Effect of multivitamin and multimineral supplements on morbidity from infections in older people (MAVIS trial): pragmatic, randomised, double blind, placebo controlled trial
BMJ 2005; 331 doi: https://doi.org/10.1136/bmj.331.7512.324 (Published 04 August 2005) Cite this as: BMJ 2005;331:324All rapid responses
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Avenell et al. reported the results of a multivitamin-multimineral
trial on infections in 910 participants aged 65 or over (1). Their
supplement contained 10 mg/day of vitamin E and 60 mg/day of vitamin C. In
their discussion, Avenell et al. commented briefly the findings of two
trials that examined the effect of 200 mg/day of vitamin E on respiratory
infections in 652 participants aged 60 years or over (2), and in 617
participants aged 65 or over (3). Avenell did not refer to our analysis of
the Alpha-Tocopherol Beta-Carotene (ATBC) Study participants aged 65 or
over, even though this subgroup consisted of 2,005 people (4), which is a
substantially larger study population compared with the cited vitamin E
trials. We found that 4-year supplementation of 50 mg/day of vitamin E
reduced common cold incidence among city-dwellers smoking 5-14 cigarettes
per day (Relative Risk [RR] = 0.72; 95% CI: 0.62-0.83), but had no effect
on those living out of cities or smoking more (RR = 0.99; 95% CI: 0.94-
1.05)(4). These confidence intervals are so divergent that they imply
heterogeneity in the effects of vitamin E supplementation in elderly
people.
Strong evidence of heterogeneity was also found in the effect of
vitamin E on pneumonia incidence in the ATBC Study (5), and in a few meta-
analyses of the effect of vitamin C on common cold incidence (6,7) but
these analyses were not focused on elderly people. Furthermore, the
statistically significant increase in the number of elderly participants
with fever in the vitamin E group (P = 0.009) of the Graat et al. trial
(2) indicates that the question is not just whether vitamin E is
ineffective or beneficial, but it may also be harmful in some population
groups. Heterogeneity in the effects of vitamins E and C is fundamentally
important since it restricts broad generalizations from individual trials
irrespective of whether the finding is positive or negative, and whether
or not the trial is large and carefully conducted.
The doses of vitamins E and C were very low in Avenell’s trial in
comparison with the previous trials, and therefore the absence of any
effect is not informative as regards these two vitamins. Also, the study
population in Avenell’s trial is so small that there would be low
statistical power to explore potential subgroup differences even if the
doses of these vitamins had been higher. For such reasons, Avenell’s trial
does not add to our understanding about the possible effects of vitamins E
and C on infections.
Finally, Avenell et al. (1) misrepresented the findings of the
Meydani et al. trial (3), since Meydani did not find credible evidence for
beneficial effects of vitamin E on respiratory tract infections. In their
intention to treat analysis (Table 3 of ref. 3), Meydani calculated 13
different P-values and only one of them was lower than 0.05, and even that
one was only marginally significant (P = 0.048 for the "no. of
participants with ≥1 respiratory infection"). In a series of 20
random events, we are expecting, on average, one P-value lower than 0.05
and therefore a single marginally significant difference in a series of 13
calculations is not evidence of a treatment effect.
1. Avenell A, Campbell MK, Cook JA, et al. Effect of multivitamin and
multimineral supplements on morbidity from infections in older people. BMJ
2005;331:324-9.
2. Graat JM, Schouten EG, Kok FJ. Effect of daily vitamin E and
multivitamin-mineral supplementation on acute respiratory tract infections
in elderly persons. JAMA 2002;288:715-21.
3. Meydani SN, Leka LS, Fine BC, et al. Vitamin E and respiratory
tract infections in elderly nursing home residents. JAMA 2004;292:828-36.
4. Hemilä H, Kaprio J, Albanes D, Heinonen OP, Virtamo J. Vitamin C,
vitamin E, and beta-carotene in relation to common cold incidence in male
smokers. Epidemiology 2002;13:32-7.
5. Hemilä H, Virtamo J, Albanes D, Kaprio J. Vitamin E and beta-
carotene supplementation and hospital-treated pneumonia incidence in male
smokers. Chest 2004;125:557-65.
