Rapid Responses to:
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Rapid Responses: Rapid Responses published:
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Caregivers negatively rate the effect of cholinesterase inhibitors.
- Harald G. De Cauwer (11 August 2005)
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Re: Caregivers negatively rate the effect of cholinesterase inhibitors.
- David G Wilkinson (12 August 2005)
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Evidence for cholinesterase inhibitors in AD
- David G Wilkinson (13 August 2005)
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Cholinesterase Inhibitors for people with Alzheimer's disease
- Neil Hunt, Action on Alzheimer's Drugs alliance (13 August 2005)
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Re: Re: Caregivers negatively rate the effect of cholinesterase inhibitors.
- Harald G. De Cauwer (13 August 2005)
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Cholinesterase inhibitors or Evidence-based medicine?
- Galeno J. Rojas (14 August 2005)
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What is the clinically meaningful NNT/NNH for cholinesterase inhbitors or memantine in Alzheimer's disease?
- Thomas L. Perry (14 August 2005)
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Flawed from the beginning
- Laurence D Herst (14 August 2005)
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Cholinesterase inhibitors for patients with Alzheimer's disease: the experience of Brazilian Ministry of Health
- Pedro Schestatsky, Márcia Lorena F. Chaves, Paulo Dornelles Picon (15 August 2005)
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The Timing of Published Non-Confirmatory Data Re-Analysis Deserves Attention
- Stefan P Kruszewski , M.D., & Jeffrey A Brown, M.D., J.D., M.P.H., Clinical Associate Professor of Psychiatry, University of Medicine and Dentistry of New Jersey (16 August 2005)
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Acetylcholinesterase inhibitors for people with Down's Syndrome and Alzheimer's dementia
- Jennifer D Dolman, Karen Poon (23 August 2005)
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The baby has been thrown out with the bath water
- Rupert McShane, Lon Schneider (2 September 2005)
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The Cochrane reviews of the cholinesterase inhibitors
- JACQUELINE S BIRKS (5 September 2005)
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Cholinesterase inhibitors do have a place in the management of Alzheimer's disease
- Chittaranjan Andrade (8 September 2005)
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People with dementia and carers experience a broad range of benefits from anticholinesterase drug treatments
- Clive Ballard, Alistair Burns, Samantha Sharp, Julia Cream, Richard Harvey (21 October 2005)
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Re: Antidementia Drugs and General Ignorance
- H Förstl (26 October 2005)
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Cholinesterase-Inhibition: How To Do It Properly !
- hans förstl (1 November 2005)
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A notice on the level of the debate on cholinesterase inhibitors in Alzheimer´s Disease
- Hendrik G. van den Bussche (24 November 2005)
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Harald G. De Cauwer, neurologist KLINA Regional Hospital - Augustijnslei 100, B2930 Brasschaat, Belgium
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Dear Sirs, I read the paper of Kaduszkiewicz et al. with great interest.1 The verdict for the cholinesterase inhibitors is rather negative. The authors conclude that the scientific basis for recommendation of cholinesterase inhibitors for the treatment of Alzheimer’s disease is questionable. Before this critical evaluation of large scale randomized clinical trials, the AD2000-study (published in the Lancet, june 2004, and also discussed in this paper) raised already doubts about the beneficial effect of donepezil.2 The study did not show any significant effect on patient- relevant outcomes. This study was highly contested but nevertheless also other authors admitted the success of the cholinesterase inhibitors had not been fully proven.3 In addition to the discussion about the indication of the cholinesterase inhibitors, I would like to report the results of a small study, conducted in our outpatient clinic of a regional hospital in Brasschaat, Antwerp, Belgium. We asked the caregiver of n=22 outpatients, treated with donepezil or galantamine, to evaluate the global status of their beloved. After 1,5 years of treatment, the caregiver was asked to fill in a questionnaire: score the global status before starting medication, after 6 months and after 1,5 year, using a visual analogue scale (VAS). A VAS-score of 0 means there are no problems at all in the global functioning of the patient, a score of 10 means the patient is dependent of others. The results were compared with the MMSE-score. n=14 patients were treated with donepezil, n=18 with galantamine. Gender: 17 F, 5 M. Age (mean; min- max): 75.0; 64-85. MMSE at start: 20; 14-26. MMSE after 6 months: 23; 14-30. MMSE after 1,5 years: 21; 9-30. VAS-score at start: 5.0; 0.1-8.6. VAS-score after 6 months 5.2; 0.1-8.1. MMSE after 1,5 years: 5.9; 0.1-10.0. Although the cognitive aspect as scored by the MMSE ameliorates slightly (+ 3 points after 6 months), the global functioning of the patient is rated rather negatively by the caregiver. There is a constant decline of the global functioning over time. Treatment with cholinesterase inhibitors seems not to be effective, as far as the appraisal of the caregiver is concerned. References: 1. Kaduszkiewicz H, Zimmermann T, Beck-Bornholdt HP, van den Bussche H. Cholinesterase inhibitors for patients with Alzheimer’s disease: systematic review of randomised clinical trials. BMJ 2005; 331(7512):321- 7. 2. Courtney C, Farrell D, Gray R, et al. Long-term donezepil treatment in 565 patients with Alzheimer’s disease (AD2000): randomised double-blind trail. Lancet 2004; 363(9427):2105-15. 3. Kaiser T., Florack C, Franz H, Sawicki PT. Donepezil in patients with Alzheimer’s disease – a critical appraisal of the AD2000 study. Med Klin (Munich) 2002; 100(3):157-60. Competing interests: None declared |
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David G Wilkinson, Consultant in Old Age Psychiatry Moorgreen Hospital, Southampton SO30 3JB
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The discrimination against AD patients apparent in recent papers should be challenged. The 'study' Dr De Cauwer describes is a straw poll and hardly very objective. However, despite showing a remarkable degree of stabilisation in global function and improvement in cognition it is somehow being presented as an indictment against the treatment. It is not a helpful addition to the debate about the utility of cholinesterase inhibitors as without a control group one cannot tell how much the patients would have deteriorated after 1.5 years. As a neurologist would you say that L-dopa had no value in your PD patient if after some initial improvement he had not worsened after 1.5 years? You would probably advocate increasing the dose not stopping it. Competing interests: None declared |
