Tomotaka Tanaka1, Hiroshi Yamagami2,3, Masafumi Ihara1, Toshiyuki Miyata2, Shigeki Miyata4, Toshimitsu Hamasaki5, Shu Amano6, Kazuki Fukuma1, Haruko Yamamoto7, Jyoji Nakagawara8, Eisuke Furui9, Shinichiro Uchiyama10,11, Boohan Hyun12, Yasumasa Yamamoto13, Yasuhiro Manabe14, Yasuhiro Ito15, Ryuzo Fukunaga16, Takeo Abumiya17, Masahiro Yasaka18, Kazuo Kitagawa10,19, Kazunori Toyoda2, Kazuyuki Nagatsuka1. 1. Department of Neurology, National Cerebral and Cardiovascular Center. 2. Department of Cerebrovascular Medicine, National Cerebral and Cardiovascular Center. 3. Department of Neurology, Kobe City Medical Center General Hospital. 4. Department of Clinical Laboratory Medicine, National Cerebral and Cardiovascular Center. 5. Department of Data Science, National Cerebral and Cardiovascular Center. 6. Department of Mathematics and Statistics, Amherst College. 7. Center for Advancing Clinical and Translational Sciences, National Cerebral and Cardiovascular Center. 8. Department of Neurosurgery, National Cerebral and Cardiovascular Center. 9. Department of Stroke Neurology, Kohnan Hospital. 10. Department of Neurology, Tokyo Women's Medical University. 11. International University of Health and Welfare, Sanno Hospital and Sanno Medical Center. 12. Department of Cerebrovascular Disease, NHO Osaka National Hospital. 13. Department of Neurology, Kyoto Second Red Cross Hospital. 14. Department of Neurology, NHO Okayama Medical Center. 15. Department of Neurology, TOYOTA Memorial Hospital. 16. Department of Cerebrovascular Disease, Hoshigaoka Medical Center. 17. Department of Neurosurgery, Hokkaido Neurosurgical Memorial Hospital. 18. Department of Cerebrovascular Medicine and Neurology, NHO Kyushu Medical Center. 19. Department of Neurology, Osaka University Graduate School of Medicine.
Abstract
BACKGROUND: CYP2C19variants are associated with the antiplatelet effects of clopidogrel against recurrent cardiovascular events. However, it remains unknown whether the elapsed time from stroke onset affects the relationship between the genetic variants and such events. To address this, we conducted a prospective cohort study to determine the effect ofCYP2C19variants on clinical outcomes in the chronic phase.Methods and Results: In total, 518 Japanese non-acute stroke patients treated with clopidogrel were registered at 14 institutions. Patients were classified into 3 clopidogrel-metabolizing groups according toCYP2C19genotype: extensive metabolizer (EM:*1/*1), intermediate metabolizer (IM:*1/*2or*1/*3), and poor metabolizer (PM:*2/*2,*2/*3, or*3/*3). Antiplatelet effects of clopidogrel were assessed by adenosine diphosphate (ADP)-induced platelet aggregation and vasodilator-stimulated phosphoprotein (VASP) phosphorylation. The endpoint was composite cerebrocardiovascular events (CVEs). In 501 successfully followed-up patients, the median time from index stroke to enrollment was 181 days. There were 28 cardiovascular and 2 major bleeding events. There were no significant differences in the rates of cardiovascular events among the groups. CONCLUSIONS: Despite associations betweenCYP2C19variants and on-clopidogrel platelet reactivity, there was no significant difference in rates of CVEs in the chronic stroke phase among the 3 clopidogrel-metabolizing groups ofCYP2C19variants.
BACKGROUND: CYP2C19variants are associated with the antiplatelet effects of clopidogrel against recurrent cardiovascular events. However, it remains unknown whether the elapsed time from stroke onset affects the relationship between the genetic variants and such events. To address this, we conducted a prospective cohort study to determine the effect ofCYP2C19variants on clinical outcomes in the chronic phase.Methods and Results: In total, 518 Japanese non-acute strokepatients treated with clopidogrel were registered at 14 institutions. Patients were classified into 3 clopidogrel-metabolizing groups according toCYP2C19genotype: extensive metabolizer (EM:*1/*1), intermediate metabolizer (IM:*1/*2or*1/*3), and poor metabolizer (PM:*2/*2,*2/*3, or*3/*3). Antiplatelet effects of clopidogrel were assessed by adenosine diphosphate (ADP)-induced platelet aggregation and vasodilator-stimulated phosphoprotein (VASP) phosphorylation. The endpoint was composite cerebrocardiovascular events (CVEs). In 501 successfully followed-up patients, the median time from index stroke to enrollment was 181 days. There were 28 cardiovascular and 2 major bleeding events. There were no significant differences in the rates of cardiovascular events among the groups. CONCLUSIONS: Despite associations betweenCYP2C19variants and on-clopidogrel platelet reactivity, there was no significant difference in rates of CVEs in the chronic stroke phase among the 3 clopidogrel-metabolizing groups ofCYP2C19variants.