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

Authors

• 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

Recommended Citation

Pan, Yuesong; Wangqin, Runqi; Li, Hao; Wang, Yilong; Meng, Xia; Johnston, S Claiborne; Simon, Tabassome; Lin, Jinxi; Zhao, Xingquan; Liu, Liping; Wang, David; and Wang, Yongjun, "Polymorphisms and Clopidogrel Efficacy and Safety in Patients With Minor Stroke or TIA" (2021). Neurology. 1810.
https://scholar.barrowneuro.org/neurology/1810