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Efficacy of Clopidogrel for Prevention of Stroke Based on CYP2C19 Allele Status in the POINT Trial.
Stroke. 2020 Jul; 51(7):2058-2065.S

Abstract

BACKGROUND AND PURPOSE

Clopidogrel is an antiplatelet drug that is metabolized to its active form by the CYP2C19 enzyme. The CHANCE trial (Clopidogrel in High-Risk Patients With Acute Nondisabling Cerebrovascular Events) found a significant interaction between loss-of-function allele status for the CYP2C19 gene and the effect of dual antiplatelet therapy with aspirin and clopidogrel on the rate of early recurrent stroke following acute transient ischemic attack/minor stroke. The POINT (Platelet-Oriented Inhibition in New TIA and Minor Ischemic Stroke Trial), similar in design to CHANCE but performed largely in North America and Europe, demonstrated a reduction in early recurrent stroke with dual antiplatelet therapy compared with aspirin alone. This substudy was done to evaluate a potential interaction between loss-of-function CYP2C19 alleles and outcome by treatment group in POINT.

METHODS

Of the 269 sites in 10 countries that enrolled patients in POINT, 134 sites participated in this substudy. DNA samples were genotyped for CYP2C19 *2, *3, and *17 alleles and classified as being carriers or noncarriers of loss-of-function alleles. Major ischemia consisted of ischemic stroke, myocardial infarction, or ischemic vascular death.

RESULTS

Nine hundred thirty-two patients provided analyzable DNA. The rates of major ischemia were 6.7% for the aspirin group versus 2.3% for the dual antiplatelet therapy group (hazard ratio, 0.33 [95% CI, 0.09-1.21]; P=0.09) among carriers of loss-of-function allele. The rates of major ischemia were 5.6% for the aspirin group versus 3.7% for the dual antiplatelet therapy group (hazard ratio, 0.65 [95% CI, 0.32-1.34]; P=0.25) among noncarriers. There was no significant interaction by genotype for major ischemia (P=0.36) or stroke (P=0.33).

CONCLUSIONS

This substudy of POINT found no significant interaction with CYP2C19 loss-of-function carrier status and outcome by treatment group. Failure to confirm the findings from the CHANCE trial may be because the loss-of-function alleles tested are not clinically important in this context or because the 2 trials had differences in racial/ethnic composition. Additionally, differences between the 2 trials might be due to chance as our statistical power was limited to 50%. Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT00991029.

Authors+Show Affiliations

Departments of Neurology (J.F.M.), Mayo Clinic, Jacksonville, FL.Neuroscience (R.L.W., L.P.F., O.A.R.), Mayo Clinic, Jacksonville, FL.Neuroscience (R.L.W., L.P.F., O.A.R.), Mayo Clinic, Jacksonville, FL.Neuroscience (R.L.W., L.P.F., O.A.R.), Mayo Clinic, Jacksonville, FL. Clinical Genomics (O.A.R.), Mayo Clinic, Jacksonville, FL.Data Coordination Unit, Department of Public Health Sciences, Medical University of South Carolina, Charleston (J.J.E.).Department of Neurology, University of California, San Francisco (M.F., J.D.E., A.S.K., K.G.Z.).Departments of Emergency Medicine (W.J.M., W.B.), University of Michigan, Ann Arbor. Neurology (W.J.M., W.B.), University of Michigan, Ann Arbor.The Emmes Corporation, Rockville, MD (A.S.L.).Departments of Emergency Medicine (W.J.M., W.B.), University of Michigan, Ann Arbor. Neurology (W.J.M., W.B.), University of Michigan, Ann Arbor.Department of Neurology, University of Buffalo Jacobs School of Medicine and Biomedical Sciences, NY (M.C.).Department of Emergency Medicine, Temple University, Philadelphia, PA (N.G.).Department of Emergency Medicine and Neurology, Emory University, Atlanta, GA (M.R., F.N.).Department of Emergency Medicine and Neurology, Emory University, Atlanta, GA (M.R., F.N.).Department of Neurology, University of California, San Francisco (M.F., J.D.E., A.S.K., K.G.Z.).Department of Neurology, University of California, San Francisco (M.F., J.D.E., A.S.K., K.G.Z.).Department of Neurology, University of California, San Francisco (M.F., J.D.E., A.S.K., K.G.Z.).Department of Neurology, University of Pennsylvania, Philadelphia (B.C.).Dean's Office, Dell Medical School, Dell Medical Center, Austin, TX (S.C.J.).

