Folic acid supplementation may be an effective strategy for lowering primary stroke risk in hypertensive patients with low baseline folate levels, Chinese researchers reported.

In the China Stroke Primary Prevention Trial (CSPPT), which included more than 20,000 adults with high blood pressure but no history of stroke or myocardial infarction, folic acid therapy appeared to significantly lower stroke risk when given with the blood pressure drug enalapril (Vasotec), compared with enalapril alone.

Results from the randomized, double-blind trial were published online this week in the Journal of the American Medical Association.

During a median of 4.5 years of treatment, 2.7% of patients who took a single daily tablet containing 10 mg of enalapril and 0.8 mg of folic acid experienced first strokes compared with 3.4% of patients who took enalapril alone (hazard ratio 0.79, 95% CI 0.68-0.93), researcher Yong Huo, MD, of Peking University First Hospital, Beijing, China, and colleagues noted.

The benefit of folic acid supplementation was most pronounced among study participants who had the lowest baseline levels of plasma folate (<5.6 ng/mL), with 2.8% of these patients in the folic acid group experiencing strokes during the study compared with 4.6% of controls.

Folate Levels Low in Much of the World Leafy green vegetables, beans, nuts, and some fruits are natural food sources of folate, and in the U.S. most grain-based products, including wheat flour, cornmeal, and rice, are fortified with the B vitamin.

This is not the case in China, however, or in many other countries, and the findings appear to support expanding fortification programs "where feasible," nutrition researchers Walter Willett, MD, and Meir Stampfer, MD, of Harvard T.H. Chan School of Public Health, wrote in an editorial published with the study.

They also support the use of folic acid supplements in high-risk populations living in areas where fortification programs are not in place, Willett and Stampfer wrote. The study included adults with hypertension whose average age was 60 at study entry. Participants took either the enalapril-folic acid single pill (n=10,348) or enalapril alone (10,354) daily during the trial. More than half (57%) also took other antihypertension medications.

The original plan was to treat patients for 5 years, but the findings were so robust that the trial was terminated after 4.5 years.

Participants Stratified by MTHFR Genotype Study participants were stratified by methylenetetrahydrofolate (MTHFR) C677T genotype, based on findings from previous trials suggesting that stroke risk associated with MTHFR C677T gene variants may be modified by folate status. The frequency of MTHFR C677T polymorphisms was 27.3% (n=5,652) for CC (normal homozygous), 49.2% (n=10,176) for CT (heterozygous variant) and 23.5% (n=4,874) for TT (homozygous variant) genotypes.

Baseline folate levels were similar among the two treatment groups within each genotype strata, and after treatment folate levels increased by a median of 11.2 ng/mL in the enalapril-folic acid group compared with 4.4 ng/mL in the enalapril group. The median increases did not differ by MTHFR C677T genotype.

Among patients with the CC genotype, folic acid therapy significantly reduced stroke risk in those with folate levels below the median (absolute risk reduction 2.1 percentage points, HR 0.45; 95% CI 0.29-0.72, P=0.001), the researchers noted.

"A similar pattern was observed to a lesser degree among those with the CT genotype, with the greatest benefit seen in the lowest quartile (absolute RR 1.4 percentage points, HR 0.6; 95% CI 0.44-1.07, P=0.10)," they wrote.

"In contrast, among those with the TT genotype, the preventive effect of folic acid therapy on stroke was mainly observed in the highest folate quartile (absolute reduction 2.8 percentage points, HR 0.24; 95% CI 0.10-0.58, P=0.001)."

Stratifying the analysis by MTHFR C677T genotype was a major study strength because MTHFR is closely linked to the production of folate, said Sylvia Wassertheil-Smoller, PhD, who is a professor of epidemiology and population health at Albert Einstein College of Medicine, Bronx, New York.

"It's a very important development, because we're always hearing about personalized medicine, and this is an attempt to further that line of research," she told MedPage Today.

Study participants with homozygous variant TT genotype had the highest stroke rates. This finding "underscores the basic principle that for trials of nutrients, in contrast to most drug trials, the baseline levels are critical to consider, and targeting individuals with low levels of the nutrient under study provides the best test of the hypothesis," Willett and Stampfer wrote.

"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," they wrote. "Individuals with the TT genotype might particularly benefit, although it seems unlikely that genotyping for that purpose would be cost-effective."

Many previous trials examining folic acid supplementation and cardiovascular risk have shown little or no protective effect for the B vitamin, but Willett and Stampfer noted than these trials had design flaws and other limitations that the "carefully designed and executed" CSPPT trial managed to avoid. They further noted that the findings may actually underestimate the true effect of folic acid supplementation on stroke risk in adults with low blood folate levels. From the American Heart Association: