Yong Huo1, Jianping Li1, Xianhui Qin2, Yining Huang3, Xiaobin Wang4, Rebecca F Gottesman5, Genfu Tang6, Binyan Wang2, Dafang Chen7, Mingli He8, Jia Fu9, Yefeng Cai10, Xiuli Shi9, Yan Zhang1, Yimin Cui11, Ningling Sun12, Xiaoying Li13, Xiaoshu Cheng14, Jian'an Wang15, Xinchun Yang16, Tianlun Yang17, Chuanshi Xiao18, Gang Zhao19, Qiang Dong20, Dingliang Zhu21, Xian Wang22, Junbo Ge23, Lianyou Zhao24, Dayi Hu12, Lisheng Liu25, Fan Fan Hou26. 1. Department of Cardiology, Peking University First Hospital, Beijing, China. 2. National Clinical Research Center for Kidney Disease, State Key Laboratory for Organ Failure Research, Renal Division, Nanfang Hospital, Southern Medical University, Guangzhou, China3Institute for Biomedicine, Anhui Medical University, Hefei, China. 3. Department of Neurology, Peking University First Hospital, Beijing, China. 4. Department of Population, Family, and Reproductive Health, Johns Hopkins University Bloomberg School of Public Health, Baltimore, Maryland. 5. Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland7Department of Epidemiology, Johns Hopkins University Bloomberg School of Public Health, Baltimore, Maryland. 6. Institute for Biomedicine, Anhui Medical University, Hefei, China8School of Health Administration, Anhui Medical University, Hefei, China. 7. Department of Epidemiology and Biostatistics, School of Public Health, Peking University Health Science Center, Beijing, China. 8. Department of Neurology, First People's Hospital, Lianyungang, China. 9. Department of Neurology, First Affiliated Hospital of Anhui Medical University, Hefei, China. 10. Department of Neurology, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou, China. 11. Department of Pharmacy, Peking University First Hospital, Beijing, China. 12. Department of Cardiology, Peking University People's Hospital, Beijing, China. 13. Department of Geriatric Cardiology, General Hospital of the People's Liberation Army, Beijing, China. 14. Department of Cardiology, Second Affiliated Hospital, Nanchang University, Nanchang, China. 15. Department of Cardiology, Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China. 16. Department of Cardiology, Beijing Chaoyang Hospital, Capital Medical University, Beijing, China. 17. Department of Cardiology, Xiangya Hospital, Central South University, Changsha, China. 18. Department of Cardiology, First Hospital of Shanxi Medical University, Taiyuan, China. 19. Department of Neurology, Xijing Hospital, Fourth Military Medical University, Xi'an, China. 20. Department of Neurology, Huashan Hospital, Fudan University, Shanghai, China. 21. State Key Laboratory of Medical Genomics, Shanghai Key Laboratory of Hypertension, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. 22. Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Beijing, China. 23. Shanghai Institute of Cardiovascular Diseases, Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai, China. 24. Department of Cardiology, Tangdu Hospital, Fourth Military Medical University, Xi'an, China. 25. Division of Hypertension, Fu-wai Hospital, Beijing, China28Beijing Hypertension League Institute, Beijing, China. 26. National Clinical Research Center for Kidney Disease, State Key Laboratory for Organ Failure Research, Renal Division, Nanfang Hospital, Southern Medical University, Guangzhou, China.