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David G Wilkinson, Consultant in Old Age Psychiatry Moorgreen Hospital, Southampton SO30 3JB
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Please spare us from another systematic review (Kaduszkiewicz et al BMJ 2005; 331: 321-327) that adds absolutely nothing to the sum of human knowledge. The hubris of this group knows no bounds, they admit to being out of step with virtually every randomised controlled trial and meta analysis so far published and yet confidently assert that they have it right and the rest of the world has somehow overlooked the obvious. This review is timely coming as the UK's National Institute for Health and Clinical Excellence (NICE) delays issuing its guidance on the only drug treatments for Alzheimer’s disease. However, even NICE acknowledges that these drugs are clinically effective, it is their cost effectiveness that it disputes. This analysis flies in the face of expert opinion and the experiences of people with dementia and their carers. The main complaint about previous studies seems to be the choice of the last observation carried forward (LOCF) as an end point in studies with non-random dropouts as if no-one undertaking studies had ever thought of that. The analysis of the data on the trial for which I was responsible (Wilkinson et al 2001) used the LOCF but with the active/placebo difference calculated at the time of dropout, not from the placebo decline at endpoint to minimise the exaggeration of the effect size in a deteriorating disease. This tendentious article displays a lack of understanding not only of the disease but also of the quality control in pivotal trials. This is exemplified by far too much being made of the theoretical problem of the LOCF analysis when the effects were often as great or greater with the observed case or completer analyses which do not impute missing values. That every last detail is not included in the published papers does not mean it did not happen or was not considered. One must lift one’s eyes to the horizon occasionally; remember if it swims, quacks and flies like a duck I am afraid it probably is a duck no matter what theoretical criticisms one has of the observer's viewpoint. Clinical practice is not about the mean changes in test scores but about individual responses. Means and confidence intervals in good RCT's are necessary to give us the confidence to use something in clinical practice but they are not the answer, experience tells us whether it is useful. To paraphrase Oscar Wilde this kind of review panders to the cynics who know the price of everything but the value of nothing. This attitude was reflected in the recent draft guidance from NICE suggesting the three drugs reviewed in this paper and memantine are not worth prescribing in the NHS in England and Wales. If this stance is also taken by the similar committee in Germany the Institut für Qualität und Wirtschaftlichkeit im Gesundheitswesen (IQWIG) it will be a triumph for the English and German Generals and a complete betrayal of those suffering in the trenches yet again. The kind of irresponsible pseudoscience demonstrated in this paper only fuels this perverse zeitgeist. Competing interests: None declared |
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Neil Hunt, Chief Executive Alzheimer's Society, Action on Alzheimer's Drugs alliance
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Dear Editor Kaduszkiewicz’s conclusions from his limited review of the only drug treatments for people with Alzheimer's disease flies in the face of available trial data, clinical practice and patient evidence. The National Institute for Clinical and Health Excellence (Nice) has recently delayed its decision on whether to continue to recommend cholinesterase inhibitors for prescription on the NHS. Nice reviewed the evidence base as part of its appraisal and concluded that they were clinically effective. It was their cost effectiveness that was questioned. There is overwhelming scientific evidence that these drug treatments benefit some people with Alzheimer's disease. Indeed, 31 rigorous placebo controlled trials in people with Alzheimer's disease have been evaluated in three Cochrane reviews. All have concluded that cholinesterase treatment results in significant overall benefit, with specific improvements in cognition and activities of daily living. What is more, the benefits of cholinesterase inhibitors are further emphasised by the largest survey of people taking one of the drugs for dementia and their carers in the UK, with 73% of the 2625 participants reporting at least some benefit from the drug treatments. This is in stark contrast to De Cauwer's limited study. Not everyone responds to the drug treatments for Alzheimer's disease, but this does not mean that they should be denied to people they may help. Currently, the only ethical and humane way to see whether this drug treatment works is to prescribe it and then monitor the response - this is the reality of clinical practice. People with dementia and their carers are directly affected by the impact of these review papers, and by Nice's decision. They should not be forgotten in this debate. Neil Hunt Action on Alzheimer's Drugs alliance Competing interests: None declared |
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Harald G. De Cauwer, Neurologist KLINA regional Hospital, Augustijnslei 100, B2930 Brasschaat, Belgium
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Dear sirs, The visual analogue scale is widely used but is, I agree, not ’objective’ at all. Nevertheless, it is a very practical tool for examining evolutive disease. In fact, most dementia rating scales e.g. the progressive deterioration scale (PDS), the Gottfries-Brane-Steen-scale, the CIBIC-plus and neuropsychiatric inventory (NPI) also use ‘subjective’ information obtained when interviewing the care-givers and/or patients. Should we no longer ask the patients and care-givers for their ‘subjective opinion’? Should we consider all studies using ‘subjective’ information invalid? The message of my reply is not to withdraw cholinesterase inhibitors as Dr. Wilkinson suggests. Untill more effective drugs are developed, one should continue with the ‘best’ medication available… PS: in my reply a typing error occurred: n=8 patients were treated with galantamine. Competing interests: None declared |
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Galeno J. Rojas, neurologist Hospital Policlinico Bancario. Argentina - Capital Federal (1416)
