Parminder Raina, PhD; Pasqualina Santaguida, PhD; Afisi Ismaila, MSc; Christopher Patterson, MD; David Cowan, MD; Mitchell Levine, MD; Lynda Booker, BSc; Mark Oremus, PhD
Disclaimer: The authors are solely responsible for the content of this review. The opinions expressed herein do not necessarily reflect the opinions of the Agency for Healthcare Research and Quality, the Ontario Ministry of Health and Long-Term Care, or the McMaster Evidence-based Practice Center.
Grant Support: Parminder Raina holds a Canadian Institute of Health Research Investigator award and an Ontario Premier's Research Excellence award. The original systematic review was funded by the Agency for Healthcare Research and Quality, U.S. Department of Health and Human Services (contract no. 290-02-0020). The update to this review was funded by the Ontario Ministry of Health and Long-Term Care and the McMaster University Evidence-based Practice Center.
Potential Financial Conflicts of Interest:Honoraria: P. Santaguida (American College of Physicians).
Requests for Single Reprints: Parminder Raina, PhD, McMaster University Evidence-based Practice Center, Department of Clinical Epidemiology and Biostatistics, McMaster University, 1280 Main Street West, DTC Room 306, Hamilton, Ontario L8S 4L8, Canada; e-mail, firstname.lastname@example.org.
Current Author Addresses: Drs. Raina, Santaguida, Ismaila, Patterson, Cowan, Levine, Booker, and Oremus: McMaster University Evidence-based Practice Center, Department of Clinical Epidemiology and Biostatistics, McMaster University, 1280 Main Street West, DTC Room 306, Hamilton, Ontario L8S 4L8, Canada.
The effectiveness of the 5 U.S. Food and Drug Administration–approved pharmacologic therapies for dementias in achieving clinically relevant improvements is unclear.
To review the evidence for the effectiveness of cholinesterase inhibitors (donepezil, galantamine, rivastigmine, and tacrine) and the neuropeptide-modifying agent memantine in achieving clinically relevant improvements, primarily in cognition, global function, behavior, and quality of life, for patients with dementia.
Cochrane Central Register of Controlled Trials, MEDLINE, PREMEDLINE, EMBASE, Allied and Complementary Medicine Database, CINAHL, AgeLine, and PsycINFO from January 1986 through November 2006.
English-language randomized, controlled trials were included in the review if they evaluated pharmacologic agents for adults with a diagnosis of dementia, did not use a crossover design, and had a quality score of at least 3 on the Jadad scale.
Data were extracted on study characteristics and outcomes, including adverse events. Effect sizes were calculated and data were combined when appropriate.
96 publications representing 59 unique studies were eligible for this review. Both cholinesterase inhibitors and memantine had consistent effects in the domains of cognition and global assessment, but summary estimates showed small effect sizes. Outcomes in the domains of behavior and quality of life were evaluated less frequently and showed less consistent effects. Most studies were of short duration (6 months), which limited their ability to detect delay in onset or progression of dementia. Three studies directly compared different cholinesterase inhibitors and found no differences in cognition and behavior.
Limitations of available studies included short duration, inclusion of only patients with mild to moderate Alzheimer disease, poor reporting of adverse events, lack of clear definitions for statistical significance, limited evaluation of behavior and quality-of-life outcomes, and limited direct comparison of different treatments.
Treatment of dementia with cholinesterase inhibitors and memantine can result in statistically significant but clinically marginal improvement in measures of cognition and global assessment of dementia.
Study flow diagram.
The term companion refers to multiple reports from a single study. The authors considered the first published study as the main paper and referred to all associated reports as “companion papers.” DSM = Diagnostic and Statistical Manual of Mental Disorders; ICD = International Classification of Diseases; NINCDS = National Institute of Neurological and Communicative Disorders and Stroke.
Summary estimates for the change in Alzheimer's Disease Assessment Scale–cognitive subscale (ADAS-cog) scores.
