Yan Han1, Hui-Hui Lv1, Xu Liu2,3, Qiang Dong4, Xiao-Li Yang1, Shi-Xu Li1, Shuai Wu1, Jian-Ming Jiang1, Zheng Luo1, De-Sheng Zhu1, Yi Zhang1, Yi Zheng1, Yang-Tai Guan1,5, Jian-Feng Xu2,3,6,7. 1. Department of Neurology, Changhai Hospital, Second Military Medical University, Shanghai, China. 2. State Key Laboratory of Genetic Engineering and Ministry of Education Key Laboratory of Contemporary Anthropology, School of Life Sciences, Fudan University, Shanghai, China. 3. Fudan Center for Genetic Epidemiology, School of Life Sciences, Fudan University, Shanghai, China. 4. Department of Neurology, Huashan Hospital, Fudan University, Shanghai, China. 5. Department of Neurology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China. 6. Fudan Institute of Urology, Huashan Hospital, Fudan University, Shanghai, China. 7. Program for Personalized Cancer Care, NorthShore University HealthSystem, Evanston, IL, USA.
Abstract
OBJECTIVES: This study sought to evaluate the influence of the genetic polymorphisms on platelet reactivity and clinical outcomes in acute ischemic stroke patients taking clopidogrel. BACKGROUND: Little research has been published on relationships between genetic polymorphisms, platelet reactivity, and clinical outcomes in stroke patients treated with clopidogrel. METHODS: Patients hospitalized in Changhai Hospital with acute ischemic stroke were randomly enrolled into treatment with a 75-mg daily maintenance dose of clopidogrel. Genotyping was detected by the MassARRAY iPLEX genotyping system (Sequenom Inc, San Diego, CA), and platelet reactivity was evaluated by the VerifyNow P2Y12 test (Accumetrics Inc., San Diego, CA). Sixteen single nucleotide polymorphisms (SNPs) within 9 genes were selected and high on-clopidogrel platelet reactivity (HPR) was defined as P2Y12 reaction units (PRU) value ≥230. The primary endpoint was ischemic events, including major adverse cardiac events (MACE), recurrence of stroke, transient ischemic attack (TIA), and the composite of vascular death, and the secondary endpoint was bleeding. RESULTS: Of the 345 patients recruited, 275 (79.7%) patients were followed up for 1 year and 122 (35.4%) patients were categorized as HPR. Among the SNPs selected, only the CYP2C19*2 allele and the CYP2C19*3 allele were statistically significantly associated with PRU (P < 0.001 and P = 0.003, respectively). Similarly, the prevalence of HPR was associated with CYP2C19*2 and CYP2C19*3 (P < 0.001 and P = 0.001, respectively). During the 1 year of follow-up, a total of 64 (23.3%) cases of clinical events occurred, including 60 ischemic events and 4 bleeding events. There were no correlation between CYP2C19 variant alleles and clinical outcomes (P > 0.05), but a statistically significant relevance was found between the HPR and the ischemic events in 1 year of follow-up (P = 0.001). CONCLUSIONS: CYP2C19*2 and CYP2C19*3 had a significant impact on clopidogrel response, but was not associated with ischemic events during 1 year of follow-up in patients with acute ischemic stroke. HPR was an independent risk factor for ischemic events, and the VerifyNow P2Y12 test may be available to guide individualized antiplatelet therapies in stroke patients in China.
OBJECTIVES: This study sought to evaluate the influence of the genetic polymorphisms on platelet reactivity and clinical outcomes in acute ischemic strokepatients taking clopidogrel. BACKGROUND: Little research has been published on relationships between genetic polymorphisms, platelet reactivity, and clinical outcomes in strokepatients treated with clopidogrel. METHODS:Patients hospitalized in Changhai Hospital with acute ischemic stroke were randomly enrolled into treatment with a 75-mg daily maintenance dose of clopidogrel. Genotyping was detected by the MassARRAY iPLEX genotyping system (Sequenom Inc, San Diego, CA), and platelet reactivity was evaluated by the VerifyNow P2Y12 test (Accumetrics Inc., San Diego, CA). Sixteen single nucleotide polymorphisms (SNPs) within 9 genes were selected and high on-clopidogrel platelet reactivity (HPR) was defined as P2Y12 reaction units (PRU) value ≥230. The primary endpoint was ischemic events, including major adverse cardiac events (MACE), recurrence of stroke, transient ischemic attack (TIA), and the composite of vascular death, and the secondary endpoint was bleeding. RESULTS: Of the 345 patients recruited, 275 (79.7%) patients were followed up for 1 year and 122 (35.4%) patients were categorized as HPR. Among the SNPs selected, only the CYP2C19*2 allele and the CYP2C19*3 allele were statistically significantly associated with PRU (P < 0.001 and P = 0.003, respectively). Similarly, the prevalence of HPR was associated with CYP2C19*2 and CYP2C19*3 (P < 0.001 and P = 0.001, respectively). During the 1 year of follow-up, a total of 64 (23.3%) cases of clinical events occurred, including 60 ischemic events and 4 bleeding events. There were no correlation between CYP2C19 variant alleles and clinical outcomes (P > 0.05), but a statistically significant relevance was found between the HPR and the ischemic events in 1 year of follow-up (P = 0.001). CONCLUSIONS:CYP2C19*2 and CYP2C19*3 had a significant impact on clopidogrel response, but was not associated with ischemic events during 1 year of follow-up in patients with acute ischemic stroke. HPR was an independent risk factor for ischemic events, and the VerifyNow P2Y12 test may be available to guide individualized antiplatelet therapies in strokepatients in China.
Authors: Alan R Shuldiner; Jeffrey R O'Connell; Kevin P Bliden; Amish Gandhi; Kathleen Ryan; Richard B Horenstein; Coleen M Damcott; Ruth Pakyz; Udaya S Tantry; Quince Gibson; Toni I Pollin; Wendy Post; Afshin Parsa; Braxton D Mitchell; Nauder Faraday; William Herzog; Paul A Gurbel Journal: JAMA Date: 2009-08-26 Impact factor: 56.272
Authors: Jessica L Mega; Sandra L Close; Stephen D Wiviott; Lei Shen; Richard D Hockett; John T Brandt; Joseph R Walker; Elliott M Antman; William Macias; Eugene Braunwald; Marc S Sabatine Journal: N Engl J Med Date: 2008-12-22 Impact factor: 91.245
Authors: Eugene Braunwald; Elliott M Antman; John W Beasley; Robert M Califf; Melvin D Cheitlin; Judith S Hochman; Robert H Jones; Dean Kereiakes; Joel Kupersmith; Thomas N Levin; Carl J Pepine; John W Schaeffer; Earl E Smith; David E Steward; Pierre Theroux; Raymond J Gibbons; Joseph S Alpert; David P Faxon; Valentin Fuster; Gabriel Gregoratos; Loren F Hiratzka; Alice K Jacobs; Sidney C Smith Journal: Circulation Date: 2002-10-01 Impact factor: 29.690