Rapid Responses to:
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Rapid Responses: Rapid Responses published:
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Confounding
- Michael Robertson (18 July 2003)
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Aspirin and Alzheimer’s disease
- Gareth P Morgan (21 July 2003)
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Reducing the risk of Alzheimer's disease: NSAIDs, fish oils, and diet
- William B. Grant (31 July 2003)
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Conclusions on NSAIDs and Alzheimer’s Disease Overstated
- David W. Price (4 August 2003)
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NSAIDs in Alzheimer's disease: Where is the clinical evidence?
- Naji Tabet (5 August 2003)
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NSAIDs and Alzheimer's: Quality before quantity
- Nandi L Siegfried, Nandi Siegfried, Jimmy Volmink, Martie Muller, and Jon Deeks (15 August 2003)
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Michael Robertson, General Practitioner Marcham Road Health Centre Abingdon Oxon England OX14 1DB
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I was disapointed not to see any acknowledgment of possible confounding factors for what is currently only an observed reduction in risk. What if having osteoarthritis is negatively associated with developing Alzheimer's? Presumably some form of OA is the likely reason why older people are on NSAIDs. Both conditions have genetic and environmental components which may well be mutually exclusive. The statement that 'NSAIDs offer some protection against the development of Alzheimer's disease' cannot yet be made with confidence. As Davey Smith and Ebrahim (1)pointed out in a recent BMJ editorial an association does not show causation and doctors have been caught out giving poorly based and premature advice (and treatment) before. A recently published randomised controlled trial failed to show any benefit from either naproxen or rofecoxib in preventing the progression of early Alzheimer's disease (2). Sadly we may be no further forward in being able to prevent or treat this condition. Dr Michael Robertson
(1) Davey Smith, G and Ebrahim, S (2002) Data dredging, bias, or confounding. BMJ 2002; 325 : 1437-8 (2) Aisen, P. S., Schafer, K. A., Grundman, M., Pfeiffer, E., Sano, M., Davis, K. L., Farlow, M. R., Jin, S., Thomas, R. G., Thal, L. J. (2003). Effects of Rofecoxib or Naproxen vs Placebo on Alzheimer Disease Progression: A Randomized Controlled Trial. JAMA 289: 2819-2826 Competing interests: None declared |
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Gareth P Morgan, Public Health Officer National Public Health Service for Wales, 36 Orchard Street, Swansea, SA1 5AQ.
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I congratulate Etminan and colleagues on their meta-analysis. The suggestion that aspirin might reduce the risk of Alzheimer’s disease has important public health implications. Another recent observational study of over 700 elderly individuals provides further evidence to support this suggestion (1) but demonstrating a reduction via a randomised controlled trial will be more difficult. One reason is that many of the elderly individuals who could be entered into such a trial would already be eligible to receive aspirin for cardiovascular prophylaxis. How then do we formulate policy to move forward? Perhaps we are approaching a time when all individuals over the age of 50 years without contraindications should be advised to take low-dose aspirin to reduce their risk of age related conditions such as cardiovascular disease, cancer and Alzheimer’s disease (2). Such policy must complement other disease reduction approaches and would require careful implementation to ensure that health inequalities are reduced rather than increased. Reference 1. Nilsson SE, Johansson B, Takkinen S, Berg S, Zarit S, McClearn G, Melander A. Does aspirin protect against Alzheimer’s disease? A study in a Swedish population-based sample aged =/>80 years. Eur J Clin Pharmacol 2003 Jun 25 [Epub ahead of print] 2. Morgan G. A qualitative illustration of the public health potential of aspirin. Medical Hypotheses 2003;60(6):900-902. Competing interests: None declared |
