

A total of 3010 patients participated in the genetic substudy, of whom 2836 were successfully genotyped for all 4 SNPs (eFigure 1 in Supplement 2). Compared with the 2334 individuals without genetic data, patients included in this genetic study were less likely to have a history of ischemic stroke but more likely to have a history of congestive heart failure and a diagnosis of minor stroke rather than TIA and to be taking concomitant antihypertensive agents (eTable 1 in Supplement 2). The baseline characteristics between the clopidogrel plus aspirin and aspirin alone groups were well balanced in this genetic substudy (eTable 2 in the Supplement 2).

Among the 2836 patients with genetic data, the median (interquartile range) age was 61.8 (54.4-71.1) years, 1887 patients (66.5%) were male, 2077 (73.2%) presented with minor stroke, and 759 (26.8%) presented with TIA. In total, 2266 (79.9%) were TT homozygotes, 507 (17.9%) were TC heterozygotes, and 63 (2.2%) were CC homozygotes for ABCB1 –154T>C. For ABCB1, 3435C>T, 985 (34.7%) were CC homozygotes, 1424 (50.2%) were CT heterozygotes, and 427 (15.1%) were TT homozygotes. A total of 2146 patients (75.7%) were carriers of ABCB1 –154 TC/CC or 3435 CT/TT genotype (ie, carriers of minor allele of ABCB1 –154T>C or ABCB1 3435C>T). Baseline characteristics for patients with and without ABCB1 –154 TC/CC or 3435 CT/TT genotype stratified by treatment allocation are presented in Table 1.

The linkage disequilibrium block in the 2 ABCB1 SNPs was not constructed, and we did not show the haplotype in the 2 ABCB1 SNPs (D′ = 0.67). The 2 CYP2C19 genetic variants were found to be in Hardy-Weinberg equilibrium (CYP2C19*2, P = .87; CYP2C19*3, P = .36), whereas the 2 ABCB1 genetic variants were found to be deviated from Hardy-Weinberg equilibrium (ABCB1 –154T>C, P = .001; ABCB1 3435C>T, P = .02).

Efficacy Outcomes

Clopidogrel plus aspirin compared with aspirin was associated with a reduced rate of new stroke in patients with ABCB1 –154 TT and 3435 CC genotype (HR, 0.43; 95% CI, 0.26-0.71; P < .001) but not in those with ABCB1 –154 TC/CC or 3435 CT/TT genotype (HR, 0.78; 95% CI, 0.60-1.03; P = .08) (P = .04 for interaction) (Table 2). Cumulative risk of new stroke among patients with or without ABCB1 –154 TC/CC or 3435 CT/TT genotype by treatment assignment is shown in Figure 1A. Separate analyses according to CYP2C19 loss-of-function allele carrier status showed a combined association of ABCB1 and CYP2C19 polymorphisms with new stroke at 3 months (HR, 0.28; 95% CI, 0.12-0.63; P = .002 in patients with ABCB1 –154 TT and 3435 CC genotype and without CYP2C19 loss-of-function allele) (Figure 2). Similar results were observed for the outcomes of composite event (P = .04 for interaction) and ischemic stroke (P = .04 for interaction) (Table 2).

For the ABCB1 –154T>C genotype, the association of clopidogrel plus aspirin compared with aspirin with a reduced rate of new stroke was observed in TT homozygotes (7.8% vs 12.8%; HR, 0.59; 95% CI, 0.46-0.77; P < .001) but not in TC heterozygotes (9.7% vs 6.9%; HR, 1.42; 95% CI, 0.77-2.63; P = .26) or CC homozygotes (11.4% vs 17.9%; HR, 0.63; 95% CI, 0.17-2.34; P = .49; P = .047 for interaction) (eFigure 2 in the Supplement 2). Separated analyses only including noncarriers of CYP2C19 loss-of-function allele showed similar results (P = .049 for interaction), whereas the clopidogrel plus aspirin group had similar rate of new stroke as the aspirin group irrespective of ABCB1 –154T>C genotypes in carriers of CYP2C19 loss-of-function allele (P = .42 for interaction) (eFigures 3 and 4 in Supplement 2). Similar results were observed for the outcomes of composite vascular event and ischemic stroke (Table 3 and eTables 3 and 4 in Supplement 2).