For donepezil (10 mg/d) versus placebo (Alzheimer disease [AD], all severity levels), the estimate was statistically significant (P < 0.001) and tests for heterogeneity were not significant (I2 = 0.0%; P = 0.94). For donepezil (10 mg/d) versus placebo (mild cognitive impairment), the estimate was not significant (P = 0.31) and tests for heterogeneity were significant (I2 = 75.5%; P = 0.043). For donepezil (10 mg/d) versus placebo (mild to moderate vascular dementia), the estimate was significant (P < 0.001) and tests for heterogeneity were not significant (I2 = 0.0%; P = 0.84). For galantamine (24 mg) versus placebo (mild to moderate AD), the estimate was significant (P < 0.001) and tests for heterogeneity were significant (I2 = 75.5%; P = 0.001). For galantamine (24 mg) versus placebo (mild to moderate AD and vascular dementia), the estimate was significant (P < 0.001). For rivastigmine (6 mg and 12 mg) versus placebo (AD, all severity levels), the estimate was significant (P < 0.001) and tests for heterogeneity were significant (I2 = 90.8%; P < 0.001). For memantine (20 mg) versus placebo (mild to moderate AD), the estimate was not significant (P = 0.25). For memantine (20 mg) versus placebo (mild to moderate vascular dementia), the estimate was significant (P < 0.001) and tests for heterogeneity were not significant (I2 = 11.4%; P = 0.29).
Table 1. Summary Effect Sizes for Outcomes of Benefit Computed for Donepezil in at Least 2 Studies
Summary relative risks for improvement or stabilization from baseline on the clinician-based impression of change scale, with caregiver input.
For donepezil versus placebo (Alzheimer disease [AD], all severity levels), the relative risk (RR) for improvement was statistically significant (P < 0.001) and tests for heterogeneity were not significant (I2 = 0.0%; P = 0.762). For donepezil versus placebo (AD, all severity levels), the RR for improvement or stabilization was significant (P < 0.001). For donepezil versus placebo (mild to moderate vascular dementia), the RR for improvement or stabilization was not significant (P = 0.633) and tests for heterogeneity were not significant (I2 = 55.1%; P = 0.136). For galantamine versus placebo (mild to moderate AD), the RR for improvement or stabilization was significant (P < 0.001) and tests for heterogeneity were not significant (I2 = 19.9%; P > 0.20). For galantamine versus placebo (mild to moderate AD and vascular dementia), the RR for improvement or stabilization was significant (P = 0.002). For memantine versus placebo (AD, all severity levels), the RR for improvement was significant (P < 0.001) and tests for heterogeneity were not significant (I2 = 0.0%; P > 0.20). For memantine versus placebo (AD, all severity levels), the RR for improvement or stabilization was significant (P < 0.001) and tests for heterogeneity were not significant (I2 = 13.8%; P > 0.20). For rivastigmine versus placebo (AD, all severity levels), the RR for improvement or stabilization was not significant (P = 0.114).
Table 2. Summary Effect Sizes for Outcomes of Benefit and Harm Computed for Galantamine in at Least 2 Studies*
Table 3. Summary Effect Sizes for Outcomes of Benefit and Harm Computed for Rivastigmine in at Least 2 Studies*
Table 4. Summary Effect Sizes for Outcomes of Benefit Computed for Memantine in at Least 2 Studies
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Norman L. Foster
University of Utah
March 13, 2008
Appropriate Drug Treatment Depends on Cause of Dementia
To the Editors:
The evidence review by Raina et al. (1) and the associated ACP-AAFP Guidelines (2) published in the March 4, 2008 issue are disappointing and do not reflect current diagnostic practice or FDA indications for treatment. Both fail to recognize that the appropriate choice of drug treatment depends upon the cause of the dementia. They also leave the incorrect impression that the FDA has specifically approved drugs for the treatment of dementia. Instead, FDA indications are much more explicit (3). Tacrine, galantamine, and donepezil are approved only for treatment of dementia of the Alzheimer's type. Rivastigmine is only approved for treatment of the Alzheimer's type and Parkinson's disease with dementia. There are many other causes of dementia that warrant different treatment. For example, there is little disagreement that dementia due to B12 deficiency should be treated with B12 supplementation and that drugs known to reduce the risk of recurrent stroke should be used in patients with vascular dementia.