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I read the paper of Kaduszkiewicz et al. and I think is very interesting. The objective of the present pharmacologic symptomatic treatments is to delay the cognitive deteriorate, to prolong the functional capacity and thus to delay the institutionalization, to reduce the necessity of individualized attention and to offer economic benefits to the society. The drugs that improve the cognitive function through the inhibition of acetylcholinesterase are approved for the symptomatic treatment of slight to moderate Alzheimer disease. All have shown to have a similar effectiveness in improving the cognition (improvement by 6-12 months of reversible type) measured by specific scales and test. Nevertheless they vary in the amount of administered doses and adverse effects. The objective of the pharmacologic treatment would be to improve the quality of life of the patient and its relatives, besides to diminish stress of the caretakers. But little it is known of the long term effectiveness of these drugs, in addition there are very few studies that have clinically significant end points. Little it is known of the interaction between drugs with different mechanisms of action. For example an acetylcholinesterase inhibitor and vitamin E. It is alarming that most of the clinical trials are of 6 to 12 months of length, since this disease evolves in around 7 years. Almost all the clinical trials show similar improvements, almost all measures by ADAS- cognitive (neuropsychological test), but the reality is that although several drugs produce an improvement of 3 points in ADAS-cognitive, this data becomes irrelevant because no speech of quality of life for patient, nor of the activities of the daily life, far from it to diminish the progression of the disease and the consequent institutionalization. In any case, many scales finish being subjective and little sensible to the changes that take place in the patient. In addition few data are extrapolables to the clinical practice since the criteria of selection of patients in almost all the clinical trials exclude the patients with comorbidities (for example heart failure) and the patients who receive other types of drugs. Thus these clinical trials speak of effectiveness of a drug in altering certain parameter, but effectiveness and benefit for the patient do not speak of. To delay or to slow down the advance of the disease would be the objective to reach. Drugs have been enumerated that are directed to modify the progression of the disease, we spoke of antioxidants, anti- inflammatory, ginkgo biloba, and others in studies. But in spite of the clinical trials made on the matter the American Academy of Neurology it does not recommend his use, since the day of today no therapy has shown to stop or to revert of clinically significant way the process of the underlying disease.-1 It will be necessary to respond to these questions with good designed clinical trials: When it is necessary to initiate the treatment? Or How should be measured the effectiveness of drugs actually used ? And When it is necessary to stop the treatment by lack of answer or loss of efficiency fade? Which will be the long term consequences of their treatment? Which is the function of the AMYLOID-BETA PROTEIN and what it would happen after his inhibition (since nowadays the vaccine for the Alzheimer´s disease is in Phase II of investigation)?-2 Several studies have been made to measure the effectiveness of the modifiers of the Alzheimer´s disease, have studied the degree of cerebral atrophy by IRM, the LCR, genetics, but little it is known still. The reality is that it is better to have something not to have anything in this implacable disease and the fact to have something to offer to our patients does not have to cloud the necessity to continue learning on the disease of Alzheimer. 1- R. S. Doody, J.C. Stevens, C. Beck, R.M. Dubinsky, J.A. Kaye, L. Gwyther, R.C. Mohs, L.J. Thal, P.J. Whitehouse, S.T. DeKosky, and J.L. Cummings Practice parameter: Management of dementia (an evidence-based review): Report of the Quality Standards Subcommittee of the American Academy of Neurology Neurology, May 2001; 56: 1154 - 1166. 2 - S. Gilman, M. Koller, R. S. Black, L. Jenkins, S. G. Griffith, N. C. Fox, L. Eisner, L. Kirby, M. B. Rovira, F. Forette, J. -M. Orgogozo, and for the AN1792(QS-21)-201 Study Team Clinical effects of A{beta} immunization (AN1792) in patients with AD in an interrupted trial Neurology, May 10, 2005; 64(9): 1553 - 1562. Competing interests: None declared |
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Thomas L. Perry, Therapeutics Initiative, Dept. of Anaesthesiology, Pharmacology & Therapeutics University of British Columbia, Vancouver, B.C. V6T 2B5
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I have read carefully and participated in critical appraisal of all published DBRCT of cholinesterase inhibitors and memantine for Alzheimer's disease, as well as the Cochrane and other published meta-analyses. It is clear to me that cholinesterase inhibitors have a small mean effect on measures of cognitition and global status (e.g. about 0.5 point in the good direction on a scale where 1 point represents "minimal improvement"). It is equally clear to me that they cause serious adverse events in some patients and unpleasant cholinergic side effects in many. What remains unclear is what fraction of patients obtain a clinically useful benefit, or conversely are significantly harmed by treatment. I agree with Professor Wilkinson that individual benefit or harm would be the criterion for continuing drug treatment in an AD patient, as for the symptomatic or preventive treatment of any other patient or condition. Millions of patients (and their prescribing doctors) are in an analogous position when dealing with pain, mental illness, or similar chronic conditions. Parkinson's disease, in which the drug treatment has dramatically beneficial (and harmful) effects, is no more similar to AD than is the relief of surgical or cancer pain, where the effects of an individual's treatment are seldom in doubt. Do any BMJ readers think they can estimate the individual patient's probability of experiencing clinically useful benefit or significant harm more accurately than the Canadian meta-analysis (1)? Similarly, can anyone cite convincing evidence against the conclusion of the AD2000 trial (2) that it is not easy to tell which patients are "benefiting" from treatment? I would be very interested to read a carefully referenced reply. Thomas L. Perry, M.D., FRCPC 1. Lanctot KL et al. Efficacy and safety of cholinesterase inhibitors for Alzheimer’s disease: A meta-analysis. CMAJ 2003; 169: 557- 64 2. AD2000 Collaborative Group. Long-term donepezil treatment in 565 patients with Alzheimer’s disease (AD2000): randomized double-blind trial. Lancet 2004; 363: 2105-15. Competing interests: None declared |
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Laurence D Herst, Senior Psychiatrist Department of Health and Human Services, Tasmania, Australia
