title: Effect of B vitamins and lowering homocysteine on cognitive impairment in patients with previous stroke or transient ischemic attack: a prespecified secondary analysis of a randomized, placebo-controlled trial and meta-analysis.
abstract: OBJECTIVE
  High plasma total homocysteine (tHcy) has been associated with cognitive impairment but lowering tHcy with B-vitamins has produced equivocal results. We aimed to determine whether B-vitamin supplementation would reduce tHcy and the incidence of new cognitive impairment among individuals with stroke or transient ischemic attack≥6 months previously.
  
  
  METHODS
  A total of 8164 patients with stroke or transient ischemic attack were randomly allocated to double-blind treatment with one tablet daily of B-vitamins (folic acid, 2 mg; vitamin B6, 25 mg; vitamin B12, 500 μg) or placebo and followed up for 3.4 years (median) in the VITAmins TO Prevent Stroke (VITATOPS) trial. For this prespecified secondary analysis of VITATOPS, the primary outcome was a new diagnosis of cognitive impairment, defined as a Mini-Mental State Examination (MMSE) score<24 on ≥2 follow-up visits. Secondary outcomes were cognitive decline, and the mean tHcy and MMSE at final follow-up.
  
  
  RESULTS
  A total of 3089 participants (38%) voluntarily undertook the MMSE>6 months after the qualifying stroke; 2608 participants were cognitively unimpaired (MMSE≥24), of whom 2214 participants (1110 B-vitamins versus 1104 placebo) had follow-up MMSEs during 2.8 years (median). At final follow-up, allocation to B-vitamins, compared with placebo, was associated with a reduction in mean tHcy (10.2 μmol/L versus 14.2 μmol/L; P<0.001) but no change from baseline in the mean MMSE score (-0.22 points versus -0.25 points; difference, 0.03; 95% confidence interval, -0.13 to 0.19; P=0.726) and no difference in the incidence of cognitive impairment (5.51% versus 5.47%; risk ratio, 1.01; 95% confidence interval, 0.69-1.48; P=0.976), cognitive decline (9.1% versus 10.3%; risk ratio, 0.89; 0.67-1.18; P=0.414), or cognitive impairment or decline (11.0% versus 11.3%; risk ratio, 0.98; 0.75-1.27; P=0.855).
  
  
  CONCLUSIONS
  Daily supplementation with folic acid, vitamin B6, and vitamin B12 to a self-selected clinical trial cohort of cognitively unimpaired patients with previous stroke or transient ischemic attack lowered mean tHcy but had no effect on the incidence of cognitive impairment or cognitive decline, as measured by the MMSE, during a median of 2.8 years.
  
  
  BACKGROUND
  URL: http://www.controlled-trials.com. Unique identifier: ISRCTN74743444; URL: http://www.clinicaltrials.gov. Unique identifier: NCT00097669.
authors.affiliation: School of Medicine and Pharmacology, The University of Western Australia, Perth, Western Australia, Australia. graeme.hankey@uwa.edu.au
authors.forename: Graeme J
authors.initials: GJ
authors.lastname: Hankey
authors.forename: Andrew H
authors.initials: AH
authors.lastname: Ford
authors.forename: Qilong
authors.initials: Q
authors.lastname: Yi
authors.forename: John W
authors.initials: JW
authors.lastname: Eikelboom
authors.forename: Kennedy R
authors.initials: KR
authors.lastname: Lees
authors.forename: Christopher
authors.initials: C
authors.lastname: Chen
authors.forename: Denis
authors.initials: D
authors.lastname: Xavier
authors.forename: Jose C
authors.initials: JC
authors.lastname: Navarro
authors.forename: Udaya K
authors.initials: UK
authors.lastname: Ranawaka
authors.forename: Wasim
authors.initials: W
authors.lastname: Uddin
authors.forename: Stefano
authors.initials: S
authors.lastname: Ricci
authors.forename: John
authors.initials: J
authors.lastname: Gommans
authors.forename: Reinhold
authors.initials: R
authors.lastname: Schmidt
authors.forename: Osvaldo P
authors.initials: OP
authors.lastname: Almeida
authors.forename: Frank M
authors.initials: FM
authors.lastname: van Bockxmeer
mesh_terms: D000368:Aged; D003072:Cognition Disorders / Q000188:drug therapy* / Q000209:etiology / Q000517:prevention & control; D004311:Double-Blind Method; D005260:Female; D005500:Follow-Up Studies; D006710:Homocysteine / Q000037:antagonists & inhibitors / Q000097:blood; D006801:Humans; D002546:Ischemic Attack, Transient / Q000150:complications / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D010919:Placebos; D012008:Recurrence; D020521:Stroke / Q000150:complications / Q000188:drug therapy*; D016896:Treatment Outcome; D014805:Vitamin B 12 / Q000008:administration & dosage / Q000502:physiology; D014803:Vitamin B Complex / Q000008:administration & dosage / Q000494:pharmacology*
chemical_list: D010919:Placebos; D006710:Homocysteine; D014803:Vitamin B Complex; D014805:Vitamin B 12
keywords: clinical trial; cognitive impairment; homocysteine; vitamin B complex