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Combination Folic Acid and Medical Therapy Found to Prevent Stroke in Large Population-Based Trial

ARTICLE IN BRIEF

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FOLATE is found naturally in a wide variety of foods, including vegetables (especially dark leafy greens), fruits and fruit juices, nuts, beans, peas, dairy products, poultry and meat, eggs, seafood, and grains. Spinach, liver, yeast, asparagus, and Brussels sprouts are among the foods with the highest levels of folate.

In the China Stroke Primary Prevention Trial, individuals receiving folic acid plus the hypertension medication enalapril had a significant risk reduction in first stroke, first ischemic stroke, and a composite of cardiovascular events including cardiovascular death, myocardial infarction, and stroke, compared with subjects receiving enalapril only.

A large, multicenter trial involving more than 20,000 people in China has provided the most definitive evidence to date that folic acid coupled with regular medical therapy provides additional protection against stroke in those with high blood pressure.

In the China Stroke Primary Prevention Trial (CSPPT), individuals receiving folic acid plus the hypertension medication enalapril had a significant risk reduction in first stroke, first ischemic stroke, and a composite of cardiovascular events including cardiovascular death, myocardial infarction, and stroke, compared with subjects receiving enalapril only.

The link between folic acid and stroke prevention has been unclear until now, in part because studies have tended to be underpowered to study the supplement's effects on stroke prevention.

Independent experts heralded the study, published in the March 15 online edition of The Journal of the American Medical Association (JAMA), as a breakthrough because it showed stroke prevention benefits where other trials had largely failed, targeting a population — 27 communities in two Chinese provinces — that had low folate levels. The study also clearly showed that those with lower baseline levels of folate benefited the most.

The trial was halted early after a median treatment duration of 4.5 years because the results so clearly favored folic acid supplementation.

Prior to the CSPPT, there was a dearth of adequately powered randomized clinical trials on the primary prevention of stroke, said lead author Yong Huo, MD, director of cardiology at Peking University First Hospital in Beijing. “The CSPPT was the first adequately powered randomized trial specifically targeting stroke primary prevention in China — an Asian country with a high burden of stroke and a low folate intake.”

STUDY METHODOLOGY, RESULTS

A total of 20,702 participants with hypertension who had no history of stroke or myocardial infarction were randomized to receive a single daily pill containing either 10 mg of enalapril and 0.8 mg of folic acid or 10 mg of enalapril alone. The subjects were tracked from May 2008 to August 2013.

Overall, the study found that enalapril plus folic acid reduced stroke risk by 21 percent compared with the antihypertensive therapy alone.

After 4.5 years, 2.7 percent of those in the enalapril-folic acid group had a first stroke, compared with 3.4 percent of those taking only enalapril — a significant risk reduction (HR, 0.79; 95% CI, 0.68-0.93).

There was also a significant risk reduction for the enalapril-folic acid group in first ischemic stroke — 2.2 percent compared with 2.8 percent (HR, 0.76; 95% CI, 0.64-0.91), as well as in the composite of cardiovascular events — 3.1 percent compared with 3.9 percent (HR, 0.80; 95% CI, 0.69-0.92).

Researchers looked at baseline folate levels and genotype subgroups of MTHFR C677T (methylenetetrahydrofolate reductase), an enzyme that helps the body process folic acid. For those with the CC and CT genotypes — the normally functioning MTHFR — they found that the higher the baseline folate level, the lower the risk of stroke. But for those with the TT genotype, a variant that inhibits the functionality of the MTHFR enzyme, the risk was similar across all baseline folate subgroups.

Researchers found that those with the lowest baseline folate levels tended to benefit the most from folic acid supplementation. In the CC genotype subgroup, folic acid supplementation significantly reduced the risk of stroke in those with baseline folate levels that were below the median (absolute risk reduction, 2.1%; HR, 0.45; 95% CI, 0.29-0.72; p = 0.001).

In the CT genotype subgroup, a similar pattern was seen to a lesser degree; those who benefited the most were in the lowest quartile of baseline folate level (absolute risk reduction, 1.4%; HR, 0.68; 95% CI, 0.44-1.07; p = 0.10).

But in the TT genotype subgroup, the preventive effects were seen mainly in the highest baseline folate quartile (absolute reduction, 2.8%; HR, 0.24; 95% CI, 0.10-0.58; p = 0.001).

The study subjects also had a low concomitant use of lipid-lowering and anti-platelet therapies, meaning the results were less likely to be affected by interactions with those drugs. Less than 1 percent of the study participants in each group were taking lipid-lowering drugs. Past studies have not found folic acid protective when lipid-lowering and antiplatelet agents were more commonly in use.