Abstract
IMPORTANCE: Uncertainty remains about the efficacy of folic acid therapy for the primary prevention of stroke because of limited and inconsistent data. OBJECTIVE: To test the primary hypothesis that therapy with enalapril and folic acid is more effective in reducing first stroke than enalapril alone among Chinese adults with hypertension. DESIGN, SETTING, AND PARTICIPANTS: The China Stroke Primary Prevention Trial, a randomized, double-blind clinical trial conducted from May 19, 2008, to August 24, 2013, in 32 communities in Jiangsu and Anhui provinces in China. A total of 20,702 adults with hypertension without history of stroke or myocardial infarction (MI) participated in the study. INTERVENTIONS:Eligible participants, stratified by MTHFR C677T genotypes (CC, CT, and TT), were randomly assigned to receive double-blind daily treatment with a single-pill combination containing enalapril, 10 mg, and folic acid, 0.8 mg (n = 10,348) or a tablet containing enalapril, 10 mg, alone (n = 10,354). MAIN OUTCOMES AND MEASURES: The primary outcome was first stroke. Secondary outcomes included first ischemic stroke; first hemorrhagic stroke; MI; a composite of cardiovascular events consisting of cardiovascular death, MI, and stroke; and all-cause death. RESULTS: During a median treatment duration of 4.5 years, compared with the enalapril alone group, the enalapril-folic acid group had a significant risk reduction in first stroke (2.7% of participants in the enalapril-folic acid group vs 3.4% in the enalapril alone group; hazard ratio [HR], 0.79; 95% CI, 0.68-0.93), first ischemic stroke (2.2% with enalapril-folic acid vs 2.8% with enalapril alone; HR, 0.76; 95% CI, 0.64-0.91), and composite cardiovascular events consisting of cardiovascular death, MI, and stroke (3.1% with enalapril-folic acid vs 3.9% with enalapril alone; HR, 0.80; 95% CI, 0.69-0.92). The risks of hemorrhagic stroke (HR, 0.93; 95% CI, 0.65-1.34), MI (HR, 1.04; 95% CI, 0.60-1.82), and all-cause deaths (HR, 0.94; 95% CI, 0.81-1.10) did not differ significantly between the 2 treatment groups. There were no significant differences between the 2 treatment groups in the frequencies of adverse events. CONCLUSIONS AND RELEVANCE: Among adults with hypertension in China without a history of stroke or MI, the combined use of enalapril and folic acid, compared with enalapril alone, significantly reduced the risk of first stroke. These findings are consistent with benefits from folate use among adults with hypertension and low baseline folate levels. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00794885.
RCT Entities:
IMPORTANCE: Uncertainty remains about the efficacy of folic acid therapy for the primary prevention of stroke because of limited and inconsistent data. OBJECTIVE: To test the primary hypothesis that therapy with enalapril and folic acid is more effective in reducing first stroke than enalapril alone among Chinese adults with hypertension. DESIGN, SETTING, AND PARTICIPANTS: The China Stroke Primary Prevention Trial, a randomized, double-blind clinical trial conducted from May 19, 2008, to August 24, 2013, in 32 communities in Jiangsu and Anhui provinces in China. A total of 20,702 adults with hypertension without history of stroke or myocardial infarction (MI) participated in the study. INTERVENTIONS: Eligible participants, stratified by MTHFRC677T genotypes (CC, CT, and TT), were randomly assigned to receive double-blind daily treatment with a single-pill combination containing enalapril, 10 mg, and folic acid, 0.8 mg (n = 10,348) or a tablet containing enalapril, 10 mg, alone (n = 10,354). MAIN OUTCOMES AND MEASURES: The primary outcome was first stroke. Secondary outcomes included first ischemic stroke; first hemorrhagic stroke; MI; a composite of cardiovascular events consisting of cardiovascular death, MI, and stroke; and all-cause death. RESULTS: During a median treatment duration of 4.5 years, compared with the enalapril alone group, the enalapril-folic acid group had a significant risk reduction in first stroke (2.7% of participants in the enalapril-folic acid group vs 3.4% in the enalapril alone group; hazard ratio [HR], 0.79; 95% CI, 0.68-0.93), first ischemic stroke (2.2% with enalapril-folic acid vs 2.8% with enalapril alone; HR, 0.76; 95% CI, 0.64-0.91), and composite cardiovascular events consisting of cardiovascular death, MI, and stroke (3.1% with enalapril-folic acid vs 3.9% with enalapril alone; HR, 0.80; 95% CI, 0.69-0.92). The risks of hemorrhagic stroke (HR, 0.93; 95% CI, 0.65-1.34), MI (HR, 1.04; 95% CI, 0.60-1.82), and all-cause deaths (HR, 0.94; 95% CI, 0.81-1.10) did not differ significantly between the 2 treatment groups. There were no significant differences between the 2 treatment groups in the frequencies of adverse events. CONCLUSIONS AND RELEVANCE: Among adults with hypertension in China without a history of stroke or MI, the combined use of enalapril and folic acid, compared with enalapril alone, significantly reduced the risk of first stroke. These findings are consistent with benefits from folate use among adults with hypertension and low baseline folate levels. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00794885.
Authors: Lindsay H Allen; Joshua W Miller; Lisette de Groot; Irwin H Rosenberg; A David Smith; Helga Refsum; Daniel J Raiten Journal: J Nutr Date: 2018-12-01 Impact factor: 4.798