For the ABCB1 3435C>T genotype, rates of new stroke were lower in the clopidogrel plus aspirin group than in the aspirin group irrespective of ABCB1 3435C>T polymorphism (rate among CC homozygotes, 7.9% vs 12.5%; HR, 0.62; 95% CI, 0.41-0.92; P = .02; rate among CT heterozygotes, 8.8% vs 11.7%; HR, 0.75; 95% CI, 0.54-1.04; P = .08; rate among TT homozygotes, 7.1% vs 11.3%; HR, 0.62; 95% CI, 0.33-1.17; P = .14; P = .78 for interaction) (eFigure 2 in Supplement 2). The ABCB1 3435C>T genotype was not associated with modified efficacy of clopidogrel plus aspirin treatment in carriers or in noncarriers of CYP2C19 loss-of-function allele (P = .70 for interaction in carriers; and P = .94 for interaction in noncarriers) (eFigures 3 and 4 in Supplement 2). Similar results were observed as those for the outcomes of composite event and ischemic stroke (eTables 5-7 in Supplement 2).

Safety Outcomes

Patients with or without ABCB1 –154 TC/CC or 3435 CT/TT genotype in the clopidogrel plus aspirin group and the aspirin group had a similar rate of any bleeding (2.3% and 1.3% vs 1.9% and 2.2%; P = .25 for interaction) (Figure 1B and Table 2). The rate of any bleeding did not differ in separate analyses according to CYP2C19 loss-of-function allele carrier status (1.8% and 1.4% vs 1.4% and 2.1%, P = .55 for interaction in carriers; 3.0% and 1.1% vs 2.5% and 2.3%, P = .30 for interaction in noncarriers of CYP2C19 loss-of-function allele) (Figure 2).

The rate of any bleeding did not differ between patients in the clopidogrel plus aspirin group and those in the aspirin group irrespective of ABCB1 –154T>C genotype (1.7% and 1.1% vs 2.3% and 1.6%; P = .76 for interaction) (Table 3) and regardless of carrying or not carrying CYP2C19 loss-of-function allele (1.1% and 1.7% vs 1.9% and 1.5%; P = .59 for interaction in carriers; 2.6% and 0.0% vs 3.0% and 1.7%; P = .99 for interaction in noncarriers) (eTables 3 and 4 in Supplement 2).

Although the clopidogrel plus aspirin group had a higher rate of mild bleeding than the aspirin group in ABCB1 3435 CT/TT genotypes (1.7% vs 0.6%; P = .04), the interaction of treatment by ABCB1 3435C>T genotype was not significant (P = .16 for interaction) (eTable 5 in Supplement 2). The clopidogrel plus aspirin group had a similar rate of any bleeding compared with the aspirin group irrespective of ABCB1 3435C>T genotype in carriers and noncarriers of CYP2C19 loss-of-function allele (P = .30 for interaction in carriers; P = .51 for interaction in noncarriers) (eTables 6 and 7 in Supplement 2).

Discussion

A number of factors affect the clinical response to clopidogrel, including genetic variants such as in the CYP2C19 gene. Quiz Ref IDThe present analysis found that the ABCB1 polymorphism was associated with the efficacy of clopidogrel plus aspirin treatment compared with aspirin alone in patients with acute minor stroke or TIA. The ABCB1 –154TC/CC genotypes were associated with less protection from new stroke with clopidogrel only in noncarriers of the CYP2C19 loss-of-function allele compared with the ABCB1 –154TT genotype. However, the ABCB1 3435C>T polymorphism was not associated with the efficacy of clopidogrel plus aspirin treatment irrespective of CYP2C19 loss-of-function allele carrier status. The risk of bleeding for clopidogrel plus aspirin treatment compared with aspirin alone was not associated with ABCB1 genotype.

