Homocysteine lowering with folic acid and B vitamins in vascular disease.

Randomized, placebo-controlled, multicenter trial in adults aged 55 years or older with a history of vascular disease or diabetes plus additional atherosclerotic risk factors. The active intervention arm included 2758 participants recruited from 145 centers in 13 countries.

The active regimen was a daily oral combined pill containing folic acid 2.5 mg, vitamin B6 50 mg, and vitamin B12 1 mg, given for a mean follow-up of 5 years and compared with matching placebo.

The combination lowered homocysteine but did not reduce major vascular events overall. The primary outcome occurred in 519 participants (18.8%) in the active group versus 547 (19.8%) with placebo (relative risk 0.95; 95% CI 0.84 to 1.07; P = 0.41). Mean total plasma homocysteine fell from 12.2 to 9.7 μmol per liter in the active group, while it rose from 12.2 to 12.9 μmol per liter with placebo; the between-group difference in change was 3.2 μmol per liter at the end of the study. Stroke was reduced (111 [4.0%] vs 147 [5.3%]; RR 0.75; 95% CI 0.59 to 0.97; P = 0.03), but death from any cause was not different (470 [17.0%] vs 475 [17.2%]; RR 0.99; 95% CI 0.88 to 1.13; P = 0.94). Hospitalization for unstable angina was higher with active treatment (268 [9.7%] vs 219 [7.9%]; RR 1.24; 95% CI 1.04 to 1.49; P = 0.02).

The primary vascular outcome was negative despite clear biochemical homocysteine lowering, so the clinical benefit was limited. Follow-up averaged about 5 years, and results may differ by background folate exposure because participants came from both folate-fortified and non-fortified countries. The trial also showed mixed secondary findings, including a stroke reduction but no all-cause mortality benefit and more unstable angina hospitalizations.