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The commercialisation of the Cholinesterase Inhibitors (CIs) began in 1986 with the publication: Oral tetrahydroaminoacridine in long-term treatment of senile dementia, Alzheimer type.(1) Despite deliberating "long and hard before deciding to publish" (2) the NEJM was unaware that participants were charged fees to participate in the research.(3) An interim investigative report by the FDA "revealed deficiencies of sufficient importance" in the methodology of the study.(2) In 1994 a JAMA editorial expressed the view that "no studies have succeeded" in identifying patients "most likely to benefit and/or least likely to suffer side effects" of tacrine.(4) Since then the CIs have been promoted not for Alzheimer's disease, Lewy body dementia, vascular dementia, Parkinson's disease, behavioural management of dementia and more. The National Institute for Clinical Excellence (NICE) preliminary recommendations in 2005 are that donepezil, rivastigmine and galantamine not be recommended for use in the treatment of mild to moderate Alzheimer’s disease(AD).(5) The drug companies, along with psychiatrists and other specialists paid for their "expertise", have developed strategies that have exploited public vulnerability. Vast sums have been spent for a treatment of questionable benefit. With an aging population we must assess research and treatment options more carefully than we have with the CIs. 1. NEJM,Nov 1986;315:1241-5. 2. NEJM,Jan 1991;324:349. 3. NEJM,June 1987;316(25):1605-1606. 4. JAMA Chicago:Apr 1994;271:(13):1023-1024. 5. http://www.nice.org.uk/page.aspx?o=245909 Competing interests: Member, Healthy Scepticism |
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Pedro Schestatsky, Advisor of the Brazilian Ministry of Health Porto Alegre, Brazil (90035-003), Márcia Lorena F. Chaves, Paulo Dornelles Picon
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Congratulations for the very relevant work from Kaduszkiewicz et al (1) concerning the role of cholinesterase inhibitors for patients with Alzheimer's disease, which is in accordance with other authors findings (2,3). Nowadays, we have been facing a serious public health problem regarding this issue in Brazil. The pharmaceutical industry still has a great influence over some of our physicians and it has been extremely difficult for the Public Health System administration to handle with the enormous amount of drug treatments for patients with Alzheimer´s disease. The Brazilian Public Health System garantee free distribution of cholinesterase inhibitors for any patient with Alzheimer´s disease and Clinical Dementia Rating Scale of 1 or 2. Treatment is given for least 3 months and withdrawal is recommended when patient deteriorates. However, during the last 5 years, Brazilian Ministry of Health have been working on Evidence-Based-Medicine´s guidelines of high-cost treatments in the field of Neurology which is an attempt to change the current medical view throughout our country. The mentioned article published (1) perfectly fits with our purpose to spread out the principles of a rational using of such an expensive treatments in public health and to review our national guidelines in recommending those drugs for patients with Alzheimer´s disease. Sincerely yours, Dr. Pedro Schestatsky
Federal University of Rio Grande do Sul, Brazil
References: 1. Hanna Kaduszkiewicz, Thomas Zimmermann, Hans-Peter Beck-Bornholdt, and Hendrik van den Bussche. Cholinesterase inhibitors for patients with Alzheimer's disease: systematic review of randomised clinical trials. BMJ 2005; 331: 321-327 2. Vermeulen M, de Haan RJ. New therapies in neurology, but who benefits? Ned Tijdschr Geneeskd. 1999; 143(35):1764-6. 3. Hogan DB, Goldlist B, Naglie G, Patterson C. Comparison studies of cholinesterase inhibitors for Alzheimer's disease. Lancet Neurol. 2004; (10):622-6. Competing interests: None declared |
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Stefan P Kruszewski , M.D., Psychiatrist Harrisburg, Pennsylvania USA, & Jeffrey A Brown, M.D., J.D., M.P.H., Clinical Associate Professor of Psychiatry, University of Medicine and Dentistry of New Jersey
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BMJ published an important paper by Kaduszkiewicz, Zimmermann, Beck- Bornholdt and van den Bussche in their 06 August edition. (1) The paper, “Cholinesterase inhibitors for patients with Alzheimer's disease: Systematic review of randomised clinical trials”, is a meta-analysis of 22 trials. It demonstrated that flawed methodology and negligible clinical benefits undermine previously asserted recommendations for some of the commonly prescribed anticholinesterase inhibitors for Alzheimer’s disease. Separately, an important 2002 study by Ann Hamer and her associates published in the Journal of Managed Care Pharmacy (JMCP) revealed similar findings of flawed methodology and limited clinical benefits. The subject of that investigation was the “off-label” use of gabapentin, a drug approved for adjunctive use in partial seizure disorders and post-herpetic neuralgia but not for the wider variety of chronic pain and psychiatric syndromes which accounted for much of its off-label prescribing. In that study, the authors retrospectively reviewed medical records from 105 patients who were treated with gabapentin, prescriptions reimbursed by Oregon Medicaid. (2) 95% of the gabapentin prescriptions were off-label. More significantly, 88% of patients receiving gabapentin did not demonstrate a positive response. Unfortunately for those who paid the bills for gabapentin therapy and for those consumers who reported no benefit and/or unpleasant side- effects, these published negative results came almost 9 years after the successful release and marketing of gabapentin. [Gabapentin (Neurontin- Parke-Davis) was approved by the US FDA on 30 December 1993. In 2001, according to Hamer et al, gabapentin was in the top-10 drug products by total costs paid by Oregon Medicaid fee-for-service. ] One of the likely sources of over-enthusiastic off-label prescribing and lack of documented off-label benefits has been the uncritical adoption of claims of benefits based upon open-label trials or inadequately populated cohorts. Another occurs when research scientists are not expected to compare their original findings with those of longer term studies which contradict their original conclusions. Some of these problems were recently described in an investigative report by John Ioannidis that appeared in the 13 July 2005 edition of the Journal of the American Medical Association (JAMA.) (3) He reviewed 49 highly cited original clinical research studies to determine whether subsequent analysis could reiterate or replicate original positive findings. Although some studies (24%) went unchallenged, about 32% of studies----or nearly one-third of preliminary highly touted research findings involving various medicines and therapeutics---did not have the reliability and validity of their findings confirmed by follow-up research, with some outcomes