PDF: VISP
(2005)Objective
Evaluate whether high-dose multivitamin therapy with folate, B6, and B12 reduces the risk of recurrent stroke, myocardial infarction, or death in patients with a recent nondisabling stroke.
Study Summary
Intervention
Randomized, double-blind trial conducted in 3680 adults with recent nondisabling cerebral infarction. Patients were assigned to: • High-dose vitamins: folic acid 2.5 mg, B6 25 mg, B12 400 mcg daily • Low-dose vitamins: folic acid 20 mcg, B6 200 mcg, B12 6 mcg daily Trial conducted from 1996–2003 across 56 centers in the U.S., Canada, and Scotland. Subgroup analysis excluded those with low/high B12 or impaired renal function.
Study Design
Arms: Array
Outcome
• Subgroup (N=2155): 21% reduction in combined endpoint (stroke, coronary events, or death) in high-dose group; unadjusted p=0.049, adjusted p=0.056
• Benefit more pronounced in patients with B12 ≥322 pmol/L
• No increase in adverse events; dose of B12 may have been too low in elderly with absorption issues
• Trial suggested B12 status plays a key role in homocysteine reduction and vascular benefit
Bottom Line
While the original VISP trial showed no overall efficacy, an efficacy analysis of a prespecified subgroup (excluding patients with very high/low B12 and significant renal impairment) revealed a 21% reduction in the risk of combined ischemic stroke, coronary disease, or death in the high-dose vitamin group. This suggests B12 status is a key determinant of response to vitamin therapy in the era of folate fortification, potentially requiring higher B12 doses for some patients.
Major Points
- The original VISP trial was stopped due to futility, showing a very small difference in outcomes between high-dose and low-dose vitamin therapy.
- This efficacy analysis focused on a subgroup of 2155 patients (mean age 66±10.7 years) who were most likely to benefit, defined by GFR ≥46.18 and serum B12 levels between 250 and 637 pmol/L (25th to 95th percentiles).
- For the combined end point of ischemic stroke, coronary disease, or death, there was a 21% reduction in risk in the high-dose group compared with the low-dose group (unadjusted P=0.049; adjusted P=0.056).
- Kaplan-Meier analysis showed that patients with baseline B12 at or above the median (322 pmol/L) randomized to high-dose vitamin had the best overall outcome, while those with B12 less than the median assigned to low-dose had the worst (P=0.02 for combined stroke, death, and coronary events; P=0.03 for stroke and coronary events).
- Plasma total homocysteine (tHcy) significantly rises as serum B12 falls, from levels above the median (322 pmol/L), suggesting B12 levels sufficient to maintain low tHcy are higher than usually considered normal.
- The study highlights that in the era of folate fortification, B12 plays a key role in vitamin therapy for total homocysteine, and higher doses may be needed for some patients.
Study Design
- Study Type
- Randomized, double-blind trial (efficacy analysis of a subgroup)
- Randomization
- Yes
- Blinding
- Double-blind
- Sample Size
- 3680
- Centers
- 56
- Countries
- United States, Canada, Scotland
Primary Outcome
Definition: Combined endpoint of ischemic stroke, coronary disease, or death.
| Control | Intervention | HR/OR | P-value |
|---|---|---|---|
| - | - | 0.79 (0.63-1.00) | 0.049 (unadjusted); 0.056 (adjusted) |
Limitations & Criticisms
- This is a post hoc subgroup analysis of a randomized trial that originally showed futility, and thus results must be interpreted with considerable caution. While the subgroup definition was based on a priori hypotheses and applied only once, the risk of selection bias remains inherent in such analyses.
- The primary outcome was of borderline statistical significance (P=0.049 unadjusted; P=0.056 adjusted), which is a weak finding.
- The study was conducted during the era of folate fortification in North America, which may have reduced the number of patients with high tHcy who might benefit most from supplementation.
- The dose of B12 (400 mcg/day) used in the high-dose arm might have been too low for elderly patients with impaired absorption, as suggested by later studies recommending 1000 mcg/day for adequate absorption.
- The subgroup analysis found a greater benefit in a subgroup that had lower baseline tHcy than the main study, which is somewhat counterintuitive if the primary mechanism is tHcy lowering.
- The study found no significant relationship between the magnitude of tHcy reduction and subsequent cardiovascular events, which is surprising given the hypothesized mechanism.
Citation
Stroke. 2005;36:2404-2409.