Vitamin Mortality Meta-Analyses

Randomized and controlled primary or secondary prevention trials were considered appropriate for review. To limit heterogeneity between the included trials, the following inclusion criteria were enforced: the trial must have been randomized and controlled, the participants must have been supplemented with a daily MVMM formulation in at least one study arm, the MVMM must have been taken orally and administered as a monotherapy within the treatment arm, the supplementation must have taken place for $1 y, and the cohort must not have been institutionalized or have had a terminal illness (tertiary prevention). Furthermore, each trial must have reported on the number of deaths in both the control and MVMM groups, or these data must have been made available on request. As recommended (14, 15), studies without deaths were excluded from the analyses

Studies were included if they met the following criteria: 1) randomized controlled design (identical placebo or no intervention) or trials of one supplement compared with another; 2) minimum intervention period of 12 mo; 3) primary prevention trial (defined as trials with the first occurrence of a chronic disease as the primary outcome); 4) mean age ≥18 y; 5) an intervention that used dietary supplements defined according to the Directive 2002/46/EC of the European Parliament and of the Council of 10 June 2002. The following dietary supplements were included according to previous systematic reviews and meta-analyses on dietary supplements and chronic diseases (9, 12, 16): vitamins [β-carotene; vitamins A, E, C (ascorbic acid), and D (cholecalciferol, ergocalciferol)]; B vitamins (thiamin, riboflavin, niacin, pyridoxine, cobalamin, folic acid); supplements containing a combination of different vitamins; FAs (n–3 FAs [EPA, DHA, α-linolenic acid (18:3n−3)]; n–6 FAs [linoleic acid (18:2n−6)]; monounsaturated fat (olive oil); minerals (magnesium, calcium, selenium, potassium, iron, zinc, copper, iodine); multiminerals; supplements containing combinations of both vitamins and minerals; protein (amino acids); fiber (psyllium, inulin, cellulose); probiotics; prebiotics; and synbiotics; 6) oral intake (modalities of supplement intake such as liquid, pill, capsule, tablet, drops, ampoule, powdered); and 7) assessment of clinical outcomes (“primary”: all-cause mortality; “secondary”: cardiovascular mortality, cancer mortality, cardiovascular incidence, and cancer incidence).

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The exclusion criteria were as follows: 1) studies with a dietary or drug co-intervention that was not applied in all intervention or placebo and control groups; 2) studies with intravenous or parenteral administration of vitamins or minerals; 3) pregnant or lactating women; 4) mean age ≥70 y; 5) >75% of sample size assigned to secondary prevention trials [defined as trials undertaken to prevent recurrences or exacerbations of a disease that has already been diagnosed, such as in cancer survivors; survivors of myocardial infarction, stable or unstable angina pectoris, acute coronary insufficiency, coronary artery disease (verified by coronary angiography), stroke, hemodialysis, or chronic kidney disease; and subjects with the following diseases: gastrointestinal, neurological, ocular, dermatologic, rheumatoid, endocrinologic]; and 6) follow-up time not reported.

To be included, studies had to be a RCT providing information on the effect of vitamin D supplementation (with or without calcium supplementation) on total cancer incidence or mortality. When there were several publications from the same trial, the publication most fully covering the intervention period was selected.

We excluded cluster randomised trials, trials of hydroxylated vitamin D or vitamin D analogues, trials that included other interventions only in the vitamin D group, trials of fortified dairy products, and trials in populations with chronic comorbidity other than osteoporosis or frailty (appendix).

Types of studies. Randomized controlled trials evaluating an intervention with vitamin D were identified as part of the review, while review articles, commentaries, letters, observational studies were excluded.

Interventions. The intervention group was restricted to vitamin D alone or in combination with calcium treatment; the control group was placebo, no treatment or calcium only therapy. Studies of patients receiving active vitamin D and intramuscular injection of vitamin D were excluded from the review.

Outcome. The number of deaths was reported separately for the vitamin D treatment group and the control group. For articles with a large sample size, if the number of deaths was not reported by treatment, we tried to contact the authors to obtain the missing data.

Publications had to include patients ≥65 years of age who had ≥1 recorded measurement of 25(OH)D or were receiving vitamin D supplementation.

For an article to be included in our analysis, it must have met the following criteria:

1. To represent the principal published report on a randomized controlled trial evaluating an intervention with vitamin D. The addition of calcium supplements in the intervention group and the absence of a placebo for vitamin D in the control group (ie, an open-label trial) were not exclusion criteria.
2. To be independent from other studies to avoid giving double weight to estimates derived from the same trial.
3. To have deaths from any cause reported separately for the intervention and the control groups. If in an article the number of all-cause deaths was not reported by treatment group, we tried to contact corresponding authors to obtain the missing information.
4. To have subjects randomized to the intervention and control groups on an individual basis. Cluster randomization (eg, a nursing home taken as a randomization unit) was not valid because mortality in a specific cluster could be increased by a health event (eg, an influenza epidemic) affecting this cluster and not the others.
5. To have sufficient information to allow adequate estimation of the relative risks (RRs) and 95% confidence intervals (CIs) (ie, crude data or adjusted RRs and standard errors, 95% CIs, or P values) to estimate mortality risk after vitamin D intake vs placebo or control.

