Efficacy of folic acid therapy in primary prevention of stroke among adults with hypertension in China: the CSPPT randomized clinical trial.

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.

• Authors: Yong Huo, Jianping Li, Xianhui Qin, Yining Huang, Xiaobin Wang, Rebecca F Gottesman, Genfu Tang, Binyan Wang, Dafang Chen, Mingli He, Jia Fu, Yefeng Cai, Xiuli Shi, Yan Zhang, Yimin Cui, Ningling Sun, Xiaoying Li, Xiaoshu Cheng, Jian'an Wang, Xinchun Yang, Tianlun Yang, Chuanshi Xiao, Gang Zhao, Qiang Dong, Dingliang Zhu, Xian Wang, Junbo Ge, Lianyou Zhao, Dayi Hu, Lisheng Liu, Fan Fan Hou, CSPPT Investigators
• Journal: JAMA (JAMA) Vol. 313 Issue 13 Pg. 1325-35 (Apr 07 2015) ISSN: 1538-3598 [Electronic] United States
• PMID: 25771069 (Publication Type: Journal Article, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)

Chemical References

• Antihypertensive Agents
• Vitamin B Complex
• Enalapril
• Folic Acid
• Methylenetetrahydrofolate Reductase (NADPH2)

Topics

• Antihypertensive Agents (therapeutic use)
• China
• Double-Blind Method
• Drug Therapy, Combination
• Enalapril (therapeutic use)
• Folic Acid (blood, therapeutic use)
• Humans
• Hypertension (drug therapy)
• Kaplan-Meier Estimate
• Male
• Methylenetetrahydrofolate Reductase (NADPH2) (genetics)
• Middle Aged
• Polymorphism, Genetic
• Primary Prevention
• Risk
• Stroke (epidemiology, prevention & control)
• Vitamin B Complex (therapeutic use)