Cholinesterase inhibitors for dementia with Lewy bodies (Review)

Transcription

1 Cholinesterase inhibitors for dementia with Lewy bodies (Review) Wild R, Pettit TACL, Burns A This is a reprint of a Cochrane review, prepared and maintained by The Cochrane Collaboration and published in The Cochrane Library 2010, Issue 1

2 T A B L E O F C O N T E N T S HEADER ABSTRACT PLAIN LANGUAGE SUMMARY BACKGROUND OBJECTIVES METHODS RESULTS DISCUSSION AUTHORS CONCLUSIONS ACKNOWLEDGEMENTS REFERENCES CHARACTERISTICS OF STUDIES DATA AND ANALYSES Analysis 1.1. Comparison 1 Rivastigmine versus placebo, Outcome 1 Neuropsychiatric Inventory (10 items). Change from baseline. 20 weeks Analysis 1.2. Comparison 1 Rivastigmine versus placebo, Outcome 2 Neuropsychiatric Inventory (4items). Change from baseline. 20 weeks Analysis 1.3. Comparison 1 Rivastigmine versus placebo, Outcome 3 Proportion with an Adverse Event. ITT analysis. 20 weeks Analysis 1.4. Comparison 1 Rivastigmine versus placebo, Outcome 4 Proportion with a serious Adverse Event. ITT analysis. 20 weeks Analysis 1.5. Comparison 1 Rivastigmine versus placebo, Outcome 5 Drop out Rate. ITT analysis. 20 weeks Analysis 1.6. Comparison 1 Rivastigmine versus placebo, Outcome 6 Death. ITT analysis. 20 weeks Analysis 1.7. Comparison 1 Rivastigmine versus placebo, Outcome 7 Mini-Mental State Examination. Change from baseline. 20 weeks Analysis 1.8. Comparison 1 Rivastigmine versus placebo, Outcome 8 Clinician Global Change Plus. No change or worse. 20 weeks WHAT S NEW HISTORY CONTRIBUTIONS OF AUTHORS DECLARATIONS OF INTEREST INDEX TERMS i

3 [Intervention Review] Cholinesterase inhibitors for dementia with Lewy bodies Rebecca Wild 1, Tor ACL Pettit 2, Alistair Burns 3 1 Belmont Day Hospital, Royal Bolton Infirmary, Bolton, UK. 2 Cheadle Royal Hospital, Cheadle, UK. 3 Psychiatric Research Group, University of Manchester, Manchester, UK Contact address: Rebecca Wild, Belmont Day Hospital, Royal Bolton Infirmary, Minnerva Road, Bolton, BL4 7AA, UK. Rebecca.Wild@rbh.nhs.uk. Editorial group: Cochrane Dementia and Cognitive Improvement Group. