Folic Acid: A Simple Answer to a Very Large Problem?

Stroke is responsible for 1 in 19 deaths in the United States each year and is the leading cause of long-term disability — arguable an outcome worse than death.¹ More than 36 billion was spent on stroke treatment and rehabilitation in 2010.  Many strategies are used for the secondary prevention of stroke, but the real impact on health and healthcare cost can only be achieve by preventing the first stroke. Of the 795,000 people who have a stroke each year, more than 75% experience first time stroke.¹ Several risk factors have been identified and, if modified, can decrease the risk of stroke.  These include high blood pressure, smoking, physical inactivity, and a high fat diet.^1,2  Is folate deficiency a potentially modifiable risk factor for stroke too?

Folic acid, along with other B vitamins, helps break down homocysteine. Elevated homocysteine levels are associated with an increased risk for ischemic stroke.³ In United States, the Food and Drug Administration adopted mandatory fortification of cereal grains with folic acid in 1998. This mandatory fortification has resulted in a very low (< 1%) prevalence of folate deficiency in the U.S..^4,5,6   However, the rate of folate deficiency increases with age.  One study conducted in Georgia found that 1 in 15 centenarians had low folate levels.⁷  In developing countries, where folic acid fortification in food is not routine, the incidence of folate deficiency is far more common.  Folic acid has been used for stroke prevention in previous studies.  But the available data is of poor quality and the results are conflicting.² The China Stroke Primary Prevention Trial (CSPPT) was designed to determine if folic acid supplementation is effective for the primary prevention of stroke in a patient population where folate deficiency is relatively common.

The CSPPT was a double blind study conducted in 32 communities in China. Participants were randomized to receive a tablet containing both enalapril and folic acid or only enalapril. Male and female patients were included if they were 45 to 75 years old and had a diagnosis of hypertension (defined by blood pressure >140/90 or taking antihypertensive medication). Patients with a history of stroke, myocardial infarction (MI), heart failure (HF), coronary revascularization, or congenital heart disease were excluded. The study also performed genotyping on participants to assess for MTHFR C677T polymorphisms. MTHFR is the main enzyme involved in folate metabolism. Polymorphisms can result in decreased folate levels. Patients were stratified based on their genotype — CC (normal homozygous), CT (heterozygous), or TT (homozygous variant) — and randomly assigned to the study groups.  Other antihypertensive medications were allowed during the study, but B vitamins were not permitted.⁸

More than 20,700 patients enrolled in the study — 10,348 patients were randomized to enalapril with folic acid (EF) and 10,354 patients to enalapril only (EP).  Serum folate levels were obtained at baseline and study exit. Folate levels were similar at baseline and increased substantially in both groups.  Not surprisingly, folate levels increased significantly more in the group that received folic acid supplementation.  Other baseline characteristics were similar – including blood pressure, lipids, fasting glucose, smoking status, and alcohol use – in both groups.  Follow up occurred every three months.  Vital signs, adherence to study medication, concomitant medications, safety parameters, and occurrence of endpoint events were determined at each follow-up visit. The primary outcome was the occurrence of fatal or non-fatal ischemic as well as hemorrhagic stroke excluding subarachnoid hemorrhage and silent stroke. Secondary outcomes included a composite of cardiovascular death, myocardial infarction (MI), and stroke; first ischemic stroke; first hemorrhagic stroke; MI; and all cause mortality.⁸

Using an intent-to-treat analysis, the primary outcome of first stroke occurred in 282 patients (2.7%) in the EF group and 355 patients (3.4%) in the EP group (p= 0.003; HR, 0.79 [95% CI, 0.68-0.93]) with a number needed to treat of 141. The per-protocol analysis revealed similar results. The secondary outcomes found significant differences between the EF and EP groups for ischemic stroke (2.2% vs. 2.8%; HR, 0.76 [95% CI, 0.64-0.91]; p= 0.002) and the composite of cardiovascular outcomes (3.1% vs. 3.9%; HR, 0.80 [95% CI, 0.69-0.92]; p= 0.002). The secondary outcomes of MI, hemorrhagic stroke, and all cause mortality were not significantly different. When looking at the MTHFR C677T genotypes subgroups, patients with genotypes CC and CT had a significantly lower risk of stroke with folic acid supplementation if baseline folate levels were below normal. Patients with the TT genotype had a higher risk of stroke regardless of baseline folate levels.  It is possible that patients with the TT genotype may require higher folate supplementation to derive a benefit. There were no differences in the rate of adverse events.⁸

We concur with the authors’ conclusion. Folic acid supplementation combined with enalapril significantly reduces the risk of first stroke when compared to enalapril alone.⁸ Strengths of the trial include the large sample size, randomization, double blinding, and an appropriate comparator. The authors identified two variables that impact treatment effectiveness including MTHFR C677T polymorphisms and baseline folate levels. The major limitation of the study is its generalizability.  The results likely do not apply to countries where folate deficiency is uncommon.  Moreover, the frequency of MTHFR polymorphisms vary from population to population.

The healthcare costs and mortality risks associated with stroke are high and primary prevention is the key to reducing long-term disability and health care costs. The American Heart Association/American Stroke Association 2014 primary prevention of stroke guidelines state that folic acid supplementation may be considered for the primary prevention of ischemic stroke, but acknowledges the lack of evidence to support routine use.² The CSPPT trial offers evidence to support the use of folic acid in primary prevention of stroke, but only in patients that have low serum folate levels.  Given that folic acid is inexpensive and readily available over-the-counter, it is seemingly a simple answer to a very large problem.  However, we feel this should not be a blanket intervention for all patients treated for high blood pressure. We would recommend testing patients that may be at risk for low dietary intake of folic acid and using supplements only in those with a documented deficiency. Similar to the use of calcium supplements, dietary consumption must be considered first.  If a patient is determined to have folate deficiency, we recommend a daily multivitamin with 0.8mg of folic acid.  What do you think?  Should all older adults be screened for folate deficiency? Or should we forgo testing and simply recommend a daily multivitamin to everyone diagnosed with hypertension?