6. Hemilä H. Vitamin C intake and susceptibility to the common cold.
Br J Nutr 1997;77:59-72. [comments in: Br J Nutr 1997;78:857-66.]
7. Douglas RM, Hemilä H. Vitamin C for preventing and treating the
common cold. PLoS Med 2005;2:e168.
Competing interests:
None declared
Competing interests: No competing interests
Dear Sirs,
Following recent European directives tightening the sales of vitamins
and minerals, the pragmatic MAVIS trial provides further insight into
which individuals are unlikely to benefit from micronutrient
supplementation.[1] This study follows the similarly neutral results of
large studies examining isolated and combined vitamin therapy in patients
with coronary artery disease.[2][3]
However, patients with chronic multi-system illnesses such as chronic
heart failure (CHF) might be more likely to have important relative
deficiencies in multiple micronutrients due to reduced intake, increased
degradation because of metabolic stress and increased excretion.[4] In
such patients, single agent supplementation might be ineffective or
exacerbate deficiencies elsewhere with no overall change in status.
Furthermore, the potential benefits of micronutrient supplementation in
CHF given high readmissions rates, poor overall quality of life and
persistent symptoms are significant.[4]
We recently published a randomized placebo-controlled pilot study in
elderly patients with severe heart failure describing improvements in
symptoms, quality of life and left ventricular function with high-dose
multiple micronutrient supplementation.[5] Multiple micronutrient
supplements also appear to improve left ventricular function in patients
with CHF awaiting revascularisation.[6] Perhaps the lack of clear benefits
from micronutrient therapy in other groups reflects either the strategy of
single agent supplementation or the low relative risk of the populations
studied. This is one example where the traditional ’silver-bullet’
approach to therapy is counter-productive, although more likely to receive
research funding.
Sincerely,
Klaus K Witte MD, MRCP (UK)
Fellow in Cardiology,
University Health Network,
Mount Sinai Hospital,
University Avenue,
Toronto, ON,
Canada, M5J 1X5
Andrew L Clark MA, MD, FRCP
Reader and Honorary Consultant Cardiologist
Castle Hill Hospital
Castle Road, Cottingham
HU16 5JQ
John GF Cleland FRCP, FACC
Professor of Cardiology,
University of Hull,
Castle Hill Hospital,
Castle Road, Cottingham,
HU16 5JQ
1) Avenell A, Campbell MK, Cook JA, Hannaford PC, Kilonzo MM, McNeill
G, Milne AC, Ramsay CR, Seymour DG, Stephen AI, Vale LD. Effect of
multivitamin and multimineral supplements on morbidity from infections in
older people (MAVIS trial): pragmatic, randomised, double blind, placebo
controlled trial. BMJ. 2005;331:324-9
2) Collins R, Armitage J, Parish S, Sleigh P, Peto R; Heart
Protection Study Collaborative Group. MRC/BHF Heart Protection Study of
cholesterol-lowering with simvastatin in 5963 people with diabetes: a
randomised placebo-controlled trial. Lancet 2003;361:2005-16
3) Lonn E, Bosch J, Yusuf S, Sheridan P, Pogue J, Arnold JM, Ross C,
Arnold A, Sleight P, Probstfield J, Dagenais GR; HOPE and HOPE-TOO Trial
Investigators. Effects of long-term vitamin E supplementation on
cardiovascular events and cancer: a randomized controlled trial. JAMA
2005;293:1338-47
4) Witte KK, Clark AL, Cleland JG. Chronic heart failure and
micronutrients. J Am Coll Cardiol 2001;37:1765-74
5) Witte KK, Nikitin NP, Parker AC, von Haehling S, Volk HD, Anker
SD, Clark AL, Cleland JG. The effect of micronutrient supplementation on
quality-of-life and left ventricular function in elderly patients with
chronic heart failure. Eur Heart J 2005; [Epub ahead of print]
6) Jeejeebhoy F, Keith M, Freeman M, Barr A, McCall M, Kurian R,
Mazer D, Errett L. Nutritional supplementation with MyoVive repletes
essential cardiac myocyte nutrients and reduces left ventricular size in
patients with left ventricular dysfunction. Am Heart J 2002;143:1092-100
Competing interests:
None declared
Competing interests: No competing interests
Alison Avenell and the large group of investigators have done a good
trial of a commercially available nutritional supplement and the study
results are well reported. The main problems with the investigation are
several-fold and explain the non-beneficial results obtained: (i) The
composition of the supplement was not logical; it contained amounts of
vitamins and minerals that were not based on prior research, and some
effective ones like selenium and beta-carotene were not present. (ii) The
assessment criteria for nutrition and infection were subjective, rather
than objective. (iii) Selection criteria of subjects was not perfect,
since some individuals had been on supplements just over one month prior
to inclusion rather than at least 3 months. (iv) Analyses should have
focussed more on subgroups at low and high risk of nutritional
deficiencies.
