Polymorphisms and Clopidogrel Efficacy and Safety in Patients With Minor Stroke or TIA

Yuesong Pan, From the Department of Neurology (Y.P., H.L., Y.W., X.M., J.L., X.Z., L.L., Y.W.), Beijing Tiantan Hospital, Capital Medical University; China National Clinical Research Center for Neurological Diseases (Y.P., H.L., Y.W., X.M., J.L., X.Z., L.L., Y.W.), Beijing, China; Department of Neurology (R.W.), Duke University Medical Center, Durham, NC; Dell Medical School (S.C.J.), University of Texas at Austin; Department of Clinical Pharmacology and Clinical Research Platform of East of Paris (URCEST-CRC-CRB) (T.S.), Assistance Publique-Hôpitaux de Paris, Hôpital Saint Antoine (APHP.SU); Sorbonne Université (T.S.); FACT (French Alliance for Cardiovascular Clinical Trials) (T.S.), Paris, France; and Department of Neurology (D.W.), Barrow Neurological Institute, St. Joseph's Hospital and Medical Center, Phoenix, AZ.
Runqi Wangqin, From the Department of Neurology (Y.P., H.L., Y.W., X.M., J.L., X.Z., L.L., Y.W.), Beijing Tiantan Hospital, Capital Medical University; China National Clinical Research Center for Neurological Diseases (Y.P., H.L., Y.W., X.M., J.L., X.Z., L.L., Y.W.), Beijing, China; Department of Neurology (R.W.), Duke University Medical Center, Durham, NC; Dell Medical School (S.C.J.), University of Texas at Austin; Department of Clinical Pharmacology and Clinical Research Platform of East of Paris (URCEST-CRC-CRB) (T.S.), Assistance Publique-Hôpitaux de Paris, Hôpital Saint Antoine (APHP.SU); Sorbonne Université (T.S.); FACT (French Alliance for Cardiovascular Clinical Trials) (T.S.), Paris, France; and Department of Neurology (D.W.), Barrow Neurological Institute, St. Joseph's Hospital and Medical Center, Phoenix, AZ.
Hao Li, From the Department of Neurology (Y.P., H.L., Y.W., X.M., J.L., X.Z., L.L., Y.W.), Beijing Tiantan Hospital, Capital Medical University; China National Clinical Research Center for Neurological Diseases (Y.P., H.L., Y.W., X.M., J.L., X.Z., L.L., Y.W.), Beijing, China; Department of Neurology (R.W.), Duke University Medical Center, Durham, NC; Dell Medical School (S.C.J.), University of Texas at Austin; Department of Clinical Pharmacology and Clinical Research Platform of East of Paris (URCEST-CRC-CRB) (T.S.), Assistance Publique-Hôpitaux de Paris, Hôpital Saint Antoine (APHP.SU); Sorbonne Université (T.S.); FACT (French Alliance for Cardiovascular Clinical Trials) (T.S.), Paris, France; and Department of Neurology (D.W.), Barrow Neurological Institute, St. Joseph's Hospital and Medical Center, Phoenix, AZ.
Yilong Wang, From the Department of Neurology (Y.P., H.L., Y.W., X.M., J.L., X.Z., L.L., Y.W.), Beijing Tiantan Hospital, Capital Medical University; China National Clinical Research Center for Neurological Diseases (Y.P., H.L., Y.W., X.M., J.L., X.Z., L.L., Y.W.), Beijing, China; Department of Neurology (R.W.), Duke University Medical Center, Durham, NC; Dell Medical School (S.C.J.), University of Texas at Austin; Department of Clinical Pharmacology and Clinical Research Platform of East of Paris (URCEST-CRC-CRB) (T.S.), Assistance Publique-Hôpitaux de Paris, Hôpital Saint Antoine (APHP.SU); Sorbonne Université (T.S.); FACT (French Alliance for Cardiovascular Clinical Trials) (T.S.), Paris, France; and Department of Neurology (D.W.), Barrow Neurological Institute, St. Joseph's Hospital and Medical Center, Phoenix, AZ. yongjunwang@ncrcnd.org.cn.
Xia Meng, From the Department of Neurology (Y.P., H.L., Y.W., X.M., J.L., X.Z., L.L., Y.W.), Beijing Tiantan Hospital, Capital Medical University; China National Clinical Research Center for Neurological Diseases (Y.P., H.L., Y.W., X.M., J.L., X.Z., L.L., Y.W.), Beijing, China; Department of Neurology (R.W.), Duke University Medical Center, Durham, NC; Dell Medical School (S.C.J.), University of Texas at Austin; Department of Clinical Pharmacology and Clinical Research Platform of East of Paris (URCEST-CRC-CRB) (T.S.), Assistance Publique-Hôpitaux de Paris, Hôpital Saint Antoine (APHP.SU); Sorbonne Université (T.S.); FACT (French Alliance for Cardiovascular Clinical Trials) (T.S.), Paris, France; and Department of Neurology (D.W.), Barrow Neurological Institute, St. Joseph's Hospital and Medical Center, Phoenix, AZ.
S Claiborne Johnston, From the Department of Neurology (Y.P., H.L., Y.W., X.M., J.L., X.Z., L.L., Y.W.), Beijing Tiantan Hospital, Capital Medical University; China National Clinical Research Center for Neurological Diseases (Y.P., H.L., Y.W., X.M., J.L., X.Z., L.L., Y.W.), Beijing, China; Department of Neurology (R.W.), Duke University Medical Center, Durham, NC; Dell Medical School (S.C.J.), University of Texas at Austin; Department of Clinical Pharmacology and Clinical Research Platform of East of Paris (URCEST-CRC-CRB) (T.S.), Assistance Publique-Hôpitaux de Paris, Hôpital Saint Antoine (APHP.SU); Sorbonne Université (T.S.); FACT (French Alliance for Cardiovascular Clinical Trials) (T.S.), Paris, France; and Department of Neurology (D.W.), Barrow Neurological Institute, St. Joseph's Hospital and Medical Center, Phoenix, AZ.