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William B. Grant, NASA Langley Research Center (this work is independent of official duties) 12 Sir Francis Wyatt Place, Newport News, VA 23606-3660 USA
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The recent meta-analysis by Etminan et al.1 concludes that non- steroidal anti-inflammatory drugs (NSAIDs) are associated with a reduced risk of developing Alzheimer's disease (AD), with degree of protection increasing with duration of use. This result is likely correct since inflammation has been identified as a risk factor for AD.2-4 Additional studies since October 2002 have also found evidence supporting NSAIDs as risk reduction factors for AD.5 Other studies are underway.6 One paper suggests combining NSAIDs with other substances.7 While NSAIDs are very likely able to reduce the risk of AD, as pointed out by the author of the first paper linking NSAIDs to reduced risk of AD, "these drugs strike at the periphery of the inflammatory reaction. Much better results might be obtained if drugs were found that could inhibit the activation of microglia or the complement system in brain, and combinations of drugs aimed at different inflammatory targets might be much more effective than single agents."8 Also, NSAIDs have the associated risks including gastrointestinal bleeding, which affects up to 5% of those using them.9 On the other hand, recent studies have found that NSAIDs do not retard the progression of AD.10,11 However, treatment of AD once it gets past the initial stages is another matter.12,13 An alternate approach for reducing inflammation in the brain is through n-3 fatty acids such as those found in fish oil (eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA)) and, perhaps, flaxseed oil.14 Indeed, fish consumption was identified as a risk reduction factor for AD in a pioneering ecologic study15 and confirmed in a pair of subsequent cohort studies.16,17 Fish oil has also been found to reduce the inflammation associated with rheumatoid arthritis,18,19 and has been found beneficial for a large number of diseases and conditions. 20 Fish oil has two additional advantages over NSAIDs: 1 - it provides fatty acids that are very important for proper brain function; 21 and 2 - it has few adverse side effects, although consumption of fish is also associated with ingestion of mercury and other toxic and hazardous chemicals, and global fish stocks are being depleted by over fishing.22 The better way to go about reducing the risk of AD is through proper diet. As shown in Grant, total energy and total fat are important risk factors for AD, while fish and cereals are risk reduction factors. Based on a suggestion by the author,23 the findings for energy, fat, and cereals were confirmed,24 but only for those with the APOE epsilon 4 allele. The finding regarding fat has been refined to relate to saturated fat and trans-fatty acids.25,26 Alzheimer's disease is a horrible disease and a variety of approaches to reduce the risk will be more effective than any one way. The health community is encouraged to continue research on the mechanisms that lead to AD and ways to reduce the risk. References 1. Etminan M, Gill S, Samii A. Effect of non-steroidal anti-inflammatory drugs on risk of Alzheimer's disease: systematic review and meta-analysis of observational studies. BMJ. 2003;327:128. 2. Townsend KP, Obregon D, Quadros A, Patel N, Volmar Ch, Paris D, Mullan M. Proinflammatory and vasoactive effects of Abeta in the cerebrovasculature. Ann N Y Acad Sci. 2002;977:65-76. 3. Gupta A, Pansari K. Inflammation and Alzheimer's disease. Int J Clin Pract. 2003;57:36-9. 4. Quinn J, Montine T, Morrow J, Woodward WR, Kulhanek D, Eckenstein F. Inflammation and cerebral amyloidosis are disconnected in an animal model of Alzheimer's disease. J Neuroimmunol. 2003;137:32-41. 5. Landi F, Cesari M, Onder G, Russo A, Torre S, Bernabei R. Non- steroidal anti-inflammatory drug (NSAID) use and Alzheimer disease in community-dwelling elderly patients. Am J Geriatr Psychiatry. 2003;11:179- 85. 