Ke Xu1,2, Sen Ye1, Shuhua Zhang1,3, Mingwen Yang1, Tiantian Zhu4, Deyu Kong5, Jun Chen6, Lei Xu7, Jimin Li8, Hui Zhu9, Fei Wang10, Lu Yang11, Jing Zhang1, Yuansheng Fan1, Lianghong Ying1,12, Xianqing Hu1,13, Xiaofeng Zhang1,14, Noel C Chan15, Chunjian Li1. 1. Department of Cardiology, First Affiliated Hospital of Nanjing Medical University, Jiangsu, China (K.X., S.Y., S.Z., M.Y., J.Z., Y.F., L. Ying, X.H., X.Z., C.L.). 2. Department of Cardiology, Shanghai General Hospital, China (K.X.). 3. Department of Cardiology, the Second People's Hospital of Lianyungang, Jiangsu, China (S.Z.). 4. Department of Cardiology, the Affiliated Jiangning Hospital of Nanjing Medical UniversityJiangsu, China (T.Z.). 5. Department of Cardiology, Jining First People's Hospital, Shandong, China (D.K.). 6. Department of Cardiology, People's Hospital of Maanshan City, Anhui, China (J.C.). 7. Department of Cardiology, the Affiliated Sir Run Run Hospital of Nanjing Medical University, Nanjing, Jiangsu, China (L.X.). 8. Department of Cardiology, Fuyang Fifth People's Hospital, Anhui, China (J.L.). 9. Department of Geriatrics, the Affiliated Changzhou No.2 People's Hospital of Nanjing Medical University, Jiangsu, China (H.Z.). 10. Department of Cardiology, Xuzhou Children's Hospital, Jiangsu, China (F.W.). 11. Department of Cardiology, Jiangsu Province Official Hospital, Nanjing, China (L. Yang). 12. Department of Cardiology, Huai'an Hospital Affiliated to Xuzhou University, Second People's Hospital of Huai'an City, Jiangsu, China (L. Ying). 13. Department of Cardiology, Jinhua Municipal Central Hospital, Zhejiang, China (X.H.). 14. Department of Cardiology, the Second Affiliated Hospital of Medical School of Southeast University, Nanjing, Jiangsu, China (X.Z.). 15. Thrombosis and Atherosclerosis Research Institute and Department of Medicine (N.C.C.), McMaster University, Hamilton, ON, Canada.
Abstract
BACKGROUND: The genetic determinants of response to clopidogrel and aspirin are incompletely characterized. Recently, PEAR1 (platelet endothelial aggregation receptor-1) rs12041331 polymorphism has been shown to influence the platelet reactivity, but its impact on cardiovascular outcomes remains unclear in patients treated with antiplatelet agents. METHODS AND RESULTS: In this prospective cohort study, 2439 Chinese patients with acute coronary syndrome or stable coronary artery disease undergoing coronary stent implantation and receiving clopidogrel and aspirin were consecutively recruited. Their platelet reactivity was determined by light transmission aggregometry at 5 and 30 days after coronary intervention. Genotyping was performed using an improved multiplex ligation detection reaction technique. All patients completed a 30-day follow-up for clinical outcomes. Genotyping for PEAR1 showed 768 (38.3%) GG homozygotes, 941 (46.9%) GA heterozygotes, and 298 (14.8%) AA homozygotes. The 30-day incidence of major adverse cardiovascular events, the composite of cardiovascular death, nonfatal myocardial infarction, and ischemic stroke were significantly higher in AA homozygotes than in non-AA homozygotes (adjusted hazard ratio, 2.78; 95% CI, 1.13-6.82; P=0.026), irrespective of CYP2C19*2 loss-of-function polymorphism and known outcome predictors including age, sex, smoking, and diabetes mellitus. The ADP-induced platelet aggregation was significantly lower in AA homozygotes than that in GG homozygotes at both time points, although no significant difference was found for the arachidonic acid-induced platelet aggregation among the 3 groups. CONCLUSIONS: About 15% of Chinese patients undergoing coronary stent implantation were AA homozygotes for PEAR1 rs12041331. These patients had ≈3-fold increase in short-term major adverse cardiovascular events risk compared with non-AA homozygotes, and the adverse clinical outcome is unlikely to be mediated by suboptimal pharmacological response to aspirin or clopidogrel. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov . Unique identifier: NCT01968499.
BACKGROUND: The genetic determinants of response to clopidogrel and aspirin are incompletely characterized. Recently, PEAR1 (platelet endothelial aggregation receptor-1) rs12041331 polymorphism has been shown to influence the platelet reactivity, but its impact on cardiovascular outcomes remains unclear in patients treated with antiplatelet agents. METHODS AND RESULTS: In this prospective cohort study, 2439 Chinese patients with acute coronary syndrome or stable coronary artery disease undergoing coronary stent implantation and receiving clopidogrel and aspirin were consecutively recruited. Their platelet reactivity was determined by light transmission aggregometry at 5 and 30 days after coronary intervention. Genotyping was performed using an improved multiplex ligation detection reaction technique. All patients completed a 30-day follow-up for clinical outcomes. Genotyping for PEAR1 showed 768 (38.3%) GG homozygotes, 941 (46.9%) GA heterozygotes, and 298 (14.8%) AA homozygotes. The 30-day incidence of major adverse cardiovascular events, the composite of cardiovascular death, nonfatal myocardial infarction, and ischemic stroke were significantly higher in AA homozygotes than in non-AA homozygotes (adjusted hazard ratio, 2.78; 95% CI, 1.13-6.82; P=0.026), irrespective of CYP2C19*2 loss-of-function polymorphism and known outcome predictors including age, sex, smoking, and diabetes mellitus. The ADP-induced platelet aggregation was significantly lower in AA homozygotes than that in GG homozygotes at both time points, although no significant difference was found for the arachidonic acid-induced platelet aggregation among the 3 groups. CONCLUSIONS: About 15% of Chinese patients undergoing coronary stent implantation were AA homozygotes for PEAR1rs12041331. These patients had ≈3-fold increase in short-term major adverse cardiovascular events risk compared with non-AA homozygotes, and the adverse clinical outcome is unlikely to be mediated by suboptimal pharmacological response to aspirin or clopidogrel. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov . Unique identifier: NCT01968499.
Authors: Joshua P Lewis; Moeen Riaz; Sophia Xie; Galina Polekhina; Rory Wolfe; Mark Nelson; Andrew M Tonkin; Christopher M Reid; Anne M Murray; John J McNeil; Alan R Shuldiner; Paul Lacaze Journal: Clin Pharmacol Ther Date: 2020-07-20 Impact factor: 6.875