There are limited data available addressing the association of ABCB1 polymorphism with clopidogrel efficacy in stroke. Two recent studies with small sample sizes reported no association between ABCB1 polymorphisms and clinical response to clopidogrel treatment.16,17 Su et al16 reported that ABCB1 3435C>T was not associated with clopidogrel response according to platelet aggregation in clopidogrel-treated Chinese patients with ischemic stroke. Li et al17 found that the ABCB1 –129T>C (rs3213619), 1236C>T (rs1128503), and 3435C>T SNPs were not associated with clopidogrel response and recurrent ischemic events in 268 Chinese patients with extracranial or intracranial stenting. Furthermore, Kim et al21 found that the ABCB1 3′UTR A>G (rs3842) SNP, but not the ABCB1 –154T>C SNP, was associated with the development of ischemic stroke in a Korean population in a case-control study that enrolled 121 participants with ischemic stroke and 291 control participants. However, the generalization of these studies was limited by their small sample sizes and limited statistical power. Compared with previous studies, our study had a larger sample size and evaluated the association of ABCB1 polymorphism with clopidogrel efficacy in the context of CYP2C19 status. Some but not all previous studies showed that the CYP2C19 and ABCB1 polymorphisms had a combined association with adverse clinical outcomes in patients with acute coronary syndromes undergoing percutaneous coronary intervention.12,22 We observed similar combined associations of CYP2C19 and ABCB1 polymorphisms with stroke recurrence in patients with stroke or TIA in this study. Furthermore, our study observed a higher rate of mild bleeding in the clopidogrel plus aspirin group compared with the aspirin group in the ABCB1 3435 CT/TT genotypes. The mechanism is unclear and potentially owing to a small sample size. In addition, this study included a randomized control group (patients treated with aspirin alone) to evaluate the association of ABCB1 polymorphism with the efficacy of clopidogrel, whereas previous studies were conducted exclusively in patients treated with clopidogrel (with or without aspirin); our method allowed us to avoid potential confounding.23

Quiz Ref IDThe frequency of carriers of ABCB1 –154 TC/CC or 3435 CT/TT genotype in this study was 75.7%, similar to that reported in other Chinese,16,24 Mexican,24 and Native American populations24,25 and higher than that in persons of European (66.5%) and African (52.5%) descent.25 The ABCB1 –154 TC/CC or 3435 CT/TT genotype may be associated with higher P-glycoprotein expression and thus an enhanced intestinal efflux, possibly of clopidogrel.11,21 This study provided evidence that besides CYP2C19, the genetic polymorphism of ABCB1 encoding the P-glycoprotein, which plays an important role in intestinal absorption of clopidogrel, should also be considered when prescribing clopidogrel for patients with minor ischemic stroke and TIA. Genetic testing may allow clinicians to personalize antiplatelet therapy; however, its cost-effectiveness needs further investigation. Varying the dose of clopidogrel or shifting to new antiplatelet agents (eg, prasugrel) based on genetic results may be another alternative but also needs to be further evaluated.10 Future research may focus on the cost-effectiveness of genetic testing in clinical practice and evaluation of efficacy of alternatives for those with ABCB1 –154TC/CC genotypes.

Limitations

Our study has several limitations. First, enrollment in the CHANCE trial was restricted to Chinese patients. Given the variability in genetic variants across races/ethnicities, further evaluation is required before applying these results to non-Asian populations. More pharmacogenomic data in a Western population are expected from the Platelet-Oriented Inhibition in New TIA and Minor Ischemic Stroke (POINT) trial,26 which evaluated the efficacy and safety of clopidogrel plus aspirin vs aspirin alone in patients with minor stroke and TIA within 12 hours. Second, because the baseline data of stroke mechanisms were not available in the CHANCE trial, it was impossible to assess the influence of stroke mechanisms on the pharmacogenetic effect of ABCB1 in this study. Third, the event rates for bleeding were low in this population, which may limit statistical power to detect the association with the safety outcome. Fourth, caution is needed when explaining the results because the 2 ABCB1 genetic variants were deviated from Hardy-Weinberg equilibrium.

Conclusions

Among patients with minor ischemic stroke or TIA, the ABCB1 polymorphism was found to be associated with reduced efficacy of clopidogrel plus aspirin treatment compared with aspirin alone in this study. However, further validations are needed in other studies with large sample sizes.

Back to top
Article Information

Accepted for Publication: October 16, 2018.

Corresponding Author: Yongjun Wang, MD, No. 119, South 4th Ring West Road, Fengtai District, Beijing, China, 100070 (yongjunwang@ncrcnd.org.cn).

Published Online: February 11, 2019. doi:10.1001/jamaneurol.2018.4775

Author Contributions: Dr Yongjun Wang had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Pan, Chen, Yilong Wang, Li, Zhao, Liu, Yongjun Wang.