Many of the above points are highlighted in a few recent reviews
(1,2). Mitchell et al concluded that 'Multinutrient supplementation has a
significant positive correlation with immune measures' and that
multinutrient supplements are to be preferred rather than a single
nutrient because single nutrient deficiencies in the elderly are rare and
'it is not practical to identify and supplement each nutrient deficiency'
(1). The composition that has been found to be the most beneficial (3-7)
was based on dose-response curves presented by Chandra at the
International Congress of Nutrition in Adelaide in 1993. His citation
classic study (4)used amounts of vitamins and trace elements that gave an
optimum immune response and not-unexpectedly the combination boosted
immunity and reduced the occurrence of common infections that were
documented by physical examination and appropriate laboratory tests.
Combinations that are conjectural or based on Recommended Dietary
Allowances were found to be non-beneficial (1,3,8-10).
The use of an optimum micronutrient supplement based on dose-response
curves has been recognized to have considerable cost-effective benefits,
including reduction in admissions to institutions because of pneumonia and
heart disease (11).
(1) Mitchell BL, BL, Ulrich CM, McTierman A. Supplementation with
vitamins or minerals and immune function. Can the elderly benefit? Nutr
Res 2003;23:000.
(2) Chandra RK.Impact of nutritional status and nutrient supplements
on immune responses and incidence of infection in older individuals.
Ageing Res Rev 2004;3:91-104.
(3) El-Kadiki A, Sutton AJ. Role of multivitamins and mineral
supplements in preventing infections in elderly people:systematic review
and meta-analysis of randomised controlled trials. BMJ 2005;330:871-4.
(4) Chandra RK. Effect of vitamin and trace-element supplementation
on immune responses and infection in elderly subjects. Lancet
1992;340:1124-7.
(5) Jain AL. Influence of vitamins and trace-elements on the
incidence of respiratory infection in the elderly. Nutr Res 2002;22:85-7.
(6) Chandra RK. Influence of multinutrient supplement on immune
responses and infection-related illness in 50-65 old individuals. Nutr Res
2002;22:5-11.
(7) Bergmann F. Micronutrient supplement reduced respiratory
infections. Intl Cong Nutr 2005.
(8)Graat JM, Schouten EG, Kok FJ. Effect of daily vitamin E and
multivitamin-mineral supplementation on acute respiratory tract infection
on elderly persons. JAMA 2002;288:715-21.
(9) Barringer TA, Kirk JK, Santaniello AC, Foley KL, Michieulutte R.
Effect of multivitamin and mineral supplement on infection and quality of
life. Ann Intern Med 2003;138:365-71.
(10) Avenell A, Campbell MK, Cook JA, et al. Effect of multivitamin
and multimineral supplements on morbidity from infections in older people.
BMJ 2005;331:324-9.
(11). Blumberg J, Heber D, eds. Multivitamins and public
health;exploring the evidence. New York, BioScience Communications, 2004.
Competing interests:
None declared
Competing interests: No competing interests
The article by Avenell et al. raises several questions. First, it
appears that individuals were permitted in the study who had taken vitamin
supplements up to 1 month prior to beginning of the trial. Can information
on prior supplement use be provided? Assuming that more health conscious
individuals participated in the study, this proportion may be quite high,
reducing the ability to evaluate higher risk individuals.
Second, why were no biomarkers measured, at least in a subset, to
evaluate the nutritional status of the participants?
