Level 2 [mid-level] evidence


Hypertension is a common condition that may begin at age 20 to 50 years with prevalence increasing with age. An estimated 41% of persons aged 35 to 70 years have hypertension, which is associated with an increased risk of several cardiovascular and cerebrovascular diseases including stroke.

Antihypertensive medications are recommended for primary stroke prevention in patients with hypertension, and recent studies have suggested that B vitamin supplementation might also help reduce the risk of primary stroke in high risk patients (Stroke. 2010;41[6]:1205; Int J Clin Pract. 2012;66[6]:544).

A recent randomized trial compared enalapril 10 mg plus folic acid 0.8 mg vs. enalapril 10 mg alone for five years in 20,702 Chinese adults aged 45 to 75 years (mean age, 60 years) with hypertension. At enrollment, all patients had resting systolic blood pressure ≥ 140 mm Hg, diastolic blood pressure ≥ 90 mm Hg, or were taking antihypertensive medication. Other antihypertensive medications were used concomitantly during the trial by 57.1% of patients. Patients with a history of stroke, myocardial infarction, heart failure, coronary revascularization, or congenital heart disease were excluded from the trial (CSPPT trial JAMA. 2015;313[13]:1325).


The trial was terminated early after a significant difference between groups in first stroke occurrence exceeding the predefined stopping rule was reached on the fourth interim analysis. Overall treatment adherence was low, with 69.1% of patients taking 70% or greater of all study. Most patients discontinuing treatment were still followed for outcome events, and all randomized patients were included in the primary analysis.

Median baseline folate level was 8.1 ng/mL, and at last follow-up the median increase in folate level was 11.2 ng/mL with enalapril plus folic acid vs. 4.4 ng/mL with enalapril alone (no P value reported). There were no significant differences in baseline or follow-up systolic or diastolic blood pressure measurements between groups.

Comparing enalapril plus folic acid vs. enalapril alone, first stroke occurred in 2.7% vs. 3.4% (P = 0.003, NNT 141) and ischemic stroke was reported in 2.2% vs. 2.8% (P = 0.002, NNT 167). Enalapril plus folic acid was also associated with a reduction in the composite outcome of stoke, myocardial infarction, or cardiovascular death (3.1% vs. 3.9%, P = 0.002, NNT 125), but there was no significant difference between groups in rates of hemorrhagic stroke, myocardial infarction, cardiovascular death, all-cause death, or adverse events. A subgroup analysis by methylenetetrahydrofolate reductase (MTHFR) gene C677T polymorphisms found no significant differences in rate of first stroke by genotype.


The results of this trial suggest that the addition of folic acid to enalapril may result in a small, but significant, decrease in primary stroke incidence among patients with hypertension. Although the magnitude of the reduction was small, adding folic acid to antihypertensive medication may be a cheap and easy way to further reduce the risk of stroke.

It is worth considering, however, that baseline folate levels of patients in this study may be lower than in places with folate fortification, thereby limiting the generalizability of this study. Also, although the relative contribution of MTHFR was examined, it is not clear whether the frequency of MTHFR polymorphisms are similar in other populations or if differences in overall population genetics would contribute more substantially to stroke risk. 



Alan Ehrlich, MD, is a deputy editor for DynaMed, in Ipswich, Mass., and assistant clinical professor in Family Medicine, University of Massachusetts Medical School in Worcester.

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