Acquisition, analysis, or interpretation of data: Johnston, Simon, D. Wang, Meng, Yongjun Wang.

Drafting of the manuscript: Pan, D. Wang.

Critical revision of the manuscript for important intellectual content: Chen, Yilong Wang, Li, Johnston, Simon, Zhao, Liu, Meng, Yongjun Wang.

Statistical analysis: Pan.

Obtained funding: Zhao, Yongjun Wang.

Administrative, technical, or material support: Chen, Zhao, Meng.

Supervision: Chen, Yilong Wang, Li, Johnston, Zhao, Liu, D. Wang, Yongjun Wang.

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.

Funding/Support: This study was supported by grants 2016YFC0901001, 2016YFC0901002, 2017YFC1310901, 2018YFC1311700, and 2018YFC1311706 from the Ministry of Science and Technology of the People’s Republic of China and grants 2016-1-2041 and SML20150502 from the Beijing Municipal Commission of Health and Family Planning.

Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Group Members: Clopidogrel in High-Risk Patients With Acute Nondisabling Cerebrovascular Events (CHANCE) Investigators: Beijing Tiantan Hospital, Beijing, China: Yongjun Wang, MD; Yilong Wang, MD, PhD; Xingquan Zhao, MD, PhD; Dell Medical School, University of Texas at Austin, Austin: S. Claiborne Johnston, MD, PhD; Taizhou First People’s Hospital, Taizhou, China: Zhimin Wang, MD; Taiyuan Iron And Steel (Group) Co., Ltd., General Hospital, Taiyuan, China: Haiqin Xia, MD; Penglai People’s Hospital, Yantai, China: Guiru Zhang, MD; The Third People’s Hospital of Datong, Datong, China: Xudong Ren, MD; The Fourth Central Hospital of Tianjin, Tianjin, China: Chunling Ji, MD; The Second Hospital of Hebei Medical University, Shijiazhuang, China: Guohua Zhang, MD; The First Hospital of Fangshan District, Beijing, China: Jianhua Li, MD; Beijing Puren Hospital, Beijing, China: Bohua Lu, MD; Tianjin Ninghe District Hospital, Tianjin, China: Liping Wang, MD; The People’s Hospital of Zhengzhou, Zhengzhou, China: Shutao Feng, MD; Affiliated Hospital of North China Coal Medical College, Tangshan, China: Dali Wang, MD; Zhejiang Zhoushan Hospital, Zhoushan, China: WeiguoTang, MD, PhD; HanDan Central Hospital, Handan, China: Juntao Li, MD; Zhecheng People’s Hospital, Zhecheng, China: Hongtian Zhang, MD; Shanxi Medical University Second Hospital, Taiyuan, China: Guanglai Li, MD; Baotou Central Hospital, Baotou, China: Baojun Wang, MD, PhD; The General Hospital of Changjiang River Shipping, Wuhan, China: Yuhua Chen, MD; Dalian Economic And Technological Development Zone Hospital, Dalian, China: Ying Lian, MD; First Neurology Department, Affiliated Hospital of North China Coal Medical College, Tangshan, China: Bin Liu, MD; The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China: Junfang Teng, MD; First Affiliated Hospital of Liaoning Medical University, Jinzhou, China: Rubo Sui, MD; Lianyungang Municipal Hospital of TCM, Lianyungang, China: Lejun Li, MD; Central Hospital In Qiu County, Handan, China: Zhiling Yuan, MD; Tianjin First Center Hospital, Tianjin, China: Dawei Zang, MD; Renmin Hospital of Wuhan University, Wuhan, China: Zuneng Lu, MD; Qingdao Central Hospital, Qingdao, China: Li Sun, MD; Baogang