Tabassome Simon, From the Department of Neurology (Y.P., H.L., Y.W., X.M., J.L., X.Z., L.L., Y.W.), Beijing Tiantan Hospital, Capital Medical University; China National Clinical Research Center for Neurological Diseases (Y.P., H.L., Y.W., X.M., J.L., X.Z., L.L., Y.W.), Beijing, China; Department of Neurology (R.W.), Duke University Medical Center, Durham, NC; Dell Medical School (S.C.J.), University of Texas at Austin; Department of Clinical Pharmacology and Clinical Research Platform of East of Paris (URCEST-CRC-CRB) (T.S.), Assistance Publique-Hôpitaux de Paris, Hôpital Saint Antoine (APHP.SU); Sorbonne Université (T.S.); FACT (French Alliance for Cardiovascular Clinical Trials) (T.S.), Paris, France; and Department of Neurology (D.W.), Barrow Neurological Institute, St. Joseph's Hospital and Medical Center, Phoenix, AZ.
Jinxi Lin, From the Department of Neurology (Y.P., H.L., Y.W., X.M., J.L., X.Z., L.L., Y.W.), Beijing Tiantan Hospital, Capital Medical University; China National Clinical Research Center for Neurological Diseases (Y.P., H.L., Y.W., X.M., J.L., X.Z., L.L., Y.W.), Beijing, China; Department of Neurology (R.W.), Duke University Medical Center, Durham, NC; Dell Medical School (S.C.J.), University of Texas at Austin; Department of Clinical Pharmacology and Clinical Research Platform of East of Paris (URCEST-CRC-CRB) (T.S.), Assistance Publique-Hôpitaux de Paris, Hôpital Saint Antoine (APHP.SU); Sorbonne Université (T.S.); FACT (French Alliance for Cardiovascular Clinical Trials) (T.S.), Paris, France; and Department of Neurology (D.W.), Barrow Neurological Institute, St. Joseph's Hospital and Medical Center, Phoenix, AZ.
Xingquan Zhao, From the Department of Neurology (Y.P., H.L., Y.W., X.M., J.L., X.Z., L.L., Y.W.), Beijing Tiantan Hospital, Capital Medical University; China National Clinical Research Center for Neurological Diseases (Y.P., H.L., Y.W., X.M., J.L., X.Z., L.L., Y.W.), Beijing, China; Department of Neurology (R.W.), Duke University Medical Center, Durham, NC; Dell Medical School (S.C.J.), University of Texas at Austin; Department of Clinical Pharmacology and Clinical Research Platform of East of Paris (URCEST-CRC-CRB) (T.S.), Assistance Publique-Hôpitaux de Paris, Hôpital Saint Antoine (APHP.SU); Sorbonne Université (T.S.); FACT (French Alliance for Cardiovascular Clinical Trials) (T.S.), Paris, France; and Department of Neurology (D.W.), Barrow Neurological Institute, St. Joseph's Hospital and Medical Center, Phoenix, AZ.
Liping Liu, From the Department of Neurology (Y.P., H.L., Y.W., X.M., J.L., X.Z., L.L., Y.W.), Beijing Tiantan Hospital, Capital Medical University; China National Clinical Research Center for Neurological Diseases (Y.P., H.L., Y.W., X.M., J.L., X.Z., L.L., Y.W.), Beijing, China; Department of Neurology (R.W.), Duke University Medical Center, Durham, NC; Dell Medical School (S.C.J.), University of Texas at Austin; Department of Clinical Pharmacology and Clinical Research Platform of East of Paris (URCEST-CRC-CRB) (T.S.), Assistance Publique-Hôpitaux de Paris, Hôpital Saint Antoine (APHP.SU); Sorbonne Université (T.S.); FACT (French Alliance for Cardiovascular Clinical Trials) (T.S.), Paris, France; and Department of Neurology (D.W.), Barrow Neurological Institute, St. Joseph's Hospital and Medical Center, Phoenix, AZ.
David Wang, From the Department of Neurology (Y.P., H.L., Y.W., X.M., J.L., X.Z., L.L., Y.W.), Beijing Tiantan Hospital, Capital Medical University; China National Clinical Research Center for Neurological Diseases (Y.P., H.L., Y.W., X.M., J.L., X.Z., L.L., Y.W.), Beijing, China; Department of Neurology (R.W.), Duke University Medical Center, Durham, NC; Dell Medical School (S.C.J.), University of Texas at Austin; Department of Clinical Pharmacology and Clinical Research Platform of East of Paris (URCEST-CRC-CRB) (T.S.), Assistance Publique-Hôpitaux de Paris, Hôpital Saint Antoine (APHP.SU); Sorbonne Université (T.S.); FACT (French Alliance for Cardiovascular Clinical Trials) (T.S.), Paris, France; and Department of Neurology (D.W.), Barrow Neurological Institute, St. Joseph's Hospital and Medical Center, Phoenix, AZ. yongjunwang@ncrcnd.org.cn.Follow
Yongjun Wang, From the Department of Neurology (Y.P., H.L., Y.W., X.M., J.L., X.Z., L.L., Y.W.), Beijing Tiantan Hospital, Capital Medical University; China National Clinical Research Center for Neurological Diseases (Y.P., H.L., Y.W., X.M., J.L., X.Z., L.L., Y.W.), Beijing, China; Department of Neurology (R.W.), Duke University Medical Center, Durham, NC; Dell Medical School (S.C.J.), University of Texas at Austin; Department of Clinical Pharmacology and Clinical Research Platform of East of Paris (URCEST-CRC-CRB) (T.S.), Assistance Publique-Hôpitaux de Paris, Hôpital Saint Antoine (APHP.SU); Sorbonne Université (T.S.); FACT (French Alliance for Cardiovascular Clinical Trials) (T.S.), Paris, France; and Department of Neurology (D.W.), Barrow Neurological Institute, St. Joseph's Hospital and Medical Center, Phoenix, AZ. yongjunwang@ncrcnd.org.cn.

