By Seema Gupta, MD, MSPH
Primary Care Physician, Charleston, WV
Dr. Gupta reports no financial relationships relevant to this field of study.
SYNOPSIS: In a Chinese study of hypertensive adults without history of stroke or myocardial infarction, the combined use of enalapril and folic acid, compared with enalapril alone, significantly reduced the risk of first stroke.
SOURCE: Huo Y, et al. Efficacy of folic acid therapy in primary prevention of stroke among adults with hypertension in China. The CSPPT randomized clinical trial. JAMA 2015;313:1325-1335.
Stroke is the fifth leading cause of death in the United States and a major cause of disability.1,2 Worldwide, stroke is the second-most common cause of mortality and the third-most common cause of disability. About 800,000 Americans have a stroke each year, more than 600,000 of whom have had first attacks. On average, one person dies from a stroke every 4 minutes in the United States. With 6.8 million stroke survivors > 19 years of age, it remains a leading cause of functional impairment. Primary prevention is key, since more than three-fourths of strokes are first time events. An international case-control study of 6000 individuals found that 10 potentially modifiable risk factors could explain 90% of the risk of stroke occurrence.3 This illustrates that targeted interventions can potentially be implemented to prevent stroke at individual and population levels. From a prevention perspective, the effect of folic acid supplementation on cardiovascular disease, including stroke, has been studied in many observational settings and randomized trials, and results have been mixed.
In their study, Huo and colleagues conducted a randomized, double-blind clinical trial of 20,702 adults in China with hypertension who had never had a stroke or myocardial infarction (MI). The randomly assigned participants received double-blind daily treatment with a single-pill combination containing 10 mg enalapril and 0.8 mg folic acid (n = 10,348) or a tablet containing 10 mg enalapril alone (n = 10,354). Methylenetetrahydrofolate reductase (MTHFR) is the main regulatory enzyme for folate metabolism. Polymorphism of the MTHFR gene C677T leads to a reduction in enzyme activity, resulting in decreased folate levels. Study participants were also stratified by MTHFR C677T genotypes (CC, CT, and TT). The primary outcome studied was first stroke.
The trial was terminated early, after 4.5 years, per the recommendations by the data and safety monitoring board. The researchers found that the enalapril/folic acid group had a significant risk reduction in the incidence of first stroke, the primary endpoint, of 2.7% (282 events) vs 3.4% (355 events) in the enalapril-alone group (hazard ratio [HR], 0.79; 95% confidence interval [CI], 0.68-0.93). Analyses of secondary outcomes showed that the enalapril/folic acid group had a significant risk reduction in the incidence of ischemic stroke of 2.2% vs 2.8% in the enalapril alone (HR, 0.76; 95% CI, 0.64-0.91). Similar benefits were also found for composite cardiovascular events (3.1% in the enalapril/folic acid group vs 3.9% in the enalapril alone group; HR, 0.80; 95% CI, 0.69-0.92). However, no significant difference between groups was found for risk of hemorrhagic stroke or all-cause deaths. In stratified analysis performed, no significant interactions in any of the subgroups were found, including MTHFR C677T genotype. However, the beneficial effect appeared to be more pronounced in participants with lower baseline folate levels.
COMMENTARY
Folate occurs naturally in many animal products, green leafy vegetables, beans, and citrus fruits. In the United States, folic acid fortification of flour is mandated, which has led to the declining prevalence of folate deficiency. However, the most common cause of folate deficiency remains nutritional, due to poor diet and/or alcoholism. Certain conditions can also lead to increased requirements such as pregnancy, lactation, chronic hemolytic anemias, and drug-induced interference with folate metabolism (e.g., trimethoprim, methotrexate, phenytoin). Huo et al found a statistically significant reduction in risk of first stroke by 21% among adults with hypertension in China without a history of stroke or MI, with enalapril/folic acid therapy, compared with enalapril alone. In earlier studies, the possible benefits of folic acid supplementation in cardiovascular disease have been controversial. Prior studies have suggested that the greatest benefit from folate might be for stroke; however, most of the previous trials had been conducted among individuals with prior cardiovascular disease, unlike this study.4,5 Although all the current study participants had hypertension, it is likely that the results would apply to normotensive persons, though the absolute effect may not be as robust.
Therefore, the current study has significant implications for stroke prevention across the globe by utilizing a safe and inexpensive folate supplementation or fortification strategy. In the United States, this approach should be individualized to target those with the TT genotype and/or those with low or moderate folate levels.
REFERENCES
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Kochanek KD, et al. Mortality in the United States, 2013. NCHS Data Brief, No. 178. Hyattsville, MD: National Center for Health Statistics, Centers for Disease Control and Prevention, US Dept. of Health and Human Services; 2014.
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Mozzafarian D, et al. Heart disease and stroke statistics-2015 update: A report from the American Heart Association.
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O’Donnell MJ, et al. INTERSTROKE Investigators. Risk factors for ischaemic and intracerebral haemorrhagic stroke in 22 countries (the INTERSTROKE study): a case-control study. Lancet. 2010;376:112-123.
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Huo Y, et al. Efficacy of folic acid supplementation in stroke prevention: new insight from a meta-analysis. Int J Clin Pract 2012;66:544-551.
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Huang T, et al. Meta-analysis of B vitamin supplementation on plasma homocysteine, cardiovascular, and all-cause mortality. Clin Nutr 2012;31:448-454.