Hospital, Baotou, China: Dong Wang, MD; Changzhi City People’s Hospital of Shanxi Province, Changzhi, China: Liying Hou, MD; Harrison International Peace Hospital, Hengshui, China: Dongcai Yuan, MD; People’s Hospital of Linzi District, Zibo, China: Yongliang Cao, MD; Yantai Mountain Hospital, Yantai, China: Hui Li, MD; Beijing Pinggu District Hospital, Beijing, China: Xiuge Tan, MD; Taiyuan Central Hospital, Taiyuan, China: Huicong Wang, MD; Chengde Central Hospital, Chengde, China: Haisong Du, MD; Shijiazhuang Central Hospital, Shijiazhuang, China: Mingyi Liu, MD; First Neurology Department, Dalian Municipal Central Hospital, Dalian, China: Suping Wang, MD; Xi’an 141 Hospital, Xi’an, China: Qiuwu Liu, MD; Chengdu Third Municipal People’s Hospital, Chengdu, China: Zhong Zhang, MD; Affiliated Hospital of Chifeng University, Chifeng, China: Qifu Cui, MD; Zhengzhou Central Hospital, Zhengzhou, China: Runqing Wang, MD; Lihuili Hospital Medical Center, Ningbo, China: Jialin Zhao, MD; Henan Provincial People’s Hospital, Zhengzhou, China: Jiewen Zhang, MD; Jinzhong City Second Hospital, Jinzhong, China: Jianping Zhao, MD; Beijing Anzhen Hospital, Capital Medical University, Beijing, China: Qi Bi, MD, PhD; Beijing Huairou District Chinese Medicine Hospital, Beijing, China: Xiyou Qi, MD; Hebei Medical University Third Hospital, Shijiazhuang, China: Junyan Liu, MD; First Affiliated Hospital Shanxi Medical University, Taiyuan, China: Changxin Li, MD; Hebei Provincial People’s Hospital, Shijiazhuang, China: Ling Li, MD; Guangzhou First Municipal Peoples Hospital, Guangzhou, China: Xiaoping Pan, MD; Central Hospital In Cangzhou, Cangzhou, China: Junling Zhang, MD; The Chinese People’s Armed Police Force Medical School Affiliated Hospital, Tianjin, China: Derang Jiao, MD; Zhejiang Wenzhou Medical College First Affiliated Hospital, Wenzhou, China: Zhao Han, MD; Jilin Central Hospital, Jilin, China: Dawei Qian, MD; Anhui Maanshan Central Hospital, Maanshan, China: Jin Xiao, MD; Beijing Aviation Industry Central Hospital, Beijing, China: Yan Xing, MD; Luhe Hospital, Beijing, China: Huishan Du, MD; Beijing Fuxing Hospital, Capital Medical University, Beijing, China: Guang Huang, MD; The 306th Hospital of P.L.A, Beijing, China: Yongqiang Cui, MD; The First Affiliated Hospital of Tianjin University of Chinese Medicine, Tianjin, China: Yan Li, MD; Baiqiuen International Peace Hospital of People’s Liberation Army, Shijiazhuang, China: Lianyuan Feng, MD; Fourth Affiliated Hospital of China Medical University, Shenyang, China: Lianbo Gao, MD; Xiangya Hospital Central-South University, Xiangya, China: Bo Xiao, MD; Tangshan Worker’s Hospital, Tangshan, China: Yibin Cao, MD; The 1st Hospital in Handan, Handan, China: Yiping Wu, MD; Yangquan Coal (Group) Co., Ltd. General Hospital, Yangquan, China: Jinfeng Liu, MD; Tianjin Tianhe Hospital, Tianjin, China: Zhiming Zhang, MD; Nantong First People’s Hospital, Nantong, China: Zhengxie Dong, MD; The 1st Hospital of Zhangjiakou City, Zhangjiakou, China: Limin Wang, MD; West China Hospital, Chengdu, China: Li He, MD, PhD; The Second Affiliated Hospital of Shandong University of TCM, Jinan, China: