Folic Acid (supplemental, 1 mg/day)

Huo et al., CSPPT (JAMA, 2015; PMID 25771069): 20,702 Chinese adults with hypertension and no history of stroke or myocardial infarction, randomized double-blind to a single pill of enalapril 10 mg with folic acid 0.8 mg or enalapril 10 mg alone for a median 4.5 years; first stroke 2.7 percent against 3.4 percent (hazard ratio 0.79, 95% CI 0.68 to 0.93). Both arms received enalapril, so the trial isolates folic acid, but only on a background of ACE inhibitor therapy and at 0.8 mg/day, a different dose from the 1 mg/day the headline grades. Participants were not selected for folate deficiency. Zhang et al. (Clin Nutr, 2024; PMID 38824900): meta-analysis of 21 randomized trials, 115,559 participants, stroke risk 10 percent lower overall; efficacy did not vary by baseline folate, and was concentrated in areas without grain fortification (RR 0.83) and in people without prior stroke or MI (RR 0.77); no effect in fortified areas (RR 1.04). Yang et al. (Front Nutr, 2024; PMID 39155933): meta-analysis of 12 primary-prevention trials, 75,042 participants, null overall (RR 0.92, 95% CI 0.80 to 1.05) and positive only without grain fortification (RR 0.78). Grade B rather than A: a hard endpoint, but the benefit is confined to unfortified populations, was tested on a background of ACE inhibitor therapy, and the primary-prevention pool is null overall. In fortified populations such as the US the pooled trials show no benefit. This does not change the base Grade D, which reflects folic acid's failure to prevent colorectal adenoma recurrence. Funding: PubMed's record of the CSPPT report lists no funder and no conflict statement; the full JAMA report was not read in this pass, and nonfinancial support from the maker of the combination pill reported in secondary sources is not asserted here.

HOPE-2 (Lonn et al., N Engl J Med, 2006; PMID 16531613): 5,522 adults aged 55 and over with vascular disease or diabetes, folic acid 2.5 mg with B6 and B12 daily for 5 years; homocysteine fell, primary events 18.8 against 19.8 percent (relative risk 0.95, 0.84 to 1.07); stroke was lower (0.75) and hospitalization for unstable angina higher (1.24). NORVIT (Bønaa et al., N Engl J Med, 2006; PMID 16531614): 3,749 patients within a week of a heart attack; folic acid with B12 had no effect (risk ratio 1.08, 0.93 to 1.25), and the three-vitamin arm trended toward harm (1.22, 1.00 to 1.50). Martí-Carvajal et al. (Cochrane Database Syst Rev, 2017; PMID 28816346), 15 trials and 71,422 participants: no effect on myocardial infarction (risk ratio 1.02) or death from any cause (1.01), with a small stroke reduction (0.90). Lowering homocysteine did not lower heart attacks or deaths: tested, no benefit. Stroke prevention is graded on its own row.