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Folic acid supplementation substantially reduced primary stroke events in high-risk, enalapril-treated patients who had low platelets and elevated homocysteine compared with enalapril-treatment alone, according to Chinese researchers.

In a post-hoc analysis of over 10,000 adult participants from the China Stroke Primary Prevention Trial (CSPPT) with high blood pressure, the addition of folic acid to the blood pressure drug enalapril (Vasotec) had the greatest effect in patients at highest risk of stroke – reducing their primary stroke risk from 5.6% to 1.8%, a reduction of 73% (HR 0.27, P=0.003) -- whereas there was no significant effect among the low-risk group.

As shown in the study online in the , a total of 371 first strokes occurred during 4.2 years of follow-up. In the enalapril-only group, the lowest rate of first stroke (3.3%) was found in patients with high platelets (quartiles 2 to 4) and low total homocysteine (<15 mmol/l); and the highest rate (5.6%) was in patients with low platelets (quartile 1) and high total homocysteine (≥15 mmol/l) levels, reported Yong Huo, MD, of Peking University First Hospital, and colleagues.

"Our analysis has shown that baseline low platelet count and elevated homocysteine can jointly increase the risk of first stroke [which represent 77% of all strokes]," Huo said in a news release. "If the findings are further confirmed by prospective trials, we can raise the prospect that we can identify patients at high risk of developing first stroke by measuring both platelet and homocysteine, and we can remarkably lower stroke risk among this subgroup of patients with folic acid -- a simple, safe, and inexpensive treatment."

The main found that folic acid treatment reduced the risk of a first stroke by 21% on average in hypertensive adults by lowering total homocysteine levels, and hence, the risk for vascular disease.

While very high platelet counts seen in thrombocythemia also increase stroke risk, elevated total homocysteine may result in lower platelet counts by causing endothelial injury and increasing platelet adhesion to atherosclerotic vessels, the team explained.

In an , J. David Spence, MD, and Vladimir Hachinski, MD, both of Western University in London, Ontario, noted that in addition, "patients with lower platelet counts and higher homocysteine levels are more likely to have been at higher risk because they had vitamin B12 deficiency. Among folate-replete subjects, the main nutritional determinant of high homocysteine levels is [which is often overlooked]."

For the study, after stratification by methylenetetrahydrofolate reductase C677T genotypes (CC, CT, or TT), gene variants previously associated with stroke risk that may be modified by folate status, a total of 10,789 Chinese hypertensive adults -- mean age of 59.5, 38% male, with no history of stroke or myocardial infarction -- were randomly assigned to receive a combined daily dose of 10 mg enalapril and 0.8 mg folic acid (5,408 patients) or enalapril only (5,381).

The effect of folic acid treatment in people with low platelets remained consistent in subgroup analyses stratified by major covariables known to affect stroke risk, the group noted.

"The widespread belief that B vitamins do not reduce the risk of stroke is mistaken," Spence and Hachinski said. "This study not only invited confirmation of the benefit of B vitamins, but opens the door to wider applications ... with important implications for prevention of both stroke and dementia.

"For each clinical stroke, there are about 5 so-called 'silent strokes.' Because silent cerebrovascular disease may be much more common than clinical stroke, a study of folic acid treatment in patients with silent infarcts, low platelet count, and high homocysteine levels seems fully justified."

Noting a recent on the role of homocysteine and folic acid supplementation in dementia, the editorialists said there was a need for further studies of folate and methylcobalamin for prevention of both stroke and dementia.

While Huo and colleagues underscored that the study results should be considered hypothesis generating only, they concluded that "based on our findings, we can detect hypertensive adults at particular high risk of stroke and incorporate a folic acid supplement tailored to individual genetic, nutritional, and clinical characteristics. We are on the right path to figuring out cost-effective primary prevention strategies for stroke in China and beyond."

Regarding study limitations, the researchers noted that the research was a post-hoc analysis and thus subject to possible residual confounding. Also, additional clinical trials are needed to assess the generalizability of the findings; evaluate higher dosages of folic acid for any additional beneficial effects; examine platelet parameters during the follow-up period; and assess the utility of 5-methyltetrafolate, a more naturally occurring folate than folic acid.