6. Tabet N, Feldmand H. Ibuprofen for Alzheimer's disease. Cochrane Database Syst Rev. 2003;(2):CD004031. 7. Prasad KN, Cole WC, Prasad KC. Risk factors for Alzheimer's disease: role of multiple antioxidants, non-steroidal anti-inflammatory and cholinergic agents alone or in combination in prevention and treatment. J Am Coll Nutr. 2002;21:506-22. 8. McGeer PL, McGeer EG. Local neuroinflammation and the progression of Alzheimer's disease. J Neurovirol. 2002;8:529-38. 9. Laine L. The gastrointestinal effects of nonselective NSAIDs and COX-2-selective inhibitors. Semin Arthritis Rheum. 2002;32:25-32. 10. Aisen PS, Schafer KA, Grundman M, Pfeiffer E, Sano M, Davis KL, Farlow MR, Jin S, Thomas RG, Thal LJ; Alzheimer's Disease Cooperative Study. Effects of rofecoxib or naproxen vs placebo on Alzheimer disease progression: a randomized controlled trial. JAMA. 2003;289:2819-26. 11. Launer L. Nonsteroidal anti-inflammatory drug use and the risk for Alzheimer's disease: dissecting the epidemiological evidence. Drugs. 2003;63:731-9. 12. Corey-Bloom J. The ABC of Alzheimer's disease: cognitive changes and their management in Alzheimer's disease and related dementias. Int Psychogeriatr. 2002;14(Suppl 1):51-75. 13. Grossberg GT. The ABC of Alzheimer's disease: behavioral symptoms and their treatment. Int Psychogeriatr. 2002;14(Suppl 1):27-49. 14. Morris DH. Methodologic challenges in designing clinical studies to measure differences in the bioequivalence of n-3 fatty acids. Mol Cell Biochem. 2003;246:83-90. 15. Grant WB. Dietary links to Alzheimer's disease. Alz Dis Rev. 1997;2:42-55 http://www.mc.uky.edu/adreview/Vol2/Grant/grant.pdf 17. Morris CM, Evans DA, Bienias JL, et al. Consumption of fish and n -3 fatty acids and risk of incident Alzheimer disease. Arch Neurol. 2003;60:940-6. 16. Barberger-Gateau P, Letenneur L, Deschamps V, Pérès K, Jean- François Dartigues JF, Renaud S. Fish, meat, and risk of dementia: cohort study. BMJ 2002;325:932-3. 18. James MJ, Gibson RA, Cleland LG. Dietary polyunsaturated fatty acids and inflammatory mediator production. Am J Clin Nutr. 2000;71:343S- 8S. 19. Kremer JM. n-3 fatty acid supplements in rheumatoid arthritis. Am J Clin Nutr. 2000;71:349S-51S. 20. Simopoulos AP. Essential fatty acids in health and chronic disease. Am J Clin Nutr. 1999;70:560S-9S. 21. Haag M. Essential fatty acids and the brain. Can J Psychiatry. 2003;48:195-203. 22. Myers RA, Worm B. Rapid worldwide depletion of predatory fish communities. Nature 2003;423:280-3. 23. Grant WB. The APOE-epsilon4 allele and Alzheimer disease among African Americans, Hispanics, and Whites. JAMA. 1998;280:162-163. 24. Luchsinger JA, Tang MX, Shea S, Mayeux R. Caloric intake and the risk of Alzheimer disease. Arch Neurol. 2002;59:1258-63. 25. Morris MC, Evans DA, Bienias JL, Tangney CC, Bennett DA, Aggarwal N, Schneider J, Wilson RS. Dietary fats and the risk of incident Alzheimer disease. Arch Neurol. 2003;60:194-200. 26. Cooper JL. Dietary lipids in the aetiology of Alzheimer's disease; Implications for thearapy. Drugs Aging 2003;20:399-418. Competing interests: None declared |
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David W. Price, Director of Education, CPMG and Associate Professor of Family Medicine & Psychiatery, UCHSC, Denver, CO, USA 80020
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To the Editor: In the July 19 issue of BMJ, Etminan, Gill, and Samii present a concise and well done systematic review and meta-analysis on nonsteroidal anti-inflammatory drug (NSAID) use and the risk of developing subsequent Alzheimer’s Disease (AD)(1) . The trials included in the review were observational studies (6 cohort and 3 case-control). While theoretic mechanisms for protection against AD exist (prevention of senile plaque formation), the authors point out that currently, no randomized controlled trials (RCT) have examined the role of NSAIDs in prevention of AD. As the Women’s Health Initiative (2) has shown us, it is risky to overstate the findings of observational studies. In light of the lack of RCT evidence, the authors’ conclusions that “NSAIDs offer some protection against the development of Alzheimer’s disease” (in the abstract) and “Our results…show that use of an NSAID lowers the risk of developing Alzheimer’s disease” (in the discussion section) are overstated. The authors later correctly note that the appropriate dose, duration, and risk/benefit of NSAID use for AD protection are unclear (as well as the appropriate population for a prevention strategy). Pending RCTs to address these issues, it is best to note that NSAID use is associated with a decreased risk of AD. David Price, MD, FAAFP