Third, the authors describe the use of a Nutrition Assessment
questionnaire for evaluating who was at "high risk" of nutrient
deficiencies. Whereas some questions seem reasonable, a substantial
proportion of the score seems to be derived from questions such as "Have
you had a sunny holiday in the last 6 months" (scoring for FOLATE, NOT
Vitamin D), or "How many social activities do you have each week?"
(scoring for folate and vitamin D). It would be useful to know how such
an instrument relates to biomarkers in the population of study (e.g., over
age 65, free living). Most likely it is a very crude tool to define "high
risk status".
Fourth, the authors state that there were no differences in effect
based on prior high-risk status at study entry, yet fail to mention that
among those at high nutritional risk the median number of days of
infection were 7.5 in the supplement group and 13.0 in the placebo group.
Whereas the p-value for interaction was not significant, it would be worth
adding a p-value for the intervention effect specifically within the high-
risk group. Considering the poor assessment of "high-risk status" it is
interesting that there appears to be an intervention effect. This
potential effect could be stronger if "high-risk status" was defined by
better indicators.
Fifth, it would be helpful if the instrument for assessment of self-
reported infections (diary) was published online. There was apparently too
little variability in the outcome measuring number of contacts with
primary care staff for infections to make this a meaningful outcome.
Whereas the trial supports the notion of little benefit of low-dose
multivitamin/minerals among individuals with good nutritional status, it
certainly does not answer questions regarding the benefits among
individuals with mild nutritional deficiencies. The MAVIS data indicate
that there may be benefits (e.g., almost 2-fold lower reported days of
infections among supplement users compared to placebo), yet did not have
the statistical power or tools of nutritional assessment to draw valid
conclusions.
Competing interests:
None declared
Competing interests: No competing interests
The role of multivitamins is boosting immunity has for long been
accepted by physicians. This fact has been made use of while treating
elderly patients suffering from various infections. This study is
significant for physicians in the developing countries where the cost of
medical services is borne directly by the patient in the absence of a
state-sponsored health scheme. The amount saved in empirically prescribed
multivitamins can be better used by the less-affording elderly patient for
other drugs which may be more essential . Therefore, in third world
countries multivitamins should be prescribed to the elderly only if there
is a strong evidence of a nutritional deficiency and not for preventing
future infections.
Competing interests:
None declared
Competing interests: No competing interests
Sir, The study by Alison Avenell et al on the effect of multivitamins
and minerals on infection rates and wellbeing of a population of older
people (1) is a major achievement however, the question of the possible
benefit of micro-nutritional supplements remains uncertain.
To be adequately absorbed, zinc, important in the immune system,
should be taken on an empty stomach, preferably at night. Absorption is
interfered with, by amongst other things metals, such as iron and copper
included in the tablets used.
In a previous study cited by the authors, calcium and magnesium were
included in the formulation, but not in the present study. In addition
chromium may be important for a complete supplement.
It remains unclear who will benefit from which formulation of
supplements, but common sense and experience would suggest that a wide
spectrum preparation should be used and zinc given separately if possible.
Yours truly,
Dr R.J.Walden, Hon. Senior. Research Fellow, Clin. Pharmacol.,UCL,
London
richard@ walden60.fsnet.co.uk
Competing interests:
None declared
Competing interests: No competing interests
EDITOR – In a comprehensive study of micronutrient (multivitamin and
microelement) supplementation in the elderly, Avenell et al1 included iron
fumarate (a highly bio-available compound) at a daily dose of 14 mg, in a
preparatory containing also 60 mg vitamin C. A combination of fumarate
compound and vitamin C, both of which enhance iron absorption, may
increase iron uptake up to a level higher than any nutritional
recommendation for the apparently healthy elderly population. In their
study, Avenell et al1 found only about 12% of the studied population (16%
of the supplemented group and 8% of the placebo group), to be at a high
risk of iron deficiency. Since in the elderly, high iron stores generally
prevail,2 iron supplementation may further enhance those stores.3
High iron intake or stores, which augment the production of the
highly reactive and toxic hydroxyl radical,4 have been closely associated
with inflammatory reactions5 and with an increased morbidity of heart
diseases,3 6 7 cancer8 9 10 and Parkinson’s disease.11 Iron
supplementation in non-deficient subjects, might have obscured the
anticipated beneficial effect of vitamin and mineral supplementation. The
authors analyzed the supplementation effect, on the subgroup of 262
subjects (Table 5), while using a score of four deficiencies, iron,
folate, vitamin C or vitamin D. However, only 110 subjects had been
determined as iron deficient. We wonder if the statistical power is strong
enough to determine a positive effect on the iron deficient subgroup (73
supplemented and 37 placebo) versus all the subjects in the study.