Document Type

Article

Abstract

OBJECTIVE: To investigate the association between protease-activated receptor-1 (PAR-1) gene polymorphisms and efficacy of clopidogrel for minor stroke or TIA. METHODS: Three single nucleotide polymorphisms ( [681G>A, rs4244285], * [636G>A, rs4986893], and [IVSn-14 A/T, rs168753]) were genotyped among 2,924 patients randomized to clopidogrel plus aspirin (n = 1,461) or aspirin alone (n = 1,463). The primary efficacy outcome was new stroke (ischemic or hemorrhagic) and the safety outcome was any bleeding. RESULTS: Overall, 859 (29.4%) were AA homozygotes, 1,479 (50.6%) were AT heterozygotes, and 586 (20.0%) were TT homozygotes for IVSn-14 polymorphisms; 1,716 (58.7%) were carriers of at least 1 loss-of-function allele (*2 or *3). Compared with aspirin alone, patients with clopidogrel-aspirin treatment had a low risk of new stroke in patients with AT genotype (7.6% vs 11.3%; hazard ratio [HR], 0.63; 95% confidence interval [CI], 0.44-0.89) and TT genotype (5.8% vs 11.6%; HR, 0.46; 95% CI, 0.25-0.82) but not in carriers of the AA genotype (10.8% vs 11.6%; HR, 0.95; 95% CI, 0.63-1.44) ( = 0.03 for interaction). The association between IVSn-14 A/T polymorphism and clopidogrel response was present regardless of the carrier status of the loss-of-function alleles. The IVSn-14 genotypes were not associated with the risk of any bleeding for clopidogrel-aspirin treatment ( = 0.66 for interaction). CONCLUSIONS: Among patients with minor ischemic stroke or TIA who were receiving clopidogrel and aspirin, those carrying the IVSn-14 T allele had a lower rate of recurrent stroke than those who were not. CLINICALTRIALSGOV IDENTIFIER: NCT00979589.

Medical Subject Headings

Aged; Clopidogrel (therapeutic use); Double-Blind Method; Female; Genotype; Humans; Ischemic Attack, Transient (drug therapy, genetics); Male; Middle Aged; Platelet Aggregation Inhibitors (therapeutic use); Polymorphism, Single Nucleotide; Receptor, PAR-1 (genetics); Recurrence; Stroke (drug therapy, genetics); Treatment Outcome

Publication Date

1-5-2021

Publication Title

Neurology

E-ISSN

1526-632X

Volume

96

Issue

1

First Page

e1

Last Page

e9

PubMed ID

33093222

Digital Object Identifier (DOI)

10.1212/WNL.0000000000011078

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