Background - In observational studies, 3-4µmol/L lower blood homocysteine is associated with 10% proportionally lower risk of CHD and 20% lower risk of stroke. Randomized trials have not yet provided convincing evidence that lowering blood homocysteine levels with folic acid reduces cardiovascular events. Large long-term randomized trials of folic acid supplementation are needed to assess the balance of efficacy and safety reliably.
Methods and results - Between Sept 1998 and Oct 2001, 12,064 MI survivors from 88 UK hospitals were randomly allocated folic acid 2mg plus vitamin B12 1mg daily versus matching placebo. Follow-up was at 2, 4, 8 and 12 months, and then 6-monthly, for a mean of 6.7 (SD 1.5) years. Allocation to folic acid and vitamin B12 yielded reductions in homocysteine levels of 3.9µmol/L at 1 year and of 3.6µmol/L over the whole trial period. The prespecified primary outcome was MVE, which was defined as non-fatal MI, coronary death or coronary revascularisation (major coronary event: MCE), any type of stroke, or any non-coronary revascularisation. MVEs were recorded among 1537 (25.5%) patients allocated folic acid and vitamin B12 versus 1492 (24.7%) allocated placebo corresponding to a risk ratio of 1.04 (95%CI 0.97-1.12). MCEs were recorded among 20.4% vs 19.6% of the participants; stroke among 4.5% vs 4.4%; and non-coronary revascularisation among 3.0% vs 2.5%. No significant differences were observed in vascular (9.5% vs 9.0%) or non-vascular (6.8% vs 6.7%) mortality, or in cancer incidence overall (11.2% vs 10.5%) or at any particular site. As well as considering other serious adverse events, the effects on cognitive function and hearing were assessed.
Conclusion - SEARCH is the largest randomized trial to assess the effects of homocysteine-lowering treatment. Despite maintaining a 3-4µmol/L lower homocysteine levels for 6.7 years, there were no significant effects on the incidence of any type of vascular event, cancer or other major outcome. These results are consistent with results reported previously from smaller and less prolonged trials. They indicate that widespread folic acid supplementation (in order to avoid neural tube defects) through fortification of flour is safe, but will not materially affect vascular disease or cancer.
Hypothesis and Purpose: SEARCH aims to demonstrate reliably whether homocysteine lowering with 2mg folic acid plus 1mg vitamin B12 reduces cardiovascular risk. Study Design and Methods: Randomized controlled UK based multicentre trial Sample Size: 12064 patients with a history of myocardial infarction Population Studied: men and women aged 40 to 80 years with a history of myocardial infarction Intervention(s): Folic acid 2mg plus 1 mg vitamin B12 daily or matching placebo tablets Power Calculations: With 2800 primary events there is 90% power at p<0.05 to detect a difference of 10% in the primary endpoint. Primary End Points Major vascular events (MVE) defined as: non-fatal myocardial infarction or coronary death, any stroke or any arterial revascularisation. Secondary End Points MVEs separately in the first year after randomization and in the later years of the scheduled treatment period; MVEs among patients subdivided into 3 similar sized groups with respect to plasma folate levels and blood homocysteine levels at the end of the pre-randomization run-in period; MVEs in the presence and absence of the each simvastatin dose; major coronary events defined as non-fatal myocardial infarction or coronary death or any coronary revascularisation procedure; and total strokes. Outcome(s)[Statistical Plan or Main Results]: The plan is to compare the primary and other outcomes in all randomized patients in their originally allocated group, irrespective of compliance during the scheduled treatment period. All time to event analyses will be based on the first relevant event and will use log-rank methods to produce p values and cox regression analyses to calculate odds ratios and confidence intervals.