The practice of high dose of micronutrient supplementation most
prevails in many studies. El-Kadiki and Sutton12 performed a meta-analysis
on the role of multivitamin-mineral supplementation in preventing
infections in the elderly. In six studies (Chavance et al 1993, Girodon et
al 1999, Barringer et al 2003, Graat et al 2002, Jain 2002 and Girodon et
al 1997), high doses of vitamin C (of up to 300% of UK RDA), vitamin E
(600%), zinc (270%), and selenium (150%) were supplemented, thus
increasing consumption already supplied by food. In four studies
(excluding those of Girodon el al), iron was also supplemented at a high
amount (of up to 300%). The advantage of micronutrient supplementation at
high doses, beyond the suggested recommendations, may be unsafe and may
diminish the beneficial effect of small and necessary supplementation.
Avenell et al1 stated that there is “evidence of multiple nutritional
deficiencies” in older people in UK (as also prevail in the elderly in
most of the industrialized societies).13 They also stated that
“supplementation is a low cost option for improving nutritional status”
and have done all their efforts to prove it. Such efforts must be
continued because, in many studies, the relationships between morbidity
and even mortality and low vitamin status have been described. So far, no
adverse effects of cautious supplementation have been shown.
Because the deficiency risk is much higher than the risk of
reasonable supplementation, a moderate and cautious micronutrient
supplementation should be suggested for the elderly. If such a suggestion
is applicated, only after providing the beneficent effect of micronutrient
supplementation through comprehensive prospective studies, the present
generation of the elderly would not get the benefit of such a suggestion.
Unbalanced formulations of ‘multivitamins’, mostly available for the
consumer, may negatively interfere with the delicate metabolic balance of
the biochemical pathways which is crucial for a better physiological
status, particularly for the elderly.
Yosef Dror, PhD
Felicia Stern, PhD
Department of Biochemistry, Food Science and Nutrition, Faculty of
Agriculture, The Hebrew University of Jerusalem, Rehovot 76100, Israel
dror@huji.ac.il
Competing interests: The authors were members of a committee
nominated by the Israel Ministry of Health recommended micronutrient
supplementation for the elderly.14 15
1. Avenell A, Campbell MK, Cook JA, Hannaford PC, Kilonzo MM, McNeill
G, Milne AC, Ramsay CR, Seymour DG, Stephen AI, Vale LD, Writing Group of
the MAVIS. Effect of multivitamin and multimineral supplements on
morbidity from infections in older people (MAVIS trial): pragmatic,
randomised, double blind, placebo controlled trial. BMJ 2005;331;324-9.
2. Fleming DJ, Jacques PF, Tucker KL, Massaro JM, D'Agostino Sr RB, Wilson
PWF, Wood RJ. Iron status of the free-living, elderly Framingham Heart
Study cohort: An iron-replete population with a high prevalence of
elevated iron stores. Am J Clin Nutr 2001;73:638-46.
3. Fleming DJ, Tucker KL, Jacques PF, Dallal GE, Wilson PWF, Wood RJ.
Dietary factors associated with the risk of high iron stores in the
elderly Framingham Heart Study cohort. Am J ClinNutr 2002;76:1375-84.
4. Polla AS, Polla LL, PollaBS. Iron as the malignant spirit in successful
ageing. Ageing Res Rev 2003;2:25-37.
5. Sch¨umann K, Kroll S, Weiss G, Frank J, Biesalski HK, Daniel H, Friel
J, Solomons NW.Monitoring of hematological, inflammatory and oxidative
reactions to acute oral iron exposure in human volunteers: preliminary
screening for selection of potentially-responsive biomarkers. Toxicology
2005;212:10-23.
