title: Efficacy of folic acid therapy in primary prevention of stroke among adults with hypertension in China: the CSPPT randomized clinical trial.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  METHODS
  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).
  
  
  METHODS
  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
  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.
  
  
  BACKGROUND
  clinicaltrials.gov Identifier: NCT00794885.
authors.affiliation: Department of Cardiology, Peking University First Hospital, Beijing, China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Huo
authors.affiliation: Department of Cardiology, Peking University First Hospital, Beijing, China.
authors.forename: Jianping
authors.initials: J
authors.lastname: Li
authors.affiliation: 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.
authors.forename: Xianhui
authors.initials: X
authors.lastname: Qin
authors.affiliation: Department of Neurology, Peking University First Hospital, Beijing, China.
authors.forename: Yining
authors.initials: Y
authors.lastname: Huang
authors.affiliation: Department of Population, Family, and Reproductive Health, Johns Hopkins University Bloomberg School of Public Health, Baltimore, Maryland.
authors.forename: Xiaobin
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland7Department of Epidemiology, Johns Hopkins University Bloomberg School of Public Health, Baltimore, Maryland.
authors.forename: Rebecca F
authors.initials: RF
authors.lastname: Gottesman
authors.affiliation: Institute for Biomedicine, Anhui Medical University, Hefei, China8School of Health Administration, Anhui Medical University, Hefei, China.
authors.forename: Genfu
authors.initials: G
authors.lastname: Tang
authors.affiliation: 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.
authors.forename: Binyan
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authors.affiliation: Department of Epidemiology and Biostatistics, School of Public Health, Peking University Health Science Center, Beijing, China.
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authors.affiliation: Department of Neurology, First People's Hospital, Lianyungang, China.
authors.forename: Mingli
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authors.affiliation: Department of Neurology, First Affiliated Hospital of Anhui Medical University, Hefei, China.
authors.forename: Jia
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authors.lastname: Fu
authors.affiliation: Department of Neurology, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou, China.
authors.forename: Yefeng
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authors.lastname: Cai
authors.affiliation: Department of Neurology, First Affiliated Hospital of Anhui Medical University, Hefei, China.
authors.forename: Xiuli
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authors.lastname: Shi
authors.affiliation: Department of Cardiology, Peking University First Hospital, Beijing, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Pharmacy, Peking University First Hospital, Beijing, China.
authors.forename: Yimin
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authors.lastname: Cui
authors.affiliation: Department of Cardiology, Peking University People's Hospital, Beijing, China.
authors.forename: Ningling
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authors.lastname: Sun
authors.affiliation: Department of Geriatric Cardiology, General Hospital of the People's Liberation Army, Beijing, China.
authors.forename: Xiaoying
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of Cardiology, Second Affiliated Hospital, Nanchang University, Nanchang, China.
authors.forename: Xiaoshu
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authors.lastname: Cheng
authors.affiliation: Department of Cardiology, Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China.
authors.forename: Jian'an
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Cardiology, Beijing Chaoyang Hospital, Capital Medical University, Beijing, China.
authors.forename: Xinchun
authors.initials: X
authors.lastname: Yang
authors.affiliation: Department of Cardiology, Xiangya Hospital, Central South University, Changsha, China.
authors.forename: Tianlun
authors.initials: T
authors.lastname: Yang
authors.affiliation: Department of Cardiology, First Hospital of Shanxi Medical University, Taiyuan, China.
authors.forename: Chuanshi
authors.initials: C
authors.lastname: Xiao
authors.affiliation: Department of Neurology, Xijing Hospital, Fourth Military Medical University, Xi'an, China.
authors.forename: Gang
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authors.lastname: Zhao
authors.affiliation: Department of Neurology, Huashan Hospital, Fudan University, Shanghai, China.
authors.forename: Qiang
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authors.lastname: Dong
authors.affiliation: State Key Laboratory of Medical Genomics, Shanghai Key Laboratory of Hypertension, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Dingliang
authors.initials: D
authors.lastname: Zhu
authors.affiliation: Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Beijing, China.
authors.forename: Xian
authors.initials: X
authors.lastname: Wang
authors.affiliation: Shanghai Institute of Cardiovascular Diseases, Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai, China.
authors.forename: Junbo
authors.initials: J
authors.lastname: Ge
authors.affiliation: Department of Cardiology, Tangdu Hospital, Fourth Military Medical University, Xi'an, China.
authors.forename: Lianyou
authors.initials: L
authors.lastname: Zhao
authors.affiliation: Department of Cardiology, Peking University People's Hospital, Beijing, China.
authors.forename: Dayi
authors.initials: D
authors.lastname: Hu
authors.affiliation: Division of Hypertension, Fu-wai Hospital, Beijing, China28Beijing Hypertension League Institute, Beijing, China.
authors.forename: Lisheng
authors.initials: L
authors.lastname: Liu
authors.affiliation: National Clinical Research Center for Kidney Disease, State Key Laboratory for Organ Failure Research, Renal Division, Nanfang Hospital, Southern Medical University, Guangzhou, China.
authors.forename: Fan Fan
authors.initials: FF
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mesh_terms: D000959:Antihypertensive Agents / Q000627:therapeutic use*; D002681:China; D004311:Double-Blind Method; D004359:Drug Therapy, Combination; D004656:Enalapril / Q000627:therapeutic use*; D005492:Folic Acid / Q000097:blood / Q000627:therapeutic use*; D006801:Humans; D006973:Hypertension / Q000188:drug therapy*; D053208:Kaplan-Meier Estimate; D008297:Male; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000235:genetics; D008875:Middle Aged; D011110:Polymorphism, Genetic; D011322:Primary Prevention; D012306:Risk; D020521:Stroke / Q000453:epidemiology / Q000517:prevention & control*; D014803:Vitamin B Complex / Q000627:therapeutic use*
chemical_list: D000959:Antihypertensive Agents; D014803:Vitamin B Complex; D004656:Enalapril; D005492:Folic Acid; D042965:Methylenetetrahydrofolate Reductase (NADPH2)