Although the Raina review was intended to evaluate the treatment of dementia, it included studies of mild cognitive impairment, even though patients with this condition by definition do not have dementia. There are no FDA-approved drug treatments for mild cognitive impairment. It is unlikely that a single drug will effectively treat all causes of dementia and all symptoms that patients with dementia can develop. The drugs evaluated in these articles were developed primarily to address cognition. A discussion of the relative effectiveness of these drugs for specific symptoms would have been helpful. While more studies are needed, antidepressants and psychotropic agents are more likely to prove effective in treating depression and behavior than the drugs considered in these papers. Future drug treatments will have even more targeted mechanisms of action making it even more important that the cause of dementia is determined early and accurately.
Norman L. Foster, M.D.
Center for Alzheimer's Care, Imaging and Research, University of Utah
1. Raina P, Santaguida P, Ismaila A, Patterson C, Cowan D, Levine M, et al. Effectiveness of cholinesterase inhibitors and memantine for treating dementia: evidence review for a clinical practice guideline. Ann Intern Med. 2008;148:379-97. [PMID: 18316756].
2. Qaseem A, Snow V, Cross JT Jr, Forciea MA, Hopkins R Jr, Shekelle P, et al. Current pharmacologic treatment of dementia: a clinical practice guideline from the American College of Physicians and the American Academy of Family Physicians. Ann Intern Med. 2008;148:370-8. [PMID: 18316755].
3. FDA. Labels and patient package inserts.
Dr. Foster received personal compensation for speaking and serving on the Scientific Advisory Board for Myriad Pharmaceuticals and GE Healthcare. He received research support to conduct clinical trials from Merck, Myriad, Eisai, and Wyeth.
March 18, 2008
Can we learn more from dementia trials?
In their comprehensive systematic review, Raina et al. non- controversially conclude that the effect sizes for cholinesterase inhibition in Alzheimer's disease typically are small, and that translation of these effects into patients' quality of life remains problematic . There is perhaps even more to be concluded from the existing literature. If we accept that the average small effect size represents a distribution of effects, it is reasonable to ask why some people seem to do well in response to treatment and others do not. Three types of answers seem possible.
At the group level, a dose-response can be demonstrated, such that patients who are able to tolerate the highest doses commonly demonstrate effect sizes in the moderate range . This should not be gainsaid; there is also demonstrable convergence of the measures within and across trials, which suggests, a priori, that the effects are real . Even so, current evidence is only for dose, and not for type of cholinesterase inhibitor, or use in combination with other drugs. A second conclusion, also consistent with Raina et al., is that the existing measures do not adequately allow us to identify people who respond to treatment from those who do not. One reason for this might be that we have discounted improved executive function in the standard trials [4-6].
A third conclusion is that we need to pay attention to the experience of patients and caregivers to better understand not just their satisfaction with treatment (something that has been caught up in what, as argued elsewhere,  is an often-dubious "quality of life" evaluation effort). Regulatory agencies endorse patient-centred measurement, and the accompanying ACP/AAFP consensus statement equally sees this as a priority for additional dementia research. Even so, most clinical trials have not taken patient/caregiver views into account, although one that did seems to show that important aspects of the treatment response are missed by current measures [9,10]
There are reasons other than efficiency to listen to what patients and caregivers tell us about the effects of treatment. Most compellingly, what they say in trials can address clinical meaningfulness directly, and shorten the translation between the trials and what we can look for in daily practice. In addition, just as patients and caregivers stressed to us the importance of executive function long before it became fashionable to measure it in clinical trials, their experience can help us better understand how our treatments work. Especially in matters of higher cortical function, these are effects which are unlikely to emerge from pre -clinical models.