Xinchen Wang, MD; Fenyang Hospital of Shanxi Province, Fenyang, China: Xueying Guo, MD; Zhejiang Zhoushan Putuo District People’s Hospital, Zhoushan, China: Ming Wang, MD; Xiyuan Hospital of China Academy of Chinese Traditional Medicine, Beijing, China: Xiaosha Wang, MD; No.2 People’s Hospital East in Lianyungang City, Lianyungang, China: Jiandong Jiang, MD; Affiliated Hospital of Qingdao University Medical College, Qingdao, China: Renliang Zhao, MD, PhD; Qilu Hospital of Shandong University, Jinan, China: Shengnian Zhou, MD, PhD; Zibo Hospital of Traditional Chinese Medicine, Zibo, China: HaoHu, MD; Beijing Shijitan Hospital, Beijing, China: Maolin He, MD, PhD; Beijing Haidian Hospital, Beijing, China: Fengchun Yu, MD; Beijing Shunyi District Hospital, Beijing, China: Quping Ouyang, MD; Dalian Third Municipal Hospital, Dalian, China: Jingbo Zhang, MD; The First Affliated Hospital of Jinan University, Guangzhou, China: Anding Xu, MD, PhD; Navy Genaral Hospital of P.L.A, Beijing, China: Xiaokun Qi, MD; Beijing Second Artillery General Hospital, Beijing, China: Lei Wang, MD; Beijing Daxing District Hospital, Beijing, China: Fuming Shi, MD; Sichuan Province People’s Hospital, Chengdu, China: Fuqiang Guo, MD; Dalian Municipal Central Hospital, Dalian, China: Jianfeng Wang, MD; The Second Hospital in Baoding, Baoding, China: Fengli Zhao, MD; The Hospital Combine Traditional Chinese and Western Medicine in Cangzhou, Cangzhou, China: Ronghua Dou, MD; The 309th Hospital Of P.L.A, Beijing, China: Dongning Wei, MD; Liangxiang Hospital Of Fangshan District, Beijing, China: Qingwei Meng, MD; HuaXin Hospital First Hospital of Tsinghua University, Beijing, China: Yilu Xia, MD; Tianjin Huanhu Hospital, Tianjin, China, ShiminWang, MD; Shijiazhuang First Hospital, Shijiazhuang, China: Zhangcang Xue, MD; The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China: Yuming Xu, MD, PhD; Xinzhou City People’s Hospital, Xinzhou, China: Liping Ma, MD; Sichuan Province People’s Hospital of Deyang City, Deyang, China: Chun Wang, MD; First Hospital, Jilin University, Jilin, China: Jiang Wu, MD; Shandong Provincial Hospital, Jinan, China: Yifeng Du, MD; Fujian Province Hospital, Fuzhou, China: Yinzhou Wang, MD; Liaoyang City Third People’s Hospital, Liaoyang, China: Lijun Xiao, MD; Handan City Center Hospital, Handan, China: Fucong Song, MD; Beijing Chaoyang Hospital, Capital Medical University, Beijing, China: Wenli Hu, MD; Beijing University of Chinese Medicine East Hospital, Beijing, China: Zhigang Chen, MD; Hebei Medical University Fourth Hospital, Shijiazhuang, China: Qingrui Liu, MD; The Fourth Affiliated Hospital of Soochow University, Suzhou, China: Jiemin Zhang, MD; Zhejiang University of Chinese Medicine Affiliated First Hospital, Hangzhou, China: Mei Chen, MD; Affiliated Hospital of Kailuan Company Ltd, Tangshan, China, Xiaodong Yuan, MD; Affiliated Hospital of Weifang Medical University, Weifang, China: Zhihui Liu, MD; The First Hospital of Harbin Medical University, Harbin, China: Guozhong Li, MD; Dalian Friendship Hospital, Dalian, China: Xiaohong Li, MD; Tianjin Dagang Hospital, Tianjin, China: Tingchen Tian, MD.

