August 9th, 2015

Strong Support for Folate Supplements for Primary Stroke Prevention

Strong Support for Folate Supplements for Primary Stroke Prevention
March 16, 2015

NEW YORK - Folic acid supplementation significantly reduced the risk of first stroke in adults with hypertension enrolled in the Chinese Stroke Primary Prevention Trial (CSPPT). Those with low baseline folate levels showed the greatest benefits.

The findings were published March 15 in JAMA to coincide with presentation during a joint symposium of the Chinese Society of Cardiology (CSC) and the American College of Cardiology (ACC), at the ACC's annual scientific sessions in San Diego.

The CSPPT is an "important" and "carefully designed and executed" randomized trial and the results are "remarkable," Dr. Meir Stampfer and Dr. Walter Willett, of the Harvard T. H. Chan School of Public Health and Channing Division of Network Medicine, Boston, say in an accompanying editorial.

The study included 20,702 Chinese adults with hypertension and no history of stroke or MI. Roughly half were randomly allocated to daily treatment with the antihypertensive enalapril (10 mg) and half to enalapril (10 mg) combined with 0.8 mg folic acid in a single tablet.

On the advice of the data and safety monitoring board, the trial was halted early after 4.5 years, due to a significant reduction in the incidence of first stroke (the primary end point), with 282 strokes (2.7%) in the enalapril-folic acid arm versus 355 (3.4%) in the enalapril only arm, (hazard ratio, 0.79).

The benefit of folic acid was greater in those with the lowest baseline folate levels (< 5.6 ng/mL), with rates of first stroke of 2.8% (73 events among 2,600 adults) in the enalapril-folic acid arm versus 4.6% (116 events among 2,548 adults) in the enalapril only arm (HR 0.61).
"The CSPPT is the first large-scale randomized trial to test the hypothesis using individual measures of baseline folate levels," first author Dr. Yong Huo, of Peking University First Hospital, Beijing, China, and colleagues note in their article.

"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," they report.

"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," they say, in particular, among those with low or moderate folate levels and the TT genotype of the MTHFR gene, which is associated with lower circulating folate levels.

In a JAMA podcast, CSPPT investigator Dr. Xiaobin Wang, from Johns Hopkins Bloomberg School of Public Health in Baltimore, Maryland, notes that because the study focused on primary prevention of stroke in adults with hypertension, "the generalizability of our study findings to secondary prevention of stroke or adults without hypertension remains to be determined."

She also notes that the trial used a fixed dosage of folic acid (0.8 mg/d) and "findings from the subgroup analysis suggest that this dose may not be enough for participants with MTHFR TT genotype plus low baseline folate levels. The optimal dose for this subgroup remains to be established."

Dr. Stampfer and Dr. Willett say this study has "important implications for stroke prevention worldwide. Although the trial participants all had hypertension, it is likely that the results would apply to normotensive persons, although the absolute effect would be smaller."
They note that "large segments of the world's population, potentially billions of people" have low folate levels and folic acid supplementation (or fortification) is safe and inexpensive, and carries other benefits. "This study seems to support fortification programs where feasible, and supplementation should be considered where fortification will take more time to implement."
"Individuals with the TT genotype might particularly benefit, although it seems unlikely that genotyping for that purpose would be cost-effective," they add.

The trial was jointly supported by Shenzhen AUSA Pharmed Co Ltd and national, municipal, and private funding. Three authors have disclosed relationships with Shenzhen AUSA. Dr. Stampfer and Dr. Willet have no disclosures.

SOURCE: bit.ly/1Lj4coL and bit.ly/1HVBq8g

JAMA 2015.

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