To the extent that it discounts listening to patients as "mere anecdote", the evidence-based movement needs to get to grips with the gap between what trials say and what people experience. Systematic listening to patients in quantifiable ways in properly designed trials allows anecdote to become evidence, but the trials reviewed by Raina et al. show what distance we are from attaining that goal.
1. Raina P, Santaguida P, Ismaila A, et al., Effectiveness of cholinesterase inhibitors and memantine for treating dementia: evidence review for a clinical practice guideline. Ann Intern Med. 2008;148:379-97.
2. Rockwood K. Size of the treatment effect on cognition of cholinesterase inhibition in Alzheimer's disease. J Neurol Neurosurg Psychiatry. 2004;75:677-85.
3. Rockwood K, MacKnight C. Assessing the clinical importance of statistically significant improvement in anti-dementia drug trials. Neuroepidemiology. 2001;20:51-6.
4. Royall DR, Lauterbach EC, Cummings JL, et al., Executive control function: a review of its promise and challenges for clinical research. A report from the Committee on Research of the American Neuropsychiatric Association. J Neuropsychiatry Clin Neurosci. 2002;14:377-405.
5.Voss SE, Bullock RA. Executive function: the core feature of dementia? Dement Geriatr Cogn Disord. 2004;18:207-16.
6. Rockwood K, Fay S, Gorman M, Carver D, Graham JE. The clinical meaningfulness of ADAS-Cog changes in Alzheimer's disease patients treated with donepezil in an open-label trial. BMC Neurol. 2007 Aug 30;7:26.
7. Rockwood K. Quality of life outcomes. In Rockwood K, Gauthier S (eds.) Trial Designs and Outcomes in dementia Therapeutic Research. London: Taylor & Francis, 2006, 131-140.
8.Qaseem A, Snow V, Cross JT Jr, et al. Current pharmacologic treatment of dementia: a clinical practice guideline from the American College of Physicians and the American Academy of Family Physicians. Ann Intern Med. 2008;148:370-8.
9. Rockwood K, Fay S, Song X, MacKnight C, et al., Attainment of treatment goals by people with Alzheimer's disease receiving galantamine: a randomized controlled trial. CMAJ. 2006;174:1099-105.
10. Rockwood K, Fay S, Jarrett P, Asp E. Effect of galantamine on verbal repetition in AD: a secondary analysis of the VISTA trial. Neurology. 2007;68:1116-21.
In addition to the usual academic conflict of interest (evident from the references) I have worked with each of the drug companies that makes cholinesterase inhibitors, and the VISTA trial (references 9,10) was an investigator initiated, peer-reviewed double blind clinical trial, funded in part by the Canadian Institutes of Health Research, and in the majority by Janssen-Ortho Canada. I also am founder and majority shareholder of DementiaGuide Inc., a web-based company that provides information on dementia and its treatment, and that has a contract with Pfizer Canada to improve patient-centred measurement in a clinical trial.
Nancy S. Foldi
Queens College, City University of New York
April 7, 2008
Choose better neuropsychological measures
To the editors:
The review of Raina et al.,(1) and commentary of Quaseem et al.,(2) continue our debate of how to evaluate the pharmacological treatments of Alzheimer's disease (AD). However, until new drugs emerge that produce more obvious "˜clinically significant' symptom improvement, the research community needs to use objective measures that better demonstrate an individual's response to treatment. Indeed, a great frustration for physicians and families alike is the lack of any sensitive, valid, reliable, objective outcome metric to determine efficacy. Families report vague changes (e.g., the patient is more "˜alert'), but we cannot even corroborate their impression. Our current outcome measures and methodologies need correction. The industry standard ADAS-Cog(3) assesses placebo versus treatment groups, but was never designed to assess individual response. Moreover, most significant group effects appear only after 4-6 months of treatment, confounding treatment efficacy and disease progression. We need to use sensitive outcome measures that detect efficacy after short-term treatment before additional natural disease progression occurs.
