PDF: VITATOPS
(2010)Objective
To determine whether daily supplementation with folic acid, vitamin B6, and vitamin B12 reduces the risk of major vascular events in patients with recent stroke or transient ischemic attack.
Study Summary
Intervention
8164 patients with recent stroke or TIA (within 7 months) were randomized to receive either daily B vitamin supplementation (folic acid 2 mg, vitamin B6 25 mg, vitamin B12 0.5 mg) or matching placebo. Median follow-up was 3.4 years. The primary outcome was a composite of non-fatal stroke, non-fatal MI, or vascular death. Secondary outcomes included individual components, revascularization, and all-cause mortality.
Study Design
Arms: Array
Outcome
• No significant difference in stroke (RR 0.92), MI (RR 1.03), or all-cause death (RR 0.97)
• Significant reduction in vascular death (RR 0.86; p=0.04)
• Subgroup benefit in small vessel disease and intracerebral hemorrhage patients
• B vitamins reduced homocysteine by 3.8 μmol/L
• Treatment was well tolerated with no unexpected adverse events
Bottom Line
Daily administration of B vitamins (folic acid, vitamin B6, and vitamin B12) to patients with recent stroke or transient ischaemic attack was safe but not significantly more effective than placebo in reducing the incidence of major vascular events. These results do not support the routine use of B vitamins to prevent recurrent stroke, though ongoing trials and meta-analyses will provide more statistical power.
Major Points
- 8164 patients (4089 assigned to B vitamins, 4075 to placebo) with recent stroke or TIA (within past 7 months) were randomized across 123 medical centers in 20 countries.
- Patients were followed for a median duration of 3.4 years (IQR 2.0–5.5).
- The primary endpoint (composite of stroke, myocardial infarction, or vascular death) occurred in 616 (15%) patients assigned to B vitamins and 678 (17%) assigned to placebo (risk ratio [RR] 0.91, 95% CI 0.82 to 1.00, p=0.05; absolute risk reduction 1.56%, -0.01 to 3.16).
- Treatment with B vitamins was not associated with a significant reduction in RR for non-fatal or fatal stroke (p=0.25), non-fatal or fatal myocardial infarction (p=0.86), or death from any cause (p=0.49).
- However, B vitamins were associated with a significant reduction in death from vascular causes (p=0.04).
- The mean total homocysteine concentration was significantly lower in the B vitamins group at follow-up (10.5 µmol/L vs 14.3 µmol/L in placebo, difference 3.8 µmol/L, p<0.0001).
- There were no unexpected serious adverse reactions and no significant differences in common adverse effects between the treatment groups.
- The meta-analysis results updated by VITATOPS, indicate that B vitamins are not significantly more effective than control treatments in reducing composite of stroke, MI, or vascular death (RR 0.99, CI 0.94-1.03, p=0.49).
Study Design
- Study Type
- Randomised, double-blind, parallel, placebo-controlled trial
- Randomization
- Yes
- Blinding
- Patients, clinicians, carers, and investigators who assessed outcomes were masked to the assigned intervention. Data monitoring and safety committee were unmasked.
- Sample Size
- 8164
- Follow-up
- Median 3.4 years (IQR 2.0–5.5)
- Centers
- 123
- Countries
- 20 countries from four continents (e.g., Australia, Singapore, UK, India, Italy, Brazil, Canada)
Primary Outcome
Definition: Composite of non-fatal stroke, non-fatal myocardial infarction, and death attributable to vascular causes.
| Control | Intervention | HR/OR | P-value |
|---|---|---|---|
| 678 (17%) | 616 (15%) | 0.91 (0.82 to 1.00) | 0.05 |
Limitations & Criticisms
- The primary outcome had a p-value of 0.05, which is at the threshold of statistical significance, suggesting a borderline effect. The 95% CIs for the primary outcome suggest that B vitamins might reduce the risk by as much as 18% or as little as 0%, indicating the findings do not definitively confirm a clinically significant benefit.
- The actual primary outcome event rate in the placebo group (4.8% per year) was lower than expected (8.0% per year), leading to a prolonged recruitment and follow-up period and potentially diluting the observed effect.
- The high, yet similar, rates of non-adherence (discontinuation of trial drugs) and loss to follow-up (9% total loss) in each treatment group could have biased the results towards the null.
- The median duration of adherence to treatment was 2.8 years, and median follow-up was 3.4 years, which might not have been long enough to adequately identify or exclude any long-term effects of B vitamins.
- The trial was partly affected by mandatory background fortification of food with folic acid in some participating countries, potentially reducing the baseline homocysteine differences between groups.
Citation
Lancet Neurol 2010; 9: 855–65