It is clear that high levels of total homocysteine (tHcy) are a strong, graded risk factor for vascular disease. This is particularly true for cardioembolic stroke; high levels of tHcy quadruple the risk of stroke in atrial fibrillation. Vitamin therapy with folic acid, B6, and B12 can lower levels of tHcy, so it was logical to think that they should reduce the risk of cardiovascular events.
No Benefit in Early Trials
However, the early clinical trials did not support this hypothesis. The first large trial, the showed no benefit.
In 2006, after the simultaneous publication in the New England Journal of Medicine of both the and the , it became common to think that "Homocysteine is dead." In that same issue, Joseph Loscalzo, MD, PhD, that the reason B vitamins didn't prevent cardiovascular events was because of high doses of folic acid.
Why was there no benefit? Reasons why there was no benefit of B Vitamins in the VISP trial included:
- Folate fortification of the grain supply in North America coincided with the beginning of the trial, largely negating the benefit of folic acid
- We did not use a placebo; we used a high dose or a low dose of folate/B6/B12, and the low dose included the recommended dietary intake for B12
- Participants with low levels of serum B12 at baseline were given monthly injections of B12 in both arms of the trial, thus negating the effect of B12 in the very patients who stood to benefit the most
In Stroke in 2005, we reported the , and for the wrong reason, we also excluded patients with impaired renal function (eGFR in the lowest decile, <48 mL/min/1.73 m²). I thought patients with renal impairment would not benefit from B vitamins; I never dreamed that they would be harmed by them. We found that among patients who received high dose vitamins and could absorb B12 well (a baseline serum B12 >322 pmol/L, the median level), there was a 34% reduction of combined stroke, MI, and vascular death compared with patients who received low-dose vitamins and had a baseline serum B12 below the median.
Harm in Impaired Renal Function
Then in 2010, the Diabetic Intervention with was published in JAMA. , a high dose of B vitamins -- including 1,000 mcg daily of B12 as cyanocobalamin -- accelerated the decline of renal function and doubled cardiovascular events. All the events occurred in .
After that paper was published, I received emails pointing out that cyanocobalamin was probably harmful in patients with renal failure. Katsushi Koyama, MD, and colleagues had reported that thiocyanate, which consumes hydrogen sulfide in the excretion of cyanide, and methylcobalamin lowered levels of both tHcy and asymmetric dimethylarginine (ADMA, a nitric oxide antagonist), whereas cyanocobalamin did not lower ADMA in the in Norway.
Also in 2010, the French reported a 43% reduction of stroke with B vitamins among a population with the best renal function of all the trials and the lowest dose of cyanocobalamin (20 mcg daily as opposed to 400-1,000 mcg daily in all the other trials).
In 2011, I hypothesized with Meir Stampfer, MD, DrPH, in JAMA that the reason the early trials did not show benefit of B vitamins was among participants with impaired renal function.
The Light Goes On
Then, in 2015, along came the , which reported a 24% reduction of ischemic stroke in hypertensive patients. Importantly, among participants with eGFR greater than 60 mL/min/1.73 m², there was a and reduction of a composite outcome that included mortality. This meant that folic acid was not the culprit in the early trials.
In 2017, a reported in Lancet Neurology stratified by dose of cyanocobalamin and by renal function confirmed that B vitamins are beneficial in participants with good renal function, and that harm from cyanocobalamin in participants with poor renal function obscured the benefit.
A 2018 in the Journal of the American College of Cardiology also confirmed the benefit of B vitamins in stroke prevention. The authors suggested that folic acid should be used to prevent stroke.
Not Just Folic Acid
However, in countries where folic acid fortification exists, the main nutritional determinant of tHcy is vitamin B12. It turns out that measuring a total serum B12 is not adequate to assess adequacy of functional B12.
Only about 6% to 20% of B12 is active, so within the "normal" range of total serum B12 (about 150-600 pmol/L), many people have inadequate B12. To be confident that the serum B12 is adequate, it needs to be above 400 pmol/L. Below that, it is necessary to perform confirmatory tests such as holotranscobalamin, or measurement of the metabolites that are elevated in metabolic B12 deficiency (methylmalonic acid or, in folate-replete persons, tHcy).
Metabolic B12 deficiency was present in 30% of Canadian stroke or transient ischemic attack patients over age 71 in 2006. It is much more common in other countries with a higher prevalence of vegetarianism, but seems to be less common now in my clinic population than it was in 2006.
What does all this mean? We should be using B vitamins to prevent stroke, but we should probably be using methylcobalamin or hydroxocobalamin, not cyanocobalamin.
J. David Spence, MD, is professor of neurology and clinical pharmacology at Western University in London, Ontario, and director of the Stroke Prevention and Atherosclerosis Research Centre at the Robarts Research Institute there. He is a Gold Fellow in the Stroke Council of the American Heart Association (AHA), has served on leadership committees of both that Council and the Peripheral Vascular Disease Council of the AHA, and is author of the book "How To Prevent Your Stroke" (Vanderbilt University Press, 2006) and co-editor of "Stroke Prevention, Treatment and Rehabilitation" (McGraw-Hill Medical, 2012).