Not all neuropsychological measures are created equal. Global measures, such as ADAS-Cog (3)or the MiniMental Status Examination (4)collapse multiple cognitive domains, and while they have served important roles in efficacy studies, global measures can diffuse a true effect(5). In contrast, targeted cognitive measures exist that are sensitive to AD are delayed recall(6), learning strategy of the recency effect(7), selective(8;9) or divided attention(10). Moreover, the choice of outcome measure should directly relate to known associations with the neurotransmitter system in question: we already know that acetylcholine mediates the effect of attentional demands and memory consolidation (see 11;12). Of note is that the 70-point ADAS-Cog lacks any measures of attention, learning strategy, or consolidation.
Any neuropsychological outcome measure of drug efficacy should fulfill three mandates. First, the outcome measure has to be sensitive and valid, and has to assess a targeted cognitive function. Estimating height using a scale could tell us that heavier people tend to be taller, but using a yardstick would be better. Second we have to detect efficacy after a short-term treatment (e.g., 4-8 weeks), not only to obviate the confound of treatment and progression, but also to aid in a timely decision whether or not to continue treatment. Lastly, a best outcome measure is a response in an individual patient. AD presents as a heterogeneous disease resulting in large variance of performance, necessitating greater group differences between placebo and treatment and resulting in smaller effect sizes. The goal should be an individual's change as a function of treatment on the sensitive measure. Better measures already exist and should be applied.
(1) Raina P, Santaguida P, Ismaila A, Patterson C, Cowan D, Levine M et al. Effectiveness of cholinesterase inhibitors and memantine for treating dementia: evidence review for a clinical practice guideline. Ann Intern Med. 2008;148:379-97.
(2) Qaseem A, Snow V, Cross JT, Jr., Forciea MA, Hopkins R, Jr., Shekelle P et al. Current pharmacologic treatment of dementia: a clinical practice guideline from the American College of Physicians and the American Academy of Family Physicians. Ann Intern Med. 2008;148:370-378.
(3) Rosen WG, Mohs RC, Davis KL. A new rating scale for Alzheimer's disease. Am J Psychiatr. 1984;141:1356-64.
(4) Folstein MF, Folstein SE, McHugh PR. Mini-Mental State: A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res. 1975;12:189-98.
(5) Rockwood K. Size of the treatment effect on cognition of cholinesterase inhibition in Alzheimer's disease. J Neurol Neurosurg Psychiatry. 2004;75:677-85.
(6) Delis DC, Kaplan E, Kramer JH, Ober BA. California Verbal Learning Test - II (second edition). San Antonio, TX: The Psychological Corporation; 2000.
(7) Foldi NS, Brickman AM, Schaefer LA, Knutelska ME. Distinct serial position profiles and neuropsychological measures differentiate late life depression from normal aging and Alzheimer's disease. Psychiatry Res. 2003;120:71-84.
(8) Foldi NS, Schaefer LA, White REC, Johnson R.Jr, Berger JT, Carney MT et al. Effects of graded levels of physical similarity and density on visual selective attention in patients with Alzheimer's disease. Neuropsychology. 2005;19:5-17.
(9) Foldi NS, White RE, Schaefer LA. Detecting effects of donepezil on visual selective attention using signal detection parameters in Alzheimer's disease. Int J Geriatr Psychiatry. 2005;20:485-88.
(10) Gron G, Brandenburg I, Wunderlich AP, Riepe MW. Inhibition of hippocampal function in mild cognitive impairment: targeting the cholinergic hypothesis. Neurobiol Aging. 2006;27:78-87.
(11) Arnold HM, Nelson CL, Sarter M, Bruno JP. Sensitization of cortical acetylcholine release by repeated administration of nicotine in rats. Psychopharmacology. 2003;165:346-58.
(12) Sarter M, Bruno JP, Givens B. Attentional functions of cortical cholinergic inputs: what does it mean for learning and memory? Neurobiol Learn Mem. 2003;80:245-56.