specifically contradicted by subsequent studies. Kudos to BMJ, JAMA, and JMCP (and other comparably reputable peer- reviewed journals) for identifying research whose original findings have subsequently been seriously qualified or invalidated. We believe ethical journals have an obligation to expose research making claims of efficacy-- –especially for off-label use of medications---when these claims do not withstand subsequent prospective scrutiny. Pharmaceutical journals have a particularly strong obligation to do this since they hold a special trust in the provider community, often being the first place where new drugs are introduced and off-label use is promoted. Furthermore, we maintain that, in order to repair public and provider trust in academic and pharmaceutically-sponsored research, journals must expand their exposure of data analyses that are later found to have been biased and/or predicated upon misstatements regarding the reliability and validity of prior published results. Even more carefully considered research and publishing criteria still fall short of protecting the patient and provider communities when publication is too-long delayed. Timing is keenly important. Indeed, even after the publication of spurious data collection or misrepresented results, multi-year lapses routinely occur between non- confirmatory re-analysis and bogus preliminary findings. Therefore, if journal and media scrutiny are effectively to minimize the ramifications (morbidity, mortality and added healthcare costs) of questionable data, published re-analysis must occur, if at all possible, in close temporal relationship to the original publications. Stefan P. Kruszewski, M.D. Jeffrey A. Brown, M.D., J.D., M.P.H. Clinical Associate Professor of Psychiatry University of Medicine and Dentistry of New Jersey 1 Kaduszkiewicz H, Zimmermann T, Beck-Bornholdt HP, van den Bussche H. Cholinesterase inhibitors for patients with Alzheimer's disease: systematic review of randomised clinical trials BMJ. 2005 Aug 6; 331(7512): 321-327 2 Hamer, AN M, Haxby, DG, McFarland, BH and Ketchum, K. Gabapentin Use in a Managed Medicaid Population. JMCP 2002; 8(4): 266-271 3 Ioannidis, JP. Contradicted and Initially Stronger Effects in Highly Cited Clinical Research. JAMA. 2005; 294 (2): 218-228 Competing interests: None declared |
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Jennifer D Dolman, SpR in Learning Disabilities Gloucestershire Partnership NHS Trust Learning Disabilities Services, Gloucester. GL1 3HZ, Karen Poon
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According to Kaduszkiewicz et al. the scientific basis for recommendations of acetylcholinesterase (AChE) inhibitors for the treatment of Alzheimer’s disease is questionable. However we are concerned that a significant proportion of the population suffering from Alzheimer’s dementia appears to have been forgotten – those with learning disabilities. It is well documented that 54.5% of people with Down’s Syndrome aged 60-69 years are affected by Alzheimer’s dementia, compared to only 5% of the general population aged over 65 years. The original NICE guidelines (2001) approved the use of AChE inhibitors for the management of Alzheimer’s dementia in the context of specialist assessments and monitoring. The mini mental state examination (MMSE) was recommended as the most appropriate tool to determine treatment initiation and discontinuation. Although NICE did not specifically exclude people with learning disabilities, the MMSE is outside the normal range in this population. This has meant that the use of AChE inhibitors in people with Down’s Syndrome and dementia has been limited compared to the general population. In addition, due to important and appropriate issues regarding giving informed consent, people with learning disabilities are usually excluded from clinical trials. (As far as we are aware there are no published multicentre, double blind randomised controlled trials on the use of AChE inhibitors in people with Down’s syndrome.) Finally, it is well recognised that people with learning disabilities metabolise and respond to drugs differently (and not always predictably) from the general population. Therefore guidelines derived from double blind, randomised controlled trials should not solely be used to make decisions about the use of the drugs in people with learning disabilities. Our local SHA agreed to fund the use of AChE inhibitors in people with Down’s Syndrome and Alzheimer’s dementia provided a suitable audit tool was developed to determine the effectiveness of treatment. A Trust Down’s and Dementia care pathway was therefore developed. People with Down’s syndrome over the age of 35 years and known to the service are screened every five years using the Assessment of Motor Processing Skills (AMPS) and Dementia Questionnaire for persons with Mental Retardation (DMR). These were chosen as the most appropriate tools due to their sensitivity to change. If the client develops dementia these assessments are carried out every 3-6 months for monitoring of disease progression and treatment effectiveness. A recent audit of the pathway revealed everybody with Alzheimer’s dementia (n=30) was considered for treatment and 24 (80%) were commenced on an AChE inhibitor. The reasons for not commencing treatment were that the client’s dementia or their premorbid level of functioning was so severe that treatment would not produce worthwhile benefits and in one case only, because of concerns regarding gastrointestinal side effects. Of those who had commenced treatment 22 (92%) remained on treatment. It was continuing to be effective for 12 (50%) of clients (time from initiation 1-45 months), was too early (i.e. < 3 months since commencing treatment) to decide on effectiveness for 6 (27%) of clients and the effectiveness was being questioned in 5 (23%) of clients (time span 4 -22 months). For the two people who had stopped treatment, one had died of causes unrelated to the Alzheimer’s dementia and the other had gastrointestinal side effects (donepezil). Only one other client had suffered side effects – diarrhoea on commencing donepezil and this had abated when the dose was reduced and increased at a slower rate. The usual daily starting doses were 5mg for donepezil, 6mg for rivastigmine and 8mg for galantamine. In conclusion, since NICE (2001) did not specifically consider the needs of people with learning disabilities those of us working in the speciality have had to devise more appropriate ways of monitoring the effectiveness of AChE inhibitors in order not to exclude and therefore discriminate against people with learning disabilities having access to this treatment. Using clear assessments there is a significant proportion of people within our audit who have benefited from these drugs. We are concerned that NICE will fail to realise the need to consider other levels of evidence for people with learning disabilities. Therefore if NICE do recommend not using AChE inhibitors, people with learning disabilities could again be discriminated against. Competing interests: None declared |
