Stroke is the leading cause of death in China and second leading cause of death in the world. Primary prevention 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.
Dr. Yong Huo, MD, FACC, is the director of Heart Center of Peking University First Hospital and colleagues tested 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. Enalapril is an ACE inhibitor used to treat hypertension in adults.
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 aged 45 to 75 years old with hypertension defined as seated resting systolic blood pressure of 140 mm Hg or higher or diastolic blood pressure of 90 mm Hg or higher and without history of stroke or myocardial infarction (MI) participated in the study. Participants were tested for variations in the MTHFR C677T gene.
MTHFR stands for methyl-tetrahydrofolate reductase, an enzyme that is responsible for the process of methylation in every cell in your body. MTHFR is a common genetic variant that causes this key enzyme in the body to function at a lower than normal rate. This can lead to a variety of medical problems.
During the screening stage, each participant completed a physical examination and questionnaires on lifestyle and history of disease and medication use. Genotyping for MTHFR C677T polymorphisms was also performed.
All eligible participants were asked to take an oral daily dose of 10 mg of enalapril for a total of 3 weeks. Participants who demonstrated good adherence to the treatment and were tolerant of enalapril were entered into the next stage.
Participants were 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). Both types of tablets were concealed in a single-capsule formulation and were identical in appearance, size, color, and taste. During the trial period, continuing use of other antihypertensive drugs (mainly calcium channel blockers or diuretics), but not B vitamins, was allowed.
During a median treatment duration of 4.5 years, first stroke occurred in 282 participants (2.7 percent) in the enalapril-folic acid group compared with 355 participants (3.4 percent) in the enalapril group, representing an absolute risk reduction of 0.7 percent and a relative risk reduction of 21 percent. Analyses also showed significant reductions among participants in the enalapril-folic acid group in the risk of ischemic stroke (2.2 percent vs 2.8 percent) and composite cardiovascular events (cardiovascular death, heart attack and stroke) (3.1 percent vs 3.9 percent).
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 write 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. 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.”
In an accompanying editorial Dr. Meir Stampfer, MD, Dr.PH and Dr. Walter Willett, MD, Dr.PH, of the Harvard T. H. Chan School of Public Health and Channing Division of Network Medicine, Boston, write “Although the trial participants all had hypertension, there is little reason to doubt that the results would apply to normotensive persons, although the absolute effect would be smaller. It is possible to debate the ethics of whether a replication trial should be performed, especially because folic acid supplementation (or fortification) is safe and inexpensive, and carries other benefits. Large segments of the world’s population, potentially billions of people, including those living in northern China, Bangladesh, and Scandinavia, have low levels of folate.”
“Individuals with the TT genotype might particularly benefit, although it seems unlikely that genotyping for that purpose would be cost-effective. Also, some persons in the United States on the low end of the distribution of folate intake may benefit; effects in this subgroup would not have been detected in previous trials. Ideally, adequate folate levels would be achieved from food sources such as vegetables (especially dark green leafy vegetables), fruits and fruit juices, nuts, beans, and peas. However, for many populations, achieving adequate levels from diet alone is difficult because of expense or availability. This study seems to support fortification programs where feasible, and supplementation should be considered where fortification will take more time to implement.”
Citations
Efficacy of Folic Acid Therapy in Primary Prevention of Stroke Among Adults With Hypertension in China. JAMA, 2015; DOI: 10.1001/jama.2015.2274
Editorial Folate Supplements for Stroke Prevention Targeted Trial Trumps the Rest
JAMA – Journal of the American Medical Association Release