We only considered studies that followed up subjects for at least 1 year. Cohort studies had to include estimates of dietary intake using conventional dietary assessment tools (eg, food frequency questionnaires, food records, or 24-hour diet recall). Clinical trials had to be randomized and to compare dietary exposure with a control diet or a placebo. Crossover trials were excluded if plasma biomarkers or atherosclerotic indicators were not evaluated because coronary outcomes occurring after a crossover would be difficult to interpret.

To be included, studies had to meet pre-specified selection criteria as follow.

1. Be a randomised, placebo-controlled trial with
   • an intervention period of ≥6 months;
   • no intervention co-supplements, i.e. other antioxidants or medications, concurrently with vitamin E unless balanced by a corresponding control arm that also included the additional antioxidant, supplement or medication
2. Investigate the effect of any dose of synthetic (dl-alphatocopherol) or natural (d-alpha-tocopherol) oral vitamin E supplementation;
3. Include adult men and/or non-pregnant women;
4. Trial participants must be in good general health. On this basis, we included the following:
   • Trials in which participants were recruited from the general population;
   • Trials in which participants had non-systemic medical conditions, such as knee osteoarthritis;
   • Trials in which otherwise healthy participants had risk factors for CVD, such as smoking, hypercholesterolaemia or atherosclerosis;
   • Trials in which participants had chronic conditions, such as diabetes mellitus without serious comorbidities or complications.
5. Be undertaken in highly or very highly developed countries, defined according to the United Nations Human Development Index;
6. The number of deaths was available for intervention and control groups, and mortality was either a pre-specified primary or secondary outcome, or the methods indicated complete follow-up of participants or full ascertainment of deaths.

The following types of trials were excluded:

• Trials that selected patients on the basis of having a serious disease that may result in lower life expectancy, such as cancer, recent myocardial infarction, chronic infectious disease, Alzheimer’s disease or end stage renal disease;
• Trials undertaken in developing countries, due to the higher likelihood of participants having underlying nutritional deficiencies;
• Trials where no deaths were reported.

Randomised controlled trials (RCTs) and cluster-RCTs evaluating the effect of synthetic VAS in children aged six months to five years living in the community. We excluded studies involving children in hospital and children with disease or infection. We also excluded studies evaluating the effects of food fortification, consumption of vitamin A rich foods, or beta-carotene supplementation.

A report was dropped from further analysis if the study did not include concurrent controls or contained no original data or if the report did not address mortality, respiratory disease, or diarrhoea. Several trials that looked at cancer prevention were not considered within the scope of this analysis. On the basis of these initial broad criteria, clearly irrelevant articles were discarded after consideration by a single reviewer.

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Papers that did not include a control group, were not randomised, did not allow calculation of "intention to treat" results, or did not collect information on mortality or the incidence of respiratory or gastrointestinal infection were excluded.

Types of trials—Randomised controlled trials including cluster trials and factorial trials were included irrespective of publication status or language.

Types of participants—At the time of recruitment, children had to be aged 6 months to 5 years and apparently healthy. Children in hospital at the time of recruitment were excluded.

Types of interventions—Included studies examined synthetic oral vitamin A supplementation compared with no treatment or placebo, irrespective of dose or frequency. Studies of food fortification and β carotene supplementation were excluded as their effects can differ.

Studies were eligible for inclusion if (1) the study design was a randomized controlled trial; (2) the relative risk (RR) or the number of events for CVD, coronary heart disease (CHD), stroke, and/or all-cause mortality that occurred during the study was reported by intervention and control groups; (3) the intervention was B vitamins; and (4) there was no limitation on the intervention duration.

We included trials with the following features:

1. Type of trials: randomized controlled clinical trials and retrospective studies.
2. Population: trials included adult population with sepsis or septic shock.
3. Intervention: patients submitted to vitamin C for sepsis therapy.
4. Comparison: placebo for sepsis therapy.
5. Outcome: the primary outcome was 28-day mortality.

Trials with the following features were excluded:

1. They were not published in English.
2. They were not published as original articles.
3. They did not use adult patients.
4. They did not administrate vitamin C for sepsis therapy.
5. They included no data on mortality in patients with sepsis or septic shock.
6. Full-text articles were not available.

We included only RCTs that both reported the efficacy of vitamin C supplementation on cancer prevention and compared an intervention group with a control group. The main outcome measures included cancer incidence and mortality.