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Rupert McShane, Coordinating Editor, Cochrane Dementia and Cognitive Improvement Group Fulbrook Centre, Churchill Hospital, Oxford, OX3 7JU, Lon Schneider
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Kaduszkiewicz and her colleagues are right to realise that the conclusions which they draw about cholinesterase inhibitors (1) are out of step with those of other reviewers. Many of the imperfections that they so astutely identified are omissions in the reporting of the trials in journals, not defects in quality of the trial. Their response, which is to write off the results of those trials as non-informative, is not justified and certainly not made from the perspective of evidence-based medicine. Cochrane reviewers have not considered lack of good reporting in this area – as frustrating as that is – to be a reason to exclude trials results from further consideration. Rather they have sought additional material such as protocols and clinical study reports from the drug companies and have asked them for more information. Moreover, most, if not all the trials that Kaduszkewicz questions were carried out under Good Clinical Practice and International Conference of Harmonization guidelines (e.g. http://www.fda.gov/oc/gcp/guidance.html) in order to meet the standards necessary for regulatory review. These trials in fact meet the quality standards that Kaduszkiewicz and colleagues sought but did not find in the published reports. Their criticism of the failure of analyses to correct for multiple testing is misplaced and rests on their misunderstanding of the trials’ methodology. The oft cited Bonferroni correction is the most conservative of several post hoc adjustments for multiple comparisons that can be used in the absence of pre-specified primary outcomes. However, all the trials they included in their review had clearly specified primary outcomes, usually two co-primaries, a cognitive outcome and a global, each having to reach a p < 0.05 alpha error level. Notwithstanding this error, their paper fails to refer to any meta-analytic results. Examination of Cochrane meta-analyses shows that the effects of cholinesterase inhibitors would remain statistically significant even if Bonferroni corrections were applied to the multiple pooled outcomes in the meta-analyses. Their point about differential dropout is already widely rehearsed and understood. They are wrong to suggest that this was inadequately considered in the conclusions of Cochrane reviews. These reviews show that differential dropout occurs for rivastigmine and higher dose galantamine but not donepezil. It was carefully interpreted by comparing the last observation carried forward and completer analyses, and by retrieved dropouts analyses, when part of the protocol, so as to give the best approximation to true intention to treat analyses where available. This is the best that can be achieved without access to individual patient data. Altogether this constitutes evidence that needs to be integrated into clinical assessments of effectiveness and utility, and not dismissed out of hand. The criticism of the Mohs et al trial(2) – that investigators could remove a patient on the basis of the investigator’s clinical judgement which can be subjective - is tautological and gratuitous. The judgement was to be applied in interpreting definitions of ‘clinically evident decline’. Clinical judgement is what physicians do. This trial met its own objectives – assessment of time to loss of daily activities - which were not the same as most of the other trials. Most of these trials were designed on to show differences in mean cognitive and global function between drug and placebo groups and were not designed or powered to test post hoc for subgroups or prospectively designed to define individual responders. The authors’ comments about subgroups of responders and the need to define assessment procedures which distinguish responders are sensible, but they are not new and bear no relation to the text in the preceding sections. There is no such thing as a perfectly reported trial. But to write off the available trials as being of ‘poor’ methodological quality for the reasons offered does not adequately deal with the evidence and does nothing to promote the standing of systematic reviews - of which this was not a good example. 1. Kaduszkiewicz H et al. Cholinesterase inhibitors for patients with Alzheimer's disease: systematic review of randomised clinical trials BMJ 2005; 331: 321-327 2. Mohs RC et al A 1-year, placebo-controlled preservation of function survival study of donepezil in AD patients. Neurology. 2001 Aug 14;57(3):481-8. Competing interests: RM is paid to coordinate production of reviews by the Cochrane Dementia and Cognitive Improvement Group, has received speaking fees, support for attending conferences and support for a course he runs from all manufacturers of cholinesterase inhibitors. LS has received speaking and consulting fees from all manufacturers of cholinesterase inhibitors. |
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JACQUELINE S BIRKS, MEDICAL STATISTICIAN DIVISION OF GERATOLOGY, DEPARTMENT OF CLINICAL MEDICINE, UNIVERSITY OF OXFORD, RADCLIFFE INFIRMARY
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Many randomized controlled trials of the three cholinesterase inhibitors, donepezil, galantamine and rivastigmine, have been completed and published. Cochrane reviews of the three drugs, an individual patient data meta-analysis of donepezil by a joint team from the manufacturing company and independent scientists, and a meta-analysis of all three have been published. The combined evidence concludes that, for each of the three drugs, there are benefits for patients with Alzheimer’s disease. The three drugs are licensed for use in many countries including those of Europe, and North America. In the UK NICE has recommended their use, based on the results of trials and systematic reviews, although this is now under review on account not of efficacy but of cost effectiveness. Kaduszkiewicz et al dismiss all this evidence as worthless, because they state that without exception the trial methodology is poor and all the previous reviews are not evidence based. Are they just being vexatious? The reviews criticised included a systematic search for trials, assessment of the quality of the evidence and a synthesis of the data using meta-analysis. What is their definition of evidence based? In their own systematic review of these drugs, discussion with reference to a checklist of points led to qualitative assessment of the methodology of the trials. They criticise the Cochrane reviews for failing to assess quality and thence to recognize the methodological shortcomings which they have detected. They make the following points and mostly they are misguided. 1. No correction for multiple outcomes.
