The rationale, methods, CONSORT flowchart and primary results of the VITATOPS trial have been published
[25, 26]. In summary, VITATOPS was an investigator-led, prospective, randomised, double-blind, placebo-controlled trial in which 8164 patients with recent (within seven months) stroke or transient ischemic attack (TIA) were recruited between November 19 1998 and December 31 2008, and randomly assigned to receive either one tablet daily of B-vitamins (folic acid 2 mg, vitamin B6 25 mg, vitamin B12 500 μg) or matching placebo. Final follow-up was 30 June 2009 ensuring a minimum six months and up to 10.5 years on study medication.
The study was conducted in accordance with principles of good clinical practice and the Declaration of Helsinki, and received ethics approval in the United Kingdom from the Multicentre Research Ethics Committee for Scotland A, in New Zealand from the Multi-region Ethics Committee and from local research ethics committees applicable to each participating centre. A full list of the 127 participating centres is available in an additional file [see Additional file
1]. All patients provided written informed consent before enrolment.
Demographic and clinical characteristics of the participants recorded at baseline included; age, sex, ethnicity (of participants and their parents and grandparents), clinical details of the qualifying cerebrovascular event, current medications, past medical history (major vascular events, revascularisation procedures, depression), vascular risk factors (hypertension, smoking, hypercholesterolaemia, diabetes mellitus, ischaemic heart disease, atrial fibrillation, peripheral artery disease), alcohol intake, Oxford Handicap Score, Hospital Anxiety and Depression Score, and Mini Mental State Examination score. Cox’s proportional hazards models were used to adjust for differences in baseline variables.
Investigators were encouraged but not obligated to take blood samples from study participants who consented to these optional tests, to measure blood concentrations of tHcy, red cell folate and vitamin B12 at study entry and/or at the time of their final follow-up visit. Fasting plasma tHcy was measured by high-performance liquid chromatography, on venous blood samples collected after an overnight fast.
The primary outcome measure for the main VITATOPS study was the composite of any stroke, myocardial infarction or death due to vascular causes. In this substudy the main outcome measure was occurrence of any clinically apparent osteoporotic fracture. Osteoporotic hip fractures and time till first fracture were secondary outcome measures. Non-osteoporotic fractures were excluded from analysis.
Patients were reviewed six-monthly and data on clinical fracture outcomes were based on information obtained from clinical history, radiology reports, hospital discharge reports and health records. All hospitalisations including those for fracture were recorded prospectively, and from 2004 (following publication of the potential association between homocysteine and fracture risk
) until the end of the trial in June 2009 all clinically apparent fractures whether hospitalised or not, were recorded prospectively.
A masked adjudication committee audited all fractures. Fractures were classified as osteoporotic if they were reported to be osteoporotic by the investigator; and involved the hip (neck of femur), wrist (distal radius) or spine (vertebral), or occurred spontaneously or in the context of minor trauma; and if there was no other apparent cause (e.g. severe trauma, metastatic cancer).
The primary statistical analysis for this substudy was an intention-to-treat analysis of the incidence of any osteoporotic fracture in the placebo and B-vitamin treatment groups over the duration of follow-up. This was added to the pre-established analysis plan in 2004. A secondary per protocol on-treatment analysis would exclude any patients found to be invalid after randomisation or who had cross-over in treatment during follow-up.
The event rates were calculated as the number of events that occurred during the follow-up period divided by the total number of patients randomised. The risk ratios (treatment/placebo) of the fracture rates in the treatment and placebo groups and their 95% confidence intervals were calculated to describe the treatment effect. We used Kaplan-Meier methods to construct cumulative time-to-event curves for the two groups and the main comparison was based on a log-rank test.
We did stepwise logistic multivariable regression analysis to determine the independent risk factors for osteoporotic fracture in the study population.
Two sided significance tests were used throughout and a two-sided p-value < 0.05 was considered significant.