Dr. Huo said that the study has “provided convincing evidence that the baseline folate level is an important determinant of folic acid efficacy in stroke prevention.”

He added that even in the US, where folic acid supplementation in grains has drastically reduced the population with low folate levels, the approach could be beneficial. “A recently published US National Health and Nutrition Examination Survey indicates that there is substantial variability in blood folate levels within the US population,” Dr. Huo said. “We speculate that even in countries like the US where there is extensive folic acid fortification and a widespread use of folic acid supplements, there may still be room to further reduce stroke incidence using more targeted folic acid therapy, in particular among those with TT genotype and low or moderate folate levels.”

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DR. YONG HUO said that prior to the CSPPT, there was a dearth of adequately powered randomized clinical trials on the primary prevention of stroke. “The CSPPT was the first adequately powered randomized trial specifically targeting stroke primary prevention in China — an Asian country with a high burden of stroke and a low folate intake.”

(According to the NIH Office of Dietary Supplements, folate deficiency is uncommon in the US. But certain groups are more likely to be at risk for low levels of folate, including people with alcohol dependence, women of childbearing age, pregnant women, and people with malabsorptive disorders.)

Dr. Huo pointed out that the subgroup analysis of those with the TT variant of MTHFR showed that there might be an opportunity to further reduce stroke risk in these patients. “Whether a higher dosage of folic acid supplementation for these subgroups of hypertensive patients would lead to a greater benefit would be an interesting topic for further investigation,” he said.

EXPERTS COMMENT

Meir Stampfer, MD, a professor of epidemiology and nutrition at the Harvard School of Public Health who wrote an accompanying editorial in JAMA, praised the study and said it “addresses and, to my view, settles an important controversy that's been debated for quite a long time in the medical literature regarding the role of folate in stroke prevention.

“This study resolves lots of apparent contradictions in the literature in a very nice way by focusing on a population that's low folate at baseline,” he said.

“What was so crucial was that the investigators looked at the variation in levels rather than taking a with-or-without approach typically used in drug trials. Everybody has to have folate to live, so you're always testing more versus less as your comparison,” he said. “What these investigators showed, which made a lot of sense, is that if you don't have enough folate, additional folate does work — it's helpful and it can help prevent stroke. But if you have sufficient folate, even more is not going to work.”

But should there be screening for low folate? “Although the prevalence of low folate is much lower than before fortification,” Dr. Stampfer said, “there are still a substantial number of people with suboptimal levels. It is not clear that screening would be a good strategy, though. I think perhaps better nutrition education might be effective.”

Gustavo Saposnik, MD, an associate professor of neurology at the University of Toronto, said the study was so strong largely because it targeted primary stroke prevention, while others did not.

“The authors should also be commended for doing a study that included an inexpensive supplement,” he said.

He cautioned that the benefits of folic acid would be seen typically in those without folic acid fortification and in those not taking antiplatelet therapy. “It is possible,” he said, “that the benefits of folic acid supplementation may dissipate in patients taking antiplatelet agents.”

EXPERTS: ON COMBINATION FOLIC ACID AND MEDICAL THERAPY FOR STROKE

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DR. MEIR STAMPFER: “What was so crucial was that the investigators looked at the variation in levels rather than taking a with-or-without approach typically used in drug trials...What these investigators showed, which made a lot of sense, is that if you dont have enough folate, additional folate does work — its helpful and it can help prevent stroke. But if you have sufficient folate, even more is not going to work.”

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DR. GUSTAVO SAPOSNIK said the benefits of folic acid would be seen typically in those without folic acid fortification and in those not taking antiplatelet therapy. “It is possible that the benefits of folic acid supplementation may dissipate in patients taking antiplatelet agents.”

LINK UP FOR MORE INFORMATION:

•. Huo Y, Li J, Qin X, et al. for the CSPPT Investigators. Efficacy of folic acid therapy in primary prevention of stroke among adults with hypertension in China: The CSPPT Randomized Clinical Trial http://jama.jamanetwork.com/article.aspx?articleid=2205876. JAMA 2015; Epub 2015 March 15
    •. Stampfer M, Wilett W. Folate supplements for stroke prevention targeted trial trumps the rest http://jama.jamanetwork.com/article.aspx?articleid=2205875. JAMA 2015: Epub 2015 March 15
      •. NIH Folate Dietary Supplement Fact Sheet: http://bit.ly/NIH-folate