6. You SH, Wang Q. Ferritin in atherosclerosis. Clin Chim Acta 2005;357:1-
16.
7. Sullivan JL, Zacharski LR. Commentary: Hereditary haemochromatosis and
the hypothesis that iron depletion protects against ischemic heart
disease. Eur J Clin Invest 2001;31:375-7.
8. Mainous III AG, Wells BJ, Koopman RJ, Everett CJ, Gill JM. Iron,
lipids, and risk of cancer in the Framingham Offspring Cohort. Am J
Epidemiol 2005;161:1115-22.
9. Weiss G, Iron and immunity: a double-edged sword. Eur J Clin Invest
2002;32:70-8.
10. Lee DH, Anderson KE, Harnack LJ, Folsom AR, Jacobs JrDR. Heme iron,
zinc, alcohol consumption, and colon cancer: Iowa Women’s Health Study. J
Natl Cancer Inst 2004;96:403-7.
11. Powers KM, Smith-Weller T, Franklin GM, Longstreth JrWT, Swanson PD,
Checkoway H. Parkinson’s disease risks associated with dietary iron,
manganese, and other nutrient intakes. Neurology 2003;60:1761-6.
12. El-Kadiki A, Sutton AJ. Role of multivitamins and mineral supplements
in preventing infections in elderly people: systematic review and meta-
analysis of randomised controlled trials. BMJ 2005;330;871-6.
13. Berner YN, Stern F, Polyak Z, Dror Y. Dietary intake analysis in
institutionalized elderly: a focus on nutrient density. J Nutr Health
Aging 2002;6:275-82.
14. Dror Y, Stern F, Berner YN, Kaufmann NA, Berry E, Maaravi Y, Altman H,
Cohen A, Leventhal A, Nitzan-Kaluski D. Recommended micronutrient
supplementation for institutionalized elderly. J Nutr Health Aging
2002;6:295-300.
15. Heseker H. Micronutrients supplementation recommendations for the
elderly suggested by public committee. J Nutr Health Aging 2002;6:294.
Competing interests:
No finacial competeing interests.
The authors were members of a committee nominated by the Israel Ministry of Health recommended micronutrient supplementation for the elderly.
Competing interests: No competing interests
I am surprised that in the printed edition of the article by Alison
Avenell et al there was no space to indicate the content of the tablets.1
It would have been essential to mention, in particular, that there was a
certain amount of iron (a powerful oxidative mineral), but no selenium
(anti-oxidative effect).
1 - Alison Avenell A, Campbell MK, Cook JA, et al. Effect of
multivitamin and multimineral supplements on morbidity from infections in
older people (MAVIS trial): pragmatic, randomised, double blind, placebo
controlled trial. BMJ 2005; 331: 324-329
Competing interests:
None declared
Competing interests: No competing interests
in mean 72 year olds from what is effectively the lowest available ingredient amounts in such multi-vitamin.
If 'morbidity' is to be affected, there are at least 2 trials where
much higher than MAVIS' 60 mg vitamin C were used with significant benefit
here
(1) and here
(2) [no abstract]. The latter study used 1 g/d + 3 g/d during the first
3 days of any illness and found 40% more people seeking medical help
(56 vs. 40) and 58% more doctors visits [94 vs. 60] and a "similar"
increased prescription drug use in the placebo group.
I quote from the former study's abstract with lower doses "... subjects
in both vitamin groups experienced less severe illness than subjects in
the placebo group, with approximately 25 per cent fewer days spent indoors
because of the illness (P smaller than 0.05)." It is unfortunate that such evidence was not built on regarding at least vitamin C.
The balance of the MAVIS multi-vitamin probably redressed some deficiencies in the estimated 1/3rd of this older U.K. population -and this baseline finding might be the most important result of MAVIS.
The real value of a (probably higher dose) multi-vitamin may well be long-term, for example by reducing homocysteine levels (3), likely 10-20% but not reported in MAVIS.