2. Missing intention to treat analyses and incomplete data.
3. Different design and methodological flaws.
4. Imbalance at baseline.
Having dismissed the trials as too poor for consideration, and the apparent treatment effects as too small to be of any use, they conclude that the benefits are not proven. But then, in an about turn, they also conclude that adverse effects are without doubt present. Their criticism of the methodology of the trials and of inferences due to testing multiple outcomes without correction are all forgotten. It is to avoid decisions resting on such inconsistency of approach that the Cochrane Collaboration produces high quality systematic reviews. Jacqueline Birks
Mohs RC, Doody RS, Morris JC, Ieni JR, Rogers SL, Perdomo CA, Pratt RD. A 1-year, placebo-controlled preservation of function survival study of donepezil in AD patients. Neurology 2001;57(3):481-8. Rogers SL, Friedhoff LT and the Donepezil Study Group. The Efficacy and safety of Donepezil in patients with Alzheimer's disease: results of a US multicentre, randomised, double-blind, placebo-controlled trial. Dementia 1996;7:293-303. Birks J, Harvey R The efficacy of donepezil for mild and moderate Alzheimer’s disease (Cochrane Review). In: The Cochrane Library, issue 2, 2005. Chichester, UK: John Wiley Birks J, Grimley Evans J, Iakividou V, Tsolaki M . Rivastigmine for Alzheimer’s disease (Cochrane Review). In: The Cochrane Library, issue 2, 2005. Chichester, UK: John Wiley Olin J, Schneider L .Galantamine for Alzheimer’s disease (Cochrane Review). In: The Cochrane Library, issue 2, 2005. Chichester, UK: John Wiley Competing interests: None declared |
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Chittaranjan Andrade, Professor of Psychopharmacology National Institute of Mental Health and Neurosciences
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Sir, Kaduszkiewicz et al (1) conducted a systematic review of clinical trials of cholinesterase inhibitor treatments for Alzheimer's disease. They found that these drugs conveyed benefits that were small in magnitude, and that the clinical trials were anyway flawed in many regards. They questioned the value of these drugs for Alzheimer's patients. The review addressed only one part of the picture. Poor cognitive benefits of the treatments notwithstanding, the cholinesterase inhibitors are associated with substantial caregiver benefits. For example, in a secondary analysis, Blesa (2) observed that, after 6 months of treatment, the time spent by caregivers in assisting Alzheimer's patients was 1-1.5 h/day less with galantamine than with placebo, and the time spent in supervising the patients was a further 1.5 h/day less. Thus, galantamine saved the caregivers a total of 2.5-3 h/day. In another secondary analysis of data from two 6-month, randomized, double-blind, placebo-controlled trials conducted in 825 patients with Alzheimer's disease, Sano et al (3) showed that, relative to placebo, galantamine saved caregivers an average of 32 min/day in terms of assisting the patient with activities of daily living. The saving was 53 min/day in patients with moderate Alzheimer's disease. Furthermore, relative to placebo, galantamine-treated patients could be left unsupervised for an average of 27 min/day longer; this figure was 68 min/day in patients with moderate Alzheimer's disease. In this context, it should be noted that galantamine-related caregiver benefits are related to the neuropsychiatric benefits of the drug, and not to its cognitive benefits (4). References 1. Kaduszkiewicz H, Zimmermann T, Beck-Bornholdt H-P, van den Bussche H. Cholinesterase inhibitors for patients with Alzheimer's disease: systematic review of randomised clinical trials. BMJ 2005; 331: 321-327. 2. Blesa R. Galantamine: therapeutic effects beyond cognition. Dement Geriatr Cogn Disord 2000; 11 (suppl 1): 28-34. 3. Sano M, Wilcock GK, van Baelen B, Kavanagh S. The effects of galantamine treatment on caregiver time in Alzheimer's disease. Int J Geriatr Psychiatry 2003; 18: 942-950. 4. Cummings JL, Schneider L, Tariot PN, Kershaw PR, Yuan W. Reduction of behavioral disturbances and caregiver distress by galantamine in patients with Alzheimer's disease. Am J Psychiatry 2004; 161: 532-538. Competing interests: I have been a site investigator in multicenter clinical trials. |
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Clive Ballard, Director of Research Alzheimer's Society, Alistair Burns, Samantha Sharp, Julia Cream, Richard Harvey
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A recent review published in the BMJ(1) questioned the conclusions of the Cochrane evidence based reviews focussing on each of the 3 licensed cholinesterase inhibitors that these agents conferred significant clinical benefit.2,3,4 A subsequent letter presented qualitative data from a small group of 22 carers, which consistent with the Kaduszkiewicz et al review, suggested that the perceived benefits of treatment were modest.5 Whilst we fully agree that it is imperative that systematic evidence from the experiences of people with AD is available in the public domain and contributes to the overall evidence base when appraising pharmaceutical treatments; this information needs to be based on large systematic surveys and not small case series. To ascertain the experiences of people with dementia and their carers regarding treatment with anti-dementia drugs we undertook a postal survey of people with dementia and their carers. A questionnaire was posted to the membership of the UK Alzheimer's Society and to memory clinics in the UK for distribution to people with dementia and their carers, asking people with experience of the anti- dementia drugs to respond. In total, 2,295 people who had experience of one of the 3 licensed anticholinesterase drug treatments responded (2,060 - 77% donepezil, 474 (18%) rivastigmine, 487 (18%) galantamine). There were 18 questions in the questionnaire, with topics including the perceived benefits and side effects of drug treatment, access to and information about the drug treatments and other care services used (full questionnaire available at www.alzheimers.org.uk). A specific question asked respondents “whether, taking everything into consideration, they felt that the drug treatment they had received had worked” and to avoid asking leading questions respondents were asked, in their own words, to list up to 5 five ways in which treatment had been helpful. Overall 1,569 (68%) of people who had been treated with at least one of the anticholinesterase drugs stated that the treatment had worked. The 10 most frequently reported benefits included being more aware and more active, calmer, taking more interest in things, improved conversation, better quality of life and increased confidence, in addition to the improvements usually evaluated in clinical trials. These results are consistent with the findings of an Australian consumer survey which found 70% of those who had experience of drug treatments for dementia felt they were effective.6 Importantly the benefits experienced extended well beyond stabilization of illness and improvements in function and improved cognition and clearly illustrates that the majority of people receiving cholinesterase treatment perceive the therapies to be effective. 1) Kaduszkiewicz H, Zimmermann T, Beck-Bornholdt H, and van den Bussche H. Cholinesterase inhibitors for patients with Alzheimer's disease: systematic review of randomised clinical trials. BMJ 2005;331: 321 - 327 2)Olin J, Schneider L. Galantamine for dementia due to Alzheimer's disease (Cochrane Review), In: The Cochrane Library, Issue 1, 2004. 