Associate Professor of Family Medicine and Psychiatry, University of Colorado Health Sciences Center, Denver, Colorado, USA references: 1. Etminan M, Gill S, Samii A. Effect of non-steroidal anti- inflammatory drugs on risk of Alzheimer’s disease: systematic review and meta-analysis of observational studies. BMJ 2003;327:128-132. 2. Writing Group for the Women’s Health Initiative Investigators. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: Principal results from the Women’s Health Initiative randomized controlled trial. JAMA 2002;288:321-333. Competing interests: None declared |
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Naji Tabet, Senior Lecturer in Old Age Psychiatry Postgraduate Medical School, Faculty of Health, University of Brighton, Brighton, BN1 9PH UK
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The systematic review and meta-analysis by Etminan et al. (2003)1 is well presented, but sadly it adds little to current knowledge about NSAIDs in Alzheimer’s disease (AD). Hence, I am somewhat surprised at the undue prominence it was afforded by the BMJ through front cover emphasis. The majority of epidemiological surveys published over the past couple of decades has clearly shown that people maintained on NSAIDs (presumably for rheumatoid arthritis, osteoarthritis and other inflammatory conditions) are less likely to develop AD compared to those who are not receiving NSAIDs. However, association should not and cannot imply causation. A major confounding factor limiting the value of many of these observational studies, and by implication this systematic review, is the presence of various inflammatory processes and conditions predating AD. This is very difficult to adjust for since NSAIDs were specifically prescribed to treat such conditions and not AD. It remains unclear whether mechanisms liked to the presence of concurrent inflammatory conditions such as rheumatoid arthritis, and not NSAIDs treatment, are responsible for the reduced risk observed for the development of AD. Laboratory and animal studies have implicated inflammatory processes in the pathogenesis of Alzheimer’s disease. This is further supported by reports that some NSAIDs may decrease beta-amyloid generation.2 Therefore, it is reasonable to assess whether NSAIDs provide some protection against the development of AD. However, an appropriate approach for such an assessment allowing a meaningful conclusion is through randomized double- blind placebo-controlled trials in individuals who are not suffering from osteoarthritis and various inflammatory disorders. This is now needed in order to establish with a degree of certainty whether long term use of NSAIDs may protect individuals from developing AD, and indeed, such trials are currently underway.3 Another important question which needs to be addressed is whether NSAIDs may help those individuals who already have early AD. To date, no evidence exists to support the use of indomethacin and ibuprofen in such patients.4 Likewise, the largest multi-centre randomized controlled trial yet on this subject has found that naproxen and rofecoxib did not slow cognitive decline in mild to moderate AD.5 All NSAIDS may potentially cause serious side effects, especially, in an elderly population. Therefore, clear evidence must exist before NSAIDs can be recommended for AD either as prophylactic or therapeutic agents. To date, no such clinical evidence exists. It is unlikely that epidemiological observations, which are extremely useful in many instances, will contribute any further to this specific question. References: 1 Etminan M, Gill S, Samii A. Effects of non-steroidal anti- inflammatory drugs on risk of Alzheimer’s disease: systematic review and meta-analysis of observational studies. BMJ 2003;327:128-31 (July 19th). 