Homocysteine being the 'obligate' break down product of the sulphur protein
amino acid methionine and the vitamin B6 dependent precursor of another sulphur protein amino acid, cysteine, this non-protein amino acid and its dehydro lactone ring configuration likely play long-term deleterious
roles by affecting di-sulphide bridges in and between proteins, as well as lysine linkages and, irreversibly so, its lysyl oxidase enzyme. This affects our long-living or life-long proteins, such as collagens, elastins and glyco-proteins. Therefore, MAVIS also leaves unaddressed the issue of long term health as well as that of our long-living proteins that are affected by low nutrient intakes.
vos{at}health-heart.org
1. Anderson TW, Beaton GH, Corey P, Spero L. vitamin C: the effect of
relatively low doses. Can Med Assoc J. 1975 Apr 5;112(7):823-6. MEDLINE
1091343
2. Anderson TW, Reid DB, Beaton GH. Vitamin C and the common cold: a
double-blind trial. Can Med Assoc J. 1972 Sep 23;107(6):503-8. MEDLINE
1091343
3. Vos E. Multivitamin supplements are effective and inexpensive
agents to lower homocysteine levels. Arch Intern Med. 2001;161(5):774-5.
MEDLINE 11231722
Competing interests:
None declared
Competing interests: No competing interests
Reply to correspondence about the MAVIS trial
We thank the correspondents for their interest in our trial. The
MAVIS trial was designed as a pragmatic trial to test the influence of the
constituents of commonly available over the counter supplements on
infections in older people, as experienced by them, rather than effects on
biomarkers of immune response. Since the ability to measure vitamin and
mineral status by blood sampling in general practice is extremely limited,
this is not a practicable way of assessing nutritional risk on large
numbers of people in the community. This is why we used our nutritional
assessment questionnaire, which was validated against blood sampling (1).
The nutrient intakes provided by the supplement could also have been
achievable by dietary means. Space constraints did not allow us to
include the full details of the supplement in the printed version,
although these were provided in the online full pdf file. Selenium was
not included, as is the case with many similar supplements available over
the counter.
Nutrient interactions, either at absorption or in metabolism, are too
numerous to mention. We know too little about the optimum level and form
of nutrients to provide in supplements. We would point out to some of the
correspondents, who recommend higher dose supplements based on previous
trials, that there are serious concerns (2,3) that the quoted trials by
Chandra and Jain have been suggested as possibly being fraudulent (4,5,6).
The test reported in Table 5 is a test of an interaction between
treatment and patient risk. This is an appropriate way to test whether
there is evidence that supplementation had an effect on the number of
infection days in high risk patients not seen in low risk patients.
Selecting out the high risk patients and then comparing the high risk
supplemented group against the high risk placebo group alone has been
shown to be a less reliable method of analysis (7). Taking the difference
between the medians as representing an intervention effect with high risk
patients is misleading. The data were highly skewed with a large number
of zeros and also some sparse data. The correct representation (and
analysis) of the data is made by the incidence rate ratio of 1.04. This
fully accounted for the distribution of the data using a zero inflated
negative binomial model. The removal of only 15 cases (less than 2% of
total cases) makes the medians equal and indeed using the mean instead of
the median as the summary measure (which given the extreme skewness in the
data may be more informative in this case) shows a difference of 23.7
(placebo) versus 21.5 (intervention) a difference of only 2 infection
days.
We do not think that it is appropriate to undertake further post hoc
subgroup analyses, e.g. for those people who were at risk of iron
deficiency, in view of the small numbers involved.
We are happy to provide examples of the diary to interested
researchers. We did not collect evidence of prior supplement use, but it
was clear at recruitment that few participants had stopped supplements in
order to take part in the trial.
Alison Avenell (a.avenell@abdn.ac.uk), Marion K Campbell, Jonathan A
Cook, Philip C Hannaford, Mary M Kilonzo, Geraldine McNeill, Anne C Milne,
Craig R Ramsay, D Gwyn Seymour, Audrey I Stephen, Luke D Vale (Writing
Group of the MAVIS trial)
Health Services Research Unit, Department of General Practice and
Primary Care, Health Economics Research Unit, Department of Environmental
and Occupational Medicine, Department of Medicine and Therapeutics; School
of Medicine, University of Aberdeen, Aberdeen, Scotland
References
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Competing interests:
None declared
Competing interests: No competing interests