3)Birks J, Grimley Evans J, Iakovidou V et al. Rivastigmine for Alzheimer's disease (Cochrane Review), In: The Cochrane Library, Issue 1, 2004. 4)Birks JS, Harvey R. Donepezil for dementia due to Alzheimer's disease (Cochrane Review), In: The Cochrane Library, Issue 1, 2004. 5)De Cauwer H G, August 11, 2005 response to: Kaduszkiewicz H, Zimmermann T, Beck-Bornholdt H, and van den Bussche H. Cholinesterase inhibitors for patients with Alzheimer's disease: systematic review of randomised clinical trials. BMJ 2005;331: 321 – 327 http://bmj.bmjjournals.com/cgi/eletters/331/7512/321 6) Alzheimer’s Australia. Consumer medication survey. Alzheimer’s Australia, 2005. Competing interests: CB has received consultancy fees from Pfizer, Novartis, Janssen and Shire, honoraria for presentations and research funding from Novartis and Janssen. JC, CB and SS are employed by the Alzheimer’s Society who actively campaign for fair access to effective drug treatments for people with dementia.AB has received expenses and honoraria from companies involved in the manufacture and marketing of drugs for Alzheimer’s disease. RH has no competing interests to declare other than being a psychiatrist who prescribes cholinesterase inhibitors for patients. |
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H Förstl, Director and Chair Dept Psychiatry & Psychother TU Munich
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„Generals“ commanding committees in the British (NICE) and German (I- QUIP) health systems are feared to triumph and withhold antidotes from those suffering in the trenches, while irresponsible pseudo-science is the fuel for their perverse Zeitgeist (1). It is exactly this kind of desperate statement from an honourable colleague, which adds to our pain and shame, after the publications of the British AD2000 study and a recent German exercise in therapeutic nihilism (2). Potential malice and malingering of experts and opinion leaders have been exposed by a fresh look from a group, unburdened by previous experience. Their work was an innocent and absolutely independent by-product of the “German Dementia Competence Network”, sponsored by the German “Federal Ministry of Research”. A large number of comments have been made, indicating that several important points were missed. Here are a few more: • published evidence clearly supports the symptomatic efficacy of cholinesterase-inhibitors in (Alzheimer) dementia, but unpublished studies with non-significant results may represent a real problem (they are unavailable); • results gathered from one population (e.g. from the USA) may not be valid for other types of populations; • it is an illusion to assume that positive treatment effects can be observed reliably by an individual physician overseeing single patients or small patient groups, because of the heterogeneity of (Alzheimer) dementia and its variable course; this is one reason for carrying out large-scale, randomized, double- blind, controlled trials; • the costs for effective anti-dementia substances are currently high, - but this must and will not be eternally so; • we all want much more effective treatments for patients who already are or who will become demented in the near future, but these interventions may not become available during our lifetimes (even though generals and their propaganda of silver bullets have led the public to hold out without proper support for the last 15 years). The authors (2) and Perry (3) stated that they were unaware of means to identify individuals who will respond to anti-dementia drugs. According to the available evidence, patients with predominant cholinergic deficits will benefit most strongly from cholinesterase-inhibitors. Their clinical features are cognitive impairment plus: • recurrent confusional states (“fluctuating course”) with • visual hallucinations, • marked EEG-slowing and • particularly slim cholinergic nuclei in their high-resolution brain -scans. Some of these patients are said to suffer from the highly prevalent “dementia with Lewy-bodies” or a dementia with confusional states etc. Other beneficiaries are students and airline pilots (PubMed knows more). (1) D.G. Wilkinson. Evidence for cholinesterase-inhibitors in AD. BMJ (2005) (2) H. Kaduskiewitz et al. Cholinesterase-inhibitors for patients with AD. BMJ (2005) (3) T.L. Perry. What is the clinically meaningful TNT/NHS. BMJ (2005) Competing interests: I received fees from Eisai, Janssen-Cilag, Novartis, Pfizer, and many others |
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hans förstl, Professor Dept Psychiat Psychother TU Munich
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The work of the Hamburg-group has been criticised for being critical without offering constructive recommendations. The senior author (1) has now summarized his thoughts for the German readership on how to use acetylcholinesterase-inhibitors properly. He advises us not to use them in: • Patients suffering from relevant side-effects • Patients not eligible for treatment because of foreseeable side- effects • Patients refusing treatment • “Burned-out cases” (“Austherapierte”) showing deterioration after an initial improvement • Non-responders These profound insights deserve to be taken seriously and the van den Bussche criteria may prepare the ground for future standards regarding not only dementia treatment, but medical interventions in general. H van den Bussche (2005) Problems and questions of pharmacological therapy of Alzheimer’s disease with cholinesterase inhibitors. Z Gerontol Geriat 38; Suppl 1: 18-20 Competing interests: Fees from Eisai, Novartis, Janssen-Cilag, Pfizer and others |
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Hendrik G. van den Bussche, Director, Institute of Primary Medical Care, University Medical Center Hamburg-Eppendorf D-22145 Hamburg
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Letters to the editor intend to discuss, broaden or question the conclusions of articles published in the journal. They are part of the search for improvement of knowledge. In some cases, however, this objective is not reached. On November 1 the BMJ published a letter from Prof. Förstl (“how to do it properly!”) in which he seems to quote from an article written by me in a German journal. As this German journal is not available to most of the readers of the BMJ, I emphasize that Prof. Förstl misquoted from this article. The incriminated list he mentions is by no means an “advice not to use these drugs” in the listed groups of AD patients. What is listed are the groups not taken into account by several leading German psychiatrists when arguing an undersupply of cholinesterase inhibitors up to 90%. The arguments in this article concern questions of epidemiology and health services provision, not clinical ones. Deliberate misquoting is not a new technique to try to ridicule an author. The aim seems to be to discredit the review on cholinesterase inhibitors recently published by my colleagues and me. This review came to the conclusion that the quality of the RCTs on these drugs is questionable and thus the validity of the results is poor. Neither in this review nor in other articles was any advice given on the use of these drugs in clinical settings. We appreciate a rational debate on our position and on the conclusions to be drawn from it. We will, of course, not join the level of debate offered by Prof. Förstl. Prof. Dr. Hendrik van den Bussche (bussche@uke.uni-hamburg.de) Competing interests: None declared |
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