CSPPT: Folic Acid with Enalapril Reduces First Occurrence of Stroke in Hypertension Patients

Journal Wrap | Kim Eagle, MD, MACC, and the editors of ACC.org’s Journal Scans, present relevant articles taken from various journals.

Patients with hypertension who received enalapril along with folic acid are significantly less likely to experience a stroke than those who receive enalapril alone, according to the China Stroke Primary Prevention Trial (CSPPT) published in JAMA and presented as part of the Joint Symposium of the Chinese Society of Cardiology and the ACC during ACC.15 in San Diego, CA this past March.

The 1:1 randomized, double-blind study looked at 20,702 adults from two provinces in China, with hypertension, varying levels of folate and without a history of stroke or heart attack. Patients were divided into two groups and were randomly selected to receive daily enalapril (10 mg) and folic acid (0.8 mg) or 10 mg of enalapril alone. The study also tested for variations in the C677T gene (CC, CT and TT genotypes) that could potentially affect folate levels in participants.

After four and a half years, the first stroke occurred in only 2.7 percent of patients that received folic acid and enalapril versus the 3.4 percent occurrence of first stroke in those who received enalapril alone, representing a relative risk reduction of 21 percent. The risk of ischemic stroke and other cardiac events in the folic acid-enalapril group was also lowered significantly. Folic-enalapril group patients who started with low folate levels saw the greatest benefits.

“The CSPPT is the first large-scale randomized trial to test the hypothesis using individual measures of baseline folate levels,” said Yong Huo, MD, FACC, of Peking University First Hospital, Beijing, China. “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.”

Huo and fellow study investigators speculate that “even in countries with folic acid fortification and widespread use of folic acid supplements such as in the U.S. 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.”

According to Brian A. Ference, MD, FACC, MPhil, MSc, associate professor and clinical chief for the division of cardiovascular medicine at Wayne State University Health Center in Detroit, and member of the ACC’s Prevention of Cardiovascular Disease Section Leadership Council, this study has important implications for the treatment of hypertension in many areas of the world where folate deficiency is common.

“The question of whether folic acid supplementation will reduce the risk of stroke among persons who are folate deficient but not hypertensive, or whether adding folic acid supplementation to blood pressure (BP)-lowering therapy will reduce the risk of stroke among persons who are hypertensive but not folate deficient, cannot be addressed by this study,” he said. “However, the unique design of this study can offer some potential clues.”

Ference notes that the study results showing no significant difference in the observed reduction in the risk of stroke by naturally randomized allocation to higher or lower folic acid levels as determined by MTHFR genotype can be interpreted in one of two ways. First, it may suggest that the benefit of adding folic acid to BP- lowering medications is independent of folic acid level. In this scenario, adding folic acid to BP-lowering treatments among persons with hypertension who are not folate deficient should also further reduce the risk of stroke. A second, and perhaps more likely interpretation, however, is that once folate levels are replete beyond a certain threshold, folic acid supplementation offers no further benefit. This interpretation would suggest that adding folic acid to BP-lowering therapy among persons who are hypertensive but not folate deficient is unlikely to further reduce the risk of stroke, Ference said.

Moving forward, Ference suggests a “randomized trial is needed to evaluate the effect of folic acid supplementation when added to BP-lowering therapy on the risk of stroke among persons with hypertension who are not folate deficient.”

Huo Y, Li J, Qin X, et al. JAMA. 2015;313(13):1325-35.

Clinical Topics: Prevention, Hypertension

Keywords: CardioSource WorldNews, China, Enalapril, Folic Acid, Hypertension, Stroke, Primary Prevention

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