Meeting Presentation: This paper was presented at the 11th World Stroke Congress; October 20, 2018; Montreal, Quebec, Canada.

Data Sharing Statement: See Supplement 3.

References
1.
Wang  Y, Wang  Y, Zhao  X,  et al; CHANCE Investigators.  Clopidogrel with aspirin in acute minor stroke or transient ischemic attack.  N Engl J Med. 2013;369(1):11-19. doi:10.1056/NEJMoa1215340PubMedGoogle ScholarCrossref
2.
Kernan  WN, Ovbiagele  B, Black  HR,  et al; American Heart Association Stroke Council, Council on Cardiovascular and Stroke Nursing, Council on Clinical Cardiology, and Council on Peripheral Vascular Disease.  Guidelines for the prevention of stroke in patients with stroke and transient ischemic attack: a guideline for healthcare professionals from the American Heart Association/American Stroke Association.  Stroke. 2014;45(7):2160-2236. doi:10.1161/STR.0000000000000024PubMedGoogle ScholarCrossref
3.
Powers  WJ, Rabinstein  AA, Ackerson  T,  et al; American Heart Association Stroke Council.  2018 Guidelines for the early management of patients with acute ischemic stroke: a guideline for healthcare professionals from the American Heart Association/American Stroke Association.  Stroke. 2018;49(3):e46-e110. doi:10.1161/STR.0000000000000158PubMedGoogle ScholarCrossref
4.
Topçuoglu  MA, Arsava  EM, Ay  H.  Antiplatelet resistance in stroke.  Expert Rev Neurother. 2011;11(2):251-263. doi:10.1586/ern.10.203PubMedGoogle ScholarCrossref
5.
Mijajlovic  MD, Shulga  O, Bloch  S, Covickovic-Sternic  N, Aleksic  V, Bornstein  NM.  Clinical consequences of aspirin and clopidogrel resistance: an overview.  Acta Neurol Scand. 2013;128(4):213-219. doi:10.1111/ane.12111PubMedGoogle ScholarCrossref
6.
Zabalza  M, Subirana  I, Sala  J,  et al.  Meta-analyses of the association between cytochrome CYP2C19 loss- and gain-of-function polymorphisms and cardiovascular outcomes in patients with coronary artery disease treated with clopidogrel.  Heart. 2012;98(2):100-108. doi:10.1136/hrt.2011.227652PubMedGoogle ScholarCrossref
7.
Simon  T, Verstuyft  C, Mary-Krause  M,  et al; French Registry of Acute ST-Elevation and Non-ST-Elevation Myocardial Infarction (FAST-MI) Investigators.  Genetic determinants of response to clopidogrel and cardiovascular events.  N Engl J Med. 2009;360(4):363-375. doi:10.1056/NEJMoa0808227PubMedGoogle ScholarCrossref
8.
Jia  DM, Chen  ZB, Zhang  MJ,  et al.  CYP2C19 polymorphisms and antiplatelet effects of clopidogrel in acute ischemic stroke in China.  Stroke. 2013;44(6):1717-1719. doi:10.1161/STROKEAHA.113.000823PubMedGoogle ScholarCrossref
9.
Pan  Y, Chen  W, Xu  Y,  et al.  Genetic polymorphisms and clopidogrel efficacy for acute ischemic stroke or transient ischemic attack: a systematic review and meta-analysis.  Circulation. 2017;135(1):21-33. doi:10.1161/CIRCULATIONAHA.116.024913PubMedGoogle ScholarCrossref
10.
Wang  Y, Zhao  X, Lin  J,  et al; CHANCE investigators.  Association between CYP2C19 loss-of-function allele status and efficacy of clopidogrel for risk reduction among patients with minor stroke or transient ischemic attack.  JAMA. 2016;316(1):70-78. doi:10.1001/jama.2016.8662PubMedGoogle ScholarCrossref
11.
Momary  KM, Dorsch  MP, Bates  ER.  Genetic causes of clopidogrel nonresponsiveness: which ones really count?  Pharmacotherapy. 2010;30(3):265-274. doi:10.1592/phco.30.3.265PubMedGoogle ScholarCrossref
12.
Mega  JL, Close  SL, Wiviott  SD,  et al.  Genetic variants in ABCB1 and CYP2C19 and cardiovascular outcomes after treatment with clopidogrel and prasugrel in the TRITON-TIMI 38 trial: a pharmacogenetic analysis.  Lancet. 2010;376(9749):1312-1319. doi:10.1016/S0140-6736(10)61273-1PubMedGoogle ScholarCrossref
13.
Cayla  G, Hulot  JS, O’Connor  SA,  et al.  Clinical, angiographic, and genetic factors associated with early coronary stent thrombosis.  JAMA. 2011;306(16):1765-1774. doi:10.1001/jama.2011.1529PubMedGoogle ScholarCrossref
