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. 2018 Dec 17;2018(12):CD011906. doi: 10.1002/14651858.CD011906.pub2

Toole 2004.

Methods 2‐arm, parallel group, double‐blind, randomised controlled trial (the Vitamin Intervention for Stroke Prevention (VISP) Trial)
Participants Location: 56 centres in USA, Canada and Scotland
Recruitment: university‐affiliated hospitals, community hospitals, private neurology practices, and Veterans Affairs medical centres
Number randomised: 3680 (1853 in low‐dose vitamin group, 1827 in high‐dose vitamin group)
Participant (baseline) characteristics:

  • Age, mean (SD):

    • low‐dose: 66.2 (10.8)

    • high‐dose: 66.4 (10.8)

  • Gender:

    • low‐dose: 37.2% female

    • high‐dose: 37.7% female

  • Baseline cognitive function, MMSE mean (SD):

    • low‐dose: 26.9 (3.3)

    • high‐dose: 26.9 (3.4)


Inclusion criteria: non‐disabling ischaemic stroke (Modified Rankin Stroke Scale ≤ 3) with onset ≤ 120 days before randomisation; total homocysteine level ≥ 25th percentile for North American stroke population; age ≥ 35 years, compliance ≥ 75% with low‐dose vitamins for 1 month before randomisation
Exclusion criteria: potential sources of emboli, other major neurological illness, life expectancy < 2 years, untreated anaemia or untreated B12 deficiency, systolic blood pressure > 185 mmHg or diastolic blood pressure > 105 mmHg, refractor depression, severe cognitive impairment, alcoholism or other substance abuse, use within 30 days of medications that affect total homocysteine level, childbearing potential, participation in another trial with active intervention, general anaesthesia or hospital stay of ≥ 3 days, invasive cardiac or carotid procedures within 30 days of randomisation
Interventions Intervention (n=1827)
High‐dose multivitamin formulation contained the reference daily intakes recommended by the US Food and Drug Administration for vitamins except for its content of folic acid, vitamin B6 and vitamin B12. Folic acid 2.5 mg, vitamin B6 25 mg, vitamin B12 0.4 mg.
Comparator (n=1853)
Low‐dose multivitamin formulation contained the reference daily intakes recommended by the US Food and Drug Administration for vitamins (contained folic acid 20 μg, vitamin B6 0.2 mg, vitamin B12 6 μg)
Outcomes Outcomes relevant to review:
mean MMSE at 1‐year follow‐up
Notes "All eligible participants were given the low‐dose vitamin formulation for 1 month to determine compliance, assessed by pill counts. Only persons taking at least 75% of the vitamins during the run‐in phase were eligible to be randomized."
Risk of bias
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Low risk Quote: "Participants were randomized to the high‐dose or low‐dose vitamin groups within strata defined by clinic, sex and age (≥ 70 years, < 70 years). Permuted block randomization (with block size randomly selected as 4 or 6) was used."
Allocation concealment (selection bias) Low risk Quote: "The allocation of participants was programmed by the statistical coordinating center, encrypted, and entered into a data entry program installed on a study computer at each site. After computer verification that all eligibility criteria had been met, participants were randomly assigned 1 of 20 medication codes. Allocation information was accessible only to the drug distribution center, which bottled and distributed the vitamins to clinics, and to selected coordinating center personnel who could assist with randomization in case of computer failure."
Blinding of participants and personnel (performance bias) 
 All outcomes Low risk Quote: "Both pill formulations were manufactured (Magno‐Humphries Laboratories, Tigard, Ore) to be indistinguishable by external colour, weight or dissolution in water. No request was ever made to break the blind."
Blinding of outcome assessment (detection bias) 
 All outcomes Low risk Quote: "Both pill formulations were manufactured (Magno‐Humphries Laboratories, Tigard, Ore) to be indistinguishable by external colour, weight or dissolution in water. No request was ever made to break the blind." No information specifically on site investigators. Blind probably maintained.
Incomplete outcome data (attrition bias) 
 All outcomes Unclear risk Mean MMSE score available for 3097/3680 (84.2%) participants at 1‐year follow‐up. No information on missing participants, including group allocation.
Selective reporting (reporting bias) High risk Protocol‐specified MMSE at 24 months not reported. Number of participants with MMSE score in each treatment group at 12 months not reported.
Other bias Low risk No other risks identified