Physicians' Academy for Cardiovascular Education

Folic acid treatment reduces the risk of stroke in hypertensive patients

Platelet Count Affects Efficacy of Folic Acid in Preventing First Stroke

Literature - Kong X, Huang X, Zhao M, et al. - J Am Coll Cardiol 2018;71:2136–46

Introduction and methods

The role of platelets in the pathophysiology of atherosclerosis and atherothrombosis is well understood, however, it is not clear whether platelet count (PLT) is associated with risk of stroke [1]. Low PLT has been linked to endothelial injury, for instance in the presence of elevated total homocysteine levels (tHcy) and as a consequence, higher platelet adherence [2,3]. Moreover, increased tHcy levels is a risk factor for cardiovascular (CV) disease, but there are no relevant data regarding stroke [3,4]. The China Stroke Primary Prevention Trial (CSPPT) did show, however, that folic acid treatment, known to lower tHcy, reduces the risk of first stroke by 21% in hypertensive individuals [5].

This sub-analysis of the CSPPT, therefore prospectively evaluated the association between baseline PLT and tHcy levels and first stroke risk in Chinese hypertensive adults. Moreover, the effects of folic acid administration in these patients was assessed. Out of the 20,702 CSPPT participants, after excluding those without baseline PLT and tHcy measurements, as well as those who were receiving antiplatelet medications, 10,789 patients were eligible for this analysis.

Participants were randomly assigned in a 1:1 ratio to receive either 10 mg enalapril and 0.8 mg folic acid daily (E+FA group), or 10 mg enalapril only (E group). Median follow-up was 4.2 years and the primary outcome was the occurrence of a first nonfatal or fatal stroke (ischemic or hemorrhagic), which occurred 210 times in the E group and 161 times in the E+FA group.

Main results


In Chinese patients with hypertension, the risk of first stroke varied between subgroups based on PLT and tHcy levels. The subgroup with low PLT and high tHcy at baseline had the highest risk of first stroke over a median of 4.2 years of follow-up, and this risk was reduced by 73% with folic acid treatment. In those with high PLT and low tHcy, folic acid had no effect on reducing the risk of first stroke. If confirmed, these findings can help identify patients at high risk of stroke and who would benefit most from treatment with folic acid treatment.

Editorial comment

In their editorial article, Spence and Hachinski [6] discuss the pathophysiological background of reducing stroke risk with folic acid treatment. tHcy may promote platelet adhesion and cause low platelet counts. Patients with low platelet counts and high tHcy levels may be at higher risk, due to vitamin B12 deficiency. They also emphasize that B vitamins do reduce the risk of stroke, a finding that has been found to be attenuated by renal dysfunction in early trials.

The authors conclude: ‘Recognition that folate reduces the risk of stroke in a jurisdiction where folate fortification does not exist has important implications for prevention of both stroke and dementia. The recent recognition that harm from cyanocobalamin among study participants with renal impairment obscured the benefit of B vitamins in the early studies suggests that methylcobalamin should be used instead of cyanocobalamin. Further studies of folate and methylcobalamin should be carried out for prevention of both stroke and dementia; the findings of Kong et al. provide a strong rationale for doing so.’


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