14.
Jeong  YH, Tantry  US, Kim  IS,  et al.  Effect of CYP2C19*2 and *3 loss-of-function alleles on platelet reactivity and adverse clinical events in East Asian acute myocardial infarction survivors treated with clopidogrel and aspirin.  Circ Cardiovasc Interv. 2011;4(6):585-594. doi:10.1161/CIRCINTERVENTIONS.111.962555PubMedGoogle ScholarCrossref
15.
Wallentin  L, James  S, Storey  RF,  et al; PLATO investigators.  Effect of CYP2C19 and ABCB1 single nucleotide polymorphisms on outcomes of treatment with ticagrelor versus clopidogrel for acute coronary syndromes: a genetic substudy of the PLATO trial.  Lancet. 2010;376(9749):1320-1328. doi:10.1016/S0140-6736(10)61274-3PubMedGoogle ScholarCrossref
16.
Su  JF, Hu  XH, Li  CY.  Risk factors for clopidogrel resistance in patients with ischemic cerebral infarction and the correlation with ABCB1 gene rs1045642 polymorphism.  Exp Ther Med. 2015;9(1):267-271. doi:10.3892/etm.2014.2058PubMedGoogle ScholarCrossref
17.
Li  XQ, Ma  N, Li  XG,  et al.  Association of PON1, P2Y12 and COX1 with recurrent ischemic events in patients with extracranial or intracranial stenting.  PLoS One. 2016;11(2):e0148891. doi:10.1371/journal.pone.0148891PubMedGoogle ScholarCrossref
18.
Wang  Y, Pan  Y, Zhao  X,  et al; CHANCE Investigators.  Clopidogrel with aspirin in acute minor stroke or transient ischemic attack (CHANCE) trial: one-year outcomes.  Circulation. 2015;132(1):40-46. doi:10.1161/CIRCULATIONAHA.114.014791PubMedGoogle ScholarCrossref
19.
Wang  Y, Johnston  SC; CHANCE Investigators.  Rationale and design of a randomized, double-blind trial comparing the effects of a 3-month clopidogrel-aspirin regimen versus aspirin alone for the treatment of high-risk patients with acute nondisabling cerebrovascular event.  Am Heart J. 2010;160(3):380-386.e1. doi:10.1016/j.ahj.2010.05.017PubMedGoogle ScholarCrossref
20.
GUSTO investigators.  An international randomized trial comparing four thrombolytic strategies for acute myocardial infarction.  N Engl J Med. 1993;329(10):673-682. doi:10.1056/NEJM199309023291001PubMedGoogle ScholarCrossref
21.
Kim  YO, Kim  SY, Yun  DH, Lee  SW.  Association between ABCB1 polymorphisms and ischemic stroke in Korean population.  Exp Neurobiol. 2012;21(4):164-171. doi:10.5607/en.2012.21.4.164PubMedGoogle ScholarCrossref
22.
Park  MW, Her  SH, Kim  CJ,  et al.  Evaluation of the incremental prognostic value of the combination of CYP2C19 poor metabolizer status and ABCB1 3435 TT polymorphism over conventional risk factors for cardiovascular events after drug-eluting stent implantation in East Asians.  Genet Med. 2016;18(8):833-841. doi:10.1038/gim.2015.171PubMedGoogle ScholarCrossref
23.
Paré  G, Mehta  SR, Yusuf  S,  et al.  Effects of CYP2C19 genotype on outcomes of clopidogrel treatment.  N Engl J Med. 2010;363(18):1704-1714. doi:10.1056/NEJMoa1008410PubMedGoogle ScholarCrossref
24.
Vargas-Alarcón  G, Ramírez-Bello  J, de la Peña  A,  et al.  Distribution of ABCB1, CYP3A5, CYP2C19, and P2RY12 gene polymorphisms in a Mexican Mestizos population.  Mol Biol Rep. 2014;41(10):7023-7029. doi:10.1007/s11033-014-3590-yPubMedGoogle ScholarCrossref
25.
Santos  PC, Soares  RA, Santos  DB,  et al.  CYP2C19 and ABCB1 gene polymorphisms are differently distributed according to ethnicity in the Brazilian general population.  BMC Med Genet. 2011;12:13. doi:10.1186/1471-2350-12-13PubMedGoogle ScholarCrossref
26.
Johnston  SC, Easton  JD, Farrant  M,  et al; Clinical Research Collaboration, Neurological Emergencies Treatment Trials Network, and the POINT Investigators.  Clopidogrel and aspirin in acute ischemic stroke and high-risk TIA.  N Engl J Med. 2018;379(3):215-225. doi:10.1056/NEJMoa1800410PubMedGoogle ScholarCrossref
×