Rapid Responses to:
|
|
Rapid Responses: Rapid Responses published:
-
![[Read Rapid Response]](/icons/misc/sectionDOWN.gif)
Supplement Dosage Too Low
- Tom Greenfield (5 August 2005)
-
Multivitains: not the whole story
- Eddie Vos (6 August 2005)
-
Far too low dosage of vitamins in study
- Robert Van der Hope (6 August 2005)
-
Multivitamin and multimineral supplements in older people
- Michel R Odent (7 August 2005)
-
Micronutrient supplementation in the elderly
- Yosef Dror, Felicia Stern (11 August 2005)
-
Micro-nutrition, infections and older people
- Richard J Walden, None (13 August 2005)
-
Important observation for Third World physicians
- Rajan TD (14 August 2005)
-
Possible benefits for high-risk individuals in the MAVIS trial
- Cornelia M Ulrich (17 August 2005)
-
Supplements should contain optimum amounts of vitamins and minerals
- John Dixon (18 August 2005)
-
Multiple micronutrient supplementation - benefits might relate to the significance of the disease
- Klaus K Witte, Andrew L Clark, John GF Cleland (25 August 2005)
-
The effects of vitamin E and vitamin C on respiratory infections may vary between different population groups
- Harri Hemilä (19 September 2005)
-
Reply to correspondence about the MAVIS trial
- Alison Avenell, 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) (7 October 2005)
|
|
|||
|
Tom Greenfield, Naturopath Canterbury CT1 3RD
Send response to journal:
|
In light of the EU restricting the sale of some vitamin and mineral
supplements, this research points to how damaging it will be for the health of
the older population to implement the law. "Regular use of commonly available multivitamin and multimineral supplements by community dwelling older people who do not already take supplements is unlikely to reduce the number of self reported infections or associated use of health services" [my emphasis], and "We cannot exclude the possibility that the intakes provided in the supplement were inadequate to affect the immune system." This research used standard low-dose supplements which are based on the ridiculously low Government RNI levels: one form of vitamin E (as D, L- alpha tocopheryl acetate, rather than the more effective mixed tocopherols); a tiny amount of folic acid (200 mcg, presumably not folinic acid, which benefits those with MTHFR genetic polymorphism) when it is known that high dose folate along with B6 (higher than the 2 mg in the trial) prevents age-related increase in homocysteine; and no bioflavonoids to assist metabolism of the low-dose (60 mg) vitamin C, etc. etc. The references in this paper point to past research that shows the benefit of higher dose vitamins and minerals on older people. Rather than the tempting conclusion that multivitamins and minerals do not help the elderly, standard multivitamins should contain a label stating that after the age of 85 people may need to take higher doses of supplements to prevent morbidity. These higher doses may not however be readily available over the counter due to the impending legal restrictions. I agree with the BMJ Editorial that suggests a holistic approach to diet, but it is also important to recognise the therapeutic effects of some higher dose vitamin and mineral supplements, particularly in old age. Competing interests: None declared |
|||
|
|
|||
|
Eddie Vos, maintains health-heart.org Sutton (Qc) Canada J0E 2K0
Send response to journal:
|
The MAVIS trial found no effect on morbidity after 1 year on
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 |
|||
|
|
|||
|
Robert Van der Hope, nutritionist 32 Merri St Warrnambool Australia 3280
Send response to journal:
|
There is no way that such a low dose of supplements could have a positive clinical effect on the desired potential outcome of this study. Supplementation would need to be far higher. The very low toxicity level of most vitamins (such as Vitamin C) would allow, and warrant much higher doses for a meaningful study. Regards, Robert Van der Hope. Competing interests: None declared |
|||
|
|
|||
|
Michel R Odent, Director. Primal Health Research Centre London NW3 2JR
Send response to journal:
|
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 |
|||
|
|
|||
|
Yosef Dror, Nutritionist, retired Faculty of Agriculture, The Hebrew University of Jerusalem, Rehovot 76100, Felicia Stern
Send response to journal:
|
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
Department of Biochemistry, Food Science and Nutrition, Faculty of
Agriculture, The Hebrew University of Jerusalem, Rehovot 76100, Israel
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. |
|||
|
|
|||
|
Richard J Walden, Hon Sen Res.Fellow., Clin Pharm.,UCLon UCL WC1E 6JJ, None
Send response to journal:
|
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 |
|||
|
|
|||
|
Rajan TD, Consultant Skin & Sex Transm Diseases, Mumbai India Tel: 0091-22-26820114
Send response to journal:
|
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 |
|||
|
|
|||
|
Cornelia M Ulrich, Associate Member Fred Hutchinson Cancer Research Center
Send response to journal:
|
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 |
|||
|
|
|||
|
John Dixon, Visting Scholar MIT, 70 Massachusetts Avenue, Cambridge MA 02139, USA
Send response to journal:
|
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 |
|||
|
|
|||
|
Klaus K Witte, Fellow in Cardiology Division of cardiology, University Health Network, Mount Sinai Hopsital, Toronto, Canada, Andrew L Clark, John GF Cleland
Send response to journal:
|
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)
Andrew L Clark MA, MD, FRCP
John GF Cleland FRCP, FACC
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 |
|||
|
|
|||
|
Harri Hemilä, Associate professor Department of Public Health, POB 41, University of Helsinki, Helsinki, Finland, FIN-00014
Send response to journal:
|
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 |
|||
|
|
|||
|
Alison Avenell, Clinical research fellow Health Services Research Unit, School of Medicine, University of Aberdeen, Aberdeen, UK, AB25 2ZD, 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)
Send response to journal:
|
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 (1) McNeill G, Vyvyan J, Peace H, McKie L, Seymour G, Hendry J, et al. Predictors of micronutrient status in men and women over 75 years old living in the community, Br J Nutr 2002; 88: 55-61. (2) Smith R. Investigating the previous studies of a fraudulent author. BMJ 2005; 331: 288- 291. (3) Sutton AJ, Kadiki AE. Assessing concerns regarding the validity of three trials included in “role of multivitamins and mineral supplements in preventing infections in elderly people: systematic review and meta- analysis of randomised controlled trials”. Available at: http://bmj.bmjjournals.com/cgi/content/full/bmj.38399.495648.8F/DC2(accessed September 23, 2005). (4) Chandra RK. Effect of vitamin and trace-element supplementation on immune responses and infection in elderly subjects. Lancet 1992; 340: 1124-7. (5) Chandra RK. Influence of multinutrient supplement on immune responses and infection-related illness in 50-65 year old individuals. Nutrition Research 2002; 22: 5-11. (6) Jain AL. influence of vitamins and trace-elements on the incidence of respiratory infection in the elderly. Nutrition Research 2002; 22: 85-7. (7) Brookes ST, Whitley E, Peters TJ, Mulheran PA, Egger M, Davey Smith G. Subgroup analyses in randomised controlled trials: quantifying the risks of false-positives and false-negatives. Health Technol Assess 2001;5(33). Competing interests: None declared |
|||