In a study that included more than 20,000 adults in China with high blood pressure, but without a history of stroke or heart attack, the combined use of the hypertension medication enalapril and folic acid, compared with enalapril alone, significantly reduced the risk of first stroke, according to a study published in JAMA.  

Stroke is the leading cause of death in China and second-leading cause of death in the world. Primary prevention (prevention prior to a first episode) is particularly important because about 77% of strokes are first events. Uncertainty remains regarding the efficacy of folic acid therapy for primary prevention of stroke because of limited and inconsistent data.

Yong Huo, MD, of Peking University First Hospital, Beijing, China, and colleagues had 20,702 adults with hypertension without history of stroke or heart attack randomly assigned to receive 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 alone (10 mg; n = 10,354). The trial was conducted from May 2008 to August 2013 in 32 communities in Jiangsu and Anhui provinces in China. Participants were tested for variations in the MTHFR C677T gene (CC, CT, and TT genotypes) that may affect folate levels.

During a median treatment duration of 4.5 years, first stroke occurred in 282 participants (2.7%) in the enalapril-folic acid group compared with 355 participants (3.4%) in the enalapril group, representing an absolute risk reduction of 0.7% and a relative risk reduction of 21%. Analyses also showed significant reductions among participants in the enalapril-folic acid group in the risk of ischemic stroke (2.2% vs 2.8%) and composite cardiovascular events (cardiovascular death, heart attack and stroke) (3.1% vs 3.9%).
There was no significant difference between groups in the risk of hemorrhagic stroke, heart attack, or all-cause death, or in the frequencies of adverse events.

The authors wrote that this trial (China Stroke Primary Prevention Trial; CSPPT), with data on individual baseline folate levels and MTHFR genotypes, has provided convincing evidence that baseline folate level is an important determinant of efficacy of folic acid therapy in stroke prevention. “The CSPPT is the first large-scale randomized trial to test the hypothesis using individual measures of baseline folate levels,” authors wrote. “In this population without folic acid fortification, we observed considerable individual variation in plasma folate levels and clearly showed that the beneficial effect appeared to be more pronounced in participants with lower folate levels.”

“We speculate that even in countries with folic acid fortification and widespread use of folic acid supplements such as in the United States and Canada, there may still be room to further reduce stroke incidence using more targeted folic acid therapy—in particular, among those with the TT genotype and low or moderate folate levels.”