2 Lim GP, Yang F, Chu T, Chen P, Beech W, Teter B, et al.Ibuprofen suppresses plaque pathology and inflammation in a mouse model for Alzheimer’s disease. J Neurosci 2000;20:5709-14. 3 Launer LJ. Nonsteroidal anti-inflammatory drugs and Alzheimer’s disease: What next? JAMA 2003;289:2865-7. 4 Tabet N, Feldman H. Ibuprofen for Alzheimer’s disease. Cochrane Database Systematic Reviews 3003;2:CD004031. 5 Aisen PS, Schafer KA, Grundman M, Pfeiffer E, Sano M, Davis KL, et al. Effects of Rofecoxib or Naproxen vs placebo on Alzheimer disease progression: a randomised controlled trial. JAMA 2003;289;2819-26. Competing interests: None declared |
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Nandi L Siegfried, Co-director South African Cochrane Centre, Medical Research Council, PO Box 19070, Tygerberg, 7505, South Africa, Nandi Siegfried, Jimmy Volmink, Martie Muller, and Jon Deeks
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Etminan et al. (1) are to be commended for presenting an explicit report of their systematic review of observational studies investigating the effects of NSAIDs on Alzheimer's disease. However, the review could have been strengthened by appraisal of the quality of the included studies. Poor or highly variable quality of the included studies may influence the conclusions of a systematic review. In contrast to systematic reviews of randomised controlled trials (RCTs) no widely accepted quality assessment tools exist for reviews involving observational studies (2). We recently developed separate checklists for considering biases relating to cohort, case-control and cross-sectional studies in a systematic review of male circumcision for preventing heterosexual acquisition of HIV in men (3). We question pooling the results of the studies in this review. Unlike RCTs, observational studies cannot control for unknown or unmeasured confounders. The authors' statement that "the possibility of confounding and bias may be more significant in meta-analysis of observational studies than meta-analyses of randomised trials", trivializes the difference between the two situations. Adequately randomised trials can minimise the likelihood of selection bias and therefore confounding, in contrast to cohort and case-control studies where this limitation can never be fully overcome. Even the pooling of adjusted results from individual studies, as performed in this review, does not eliminate the problem. There is therefore a real danger that meta-analysis of the included studies may simply have produced a more precise estimate of already biased findings (4). Rather than conclude "the use of an NSAID lowers the risk of developing Alzheimer's disease", the authors might have drawn attention to the current lack of reliable evidence and called for RCTs to establish whether the use of NSAIDs for preventing Alzheimer's disease is warranted or not. Meta-analysis cannot by itself remove selection bias from observational data. 1. Mahyar Etminan, Sudeep Gill, and Ali Samii. Effect of non- steroidal anti-inflammatory drugs on risk of Alzheimer's disease: systematic review and meta-analysis of observational studies. BMJ, Jul 2003; 128 - 0. 2. J Dinnes, A Sowden, F Song, M Petticrew, J Deeks, D Altman, R D'Amico. A review of quality assessment tools for non-randomised intervention studies. Abstract. 3rd Symposium on Systematic Reviews: Beyond the Basics. Oxford, July 2000. http://www.ihs.ox.ac.uk/csm/Oralabstract2K.htm#Dinnes (accessed 14 August 2003). 3. Siegfried N, Muller M, Volmink J, Deeks J, Egger M, Low N, Weiss H, Walker S, Williamson P. Male circumcision for prevention of heterosexual acquisition of HIV in men (Cochrane Review). In: The Cochrane Library, Issue 3, 2003. Oxford: Update Software. 4. Egger M, Davey Smith G, Schneider M. Systematic reviews of observational studies. In Egger M, Davey Smith G, Altman DG (eds). Systematic reviews in health care: meta-analysis in context. 2nd edition. BMJ Books, London 2001. Competing interests: None declared |
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