Vifor AG, consultant
May 14, 2008
Authors: P. Raina, P.L. Santaguida, C. Patterson
Our recent publication(1) presents the results of a systematic review on the efficacy of cholinesterase inhibitors and memantine in the treatment of dementias. We thank Dr Rockwood for his thoughtful and perceptive response to this review and also thank Ms. Carins for bringing to our attention new information with regard to the publication by Raskind.(2)
We completely agree with Dr. Rockwood that aggregate scores on instruments which do not measure executive function may fail to capture useful improvements in individuals receiving cholinesterase inhibitors or other cognitive enhancing agents. Of the many attempts to isolate meaningful individual responses to treatment, Goal Attainment Scaling is among the most sensitive and robust. While not always a means of determining outcome, and rarely quantified in as rigorous a manner as advocated by Dr Rockwood, we share his enthusiasm for "listening to patients," the most basic and satisfying element of clinical care.
Dr. Rockwood also cites two related publications that demonstrate this point. One of these studies was eligible for our review. (3) Inclusion of this study does not alter the effect size for the mean difference ADAS-cog score (-2.39 (95% CI, -3.32"”1.46)) in the meta analysis of treatment effects of galantamine for Alzheimer's disease; nor is the heterogeneity improved (Chi Squared p=0.003, I2 =70.3%). The other study was published after completion of our review.(4)
It was also brought to our attention that there was an error within the Raskind study of galantamine. (2) The mean change for the ADAS-cog score was -1.9 for the treatment group rather than +1.9 which was stated in the original study publication. Corrections or corrigenda for previously published articles are uniformly considered by NLM to be errata. In this case searching in MEDLINE by the author's name does not return the correction; neither does the citation listed within PUBMED or OVID indicate that a correction was issued. In short, detection of such corrections is problematic due to the manner in which they are indexed; uniformity amongst journals and consistency in indexing is required. None the less, the effect size of the ADAS-cog summary estimate is still not clinically significant and does not change our interpretation of the evidence report.(1) Figure 1 shows both the addition of the study by Rockwood and the effect of this correction on the meta-analysis for galantamine; it shows a slight increase in the effect size (-3.06 (95% CI -3.53"”2.58)) and the tests for heterogeneity are no longer significant (Chi Squared p = 0.715, I2 = 0.0%). The effect size for galantamine is statisitically, but not clinically significant.
(1) Raina P, Santaguida P, Ismaila A, Patterson C, Cowan D, Levine M, et al. Effectiveness of cholinesterase inhibitors and memantine for treating dementia: evidence review for a clinical practice guideline. Ann Intern Med 2008 Mar 4;148(5):379-9.
(2) Raskind MA, Peskind ER, Wessel T, Yuan W. Galantamine in AD: A 6 -month randomized, placebo-controlled trial with a 6-month extension. The Galantamine USA-1 Study Group. Neurology 2000 Jun 27;54(12):2261-8.
(3) Rockwood K, Fay S, Song X, MacKnight C, Gorman M, Video-Imaging Synthesis of Treating Alzheimer's Disease (VISTA) Investigators. Attainment of treatment goals by people with Alzheimer's disease receiving galantamine: a randomized controlled trial.[see comment]. CMAJ Canadian Medical Association Journal 2006 Apr 11;174(8):1099-105.
(4) Rockwood K, Fay S, Jarrett P, Asp E. Effect of galantamine on verbal repetition in AD: a secondary analysis of the VISTA trial. Neurology 2007 Apr 3;68(14):1116-21.
Raina P, Santaguida P, Ismaila A, Patterson C, Cowan D, Levine M, et al. Effectiveness of Cholinesterase Inhibitors and Memantine for Treating Dementia: Evidence Review for a Clinical Practice Guideline. Ann Intern Med. 2008;148:379–397. doi: 10.7326/0003-4819-148-5-200803040-00009
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Published: Ann Intern Med. 2008;148(5):379-397.
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