Pub Type(s)

Journal Article

Language

eng

PubMed ID

32568642

Citation

Meschia, James F., et al. "Efficacy of Clopidogrel for Prevention of Stroke Based On CYP2C19 Allele Status in the POINT Trial." Stroke, vol. 51, no. 7, 2020, pp. 2058-2065.
Meschia JF, Walton RL, Farrugia LP, et al. Efficacy of Clopidogrel for Prevention of Stroke Based on CYP2C19 Allele Status in the POINT Trial. Stroke. 2020;51(7):2058-2065.
Meschia, J. F., Walton, R. L., Farrugia, L. P., Ross, O. A., Elm, J. J., Farrant, M., Meurer, W. J., Lindblad, A. S., Barsan, W., Ching, M., Gentile, N., Ross, M., Nahab, F., Easton, J. D., Kim, A. S., Zurita, K. G., Cucchiara, B., & Johnston, S. C. (2020). Efficacy of Clopidogrel for Prevention of Stroke Based on CYP2C19 Allele Status in the POINT Trial. Stroke, 51(7), 2058-2065. https://doi.org/10.1161/STROKEAHA.119.028713
Meschia JF, et al. Efficacy of Clopidogrel for Prevention of Stroke Based On CYP2C19 Allele Status in the POINT Trial. Stroke. 2020;51(7):2058-2065. PubMed PMID: 32568642.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Efficacy of Clopidogrel for Prevention of Stroke Based on CYP2C19 Allele Status in the POINT Trial. AU - Meschia,James F, AU - Walton,Ronald L, AU - Farrugia,Luca P, AU - Ross,Owen A, AU - Elm,Jordan J, AU - Farrant,Mary, AU - Meurer,William J, AU - Lindblad,Anne S, AU - Barsan,William, AU - Ching,Marilou, AU - Gentile,Nina, AU - Ross,Michael, AU - Nahab,Fadi, AU - Easton,J Donald, AU - Kim,Anthony S, AU - Zurita,Karla G, AU - Cucchiara,Brett, AU - Johnston,S Claiborne, Y1 - 2020/06/17/ PY - 2020/6/23/entrez PY - 2020/6/23/pubmed PY - 2020/6/23/medline KW - alleles KW - aspirin KW - clopidogrel KW - cytochrome P450 CYP2C19 KW - myocardial infarction SP - 2058 EP - 2065 JF - Stroke JO - Stroke VL - 51 IS - 7 N2 - BACKGROUND AND PURPOSE: Clopidogrel is an antiplatelet drug that is metabolized to its active form by the CYP2C19 enzyme. The CHANCE trial (Clopidogrel in High-Risk Patients With Acute Nondisabling Cerebrovascular Events) found a significant interaction between loss-of-function allele status for the CYP2C19 gene and the effect of dual antiplatelet therapy with aspirin and clopidogrel on the rate of early recurrent stroke following acute transient ischemic attack/minor stroke. The POINT (Platelet-Oriented Inhibition in New TIA and Minor Ischemic Stroke Trial), similar in design to CHANCE but performed largely in North America and Europe, demonstrated a reduction in early recurrent stroke with dual antiplatelet therapy compared with aspirin alone. This substudy was done to evaluate a potential interaction between loss-of-function CYP2C19 alleles and outcome by treatment group in POINT. METHODS: Of the 269 sites in 10 countries that enrolled patients in POINT, 134 sites participated in this substudy. DNA samples were genotyped for CYP2C19 *2, *3, and *17 alleles and classified as being carriers or noncarriers of loss-of-function alleles. Major ischemia consisted of ischemic stroke, myocardial infarction, or ischemic vascular death. RESULTS: Nine hundred thirty-two patients provided analyzable DNA. The rates of major ischemia were 6.7% for the aspirin group versus 2.3% for the dual antiplatelet therapy group (hazard ratio, 0.33 [95% CI, 0.09-1.21]; P=0.09) among carriers of loss-of-function allele. The rates of major ischemia were 5.6% for the aspirin group versus 3.7% for the dual antiplatelet therapy group (hazard ratio, 0.65 [95% CI, 0.32-1.34]; P=0.25) among noncarriers. There was no significant interaction by genotype for major ischemia (P=0.36) or stroke (P=0.33). CONCLUSIONS: This substudy of POINT found no significant interaction with CYP2C19 loss-of-function carrier status and outcome by treatment group. Failure to confirm the findings from the CHANCE trial may be because the loss-of-function alleles tested are not clinically important in this context or because the 2 trials had differences in racial/ethnic composition. Additionally, differences between the 2 trials might be due to chance as our statistical power was limited to 50%. Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT00991029. SN - 1524-4628 UR - https://www.unboundmedicine.com/medline/citation/32568642/Efficacy_of_Clopidogrel_for_Prevention_of_Stroke_Based_on_CYP2C19_Allele_Status_in_the_POINT_Trial L2 - https://www.ahajournals.org/doi/10.1161/STROKEAHA.119.028713?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub=pubmed DB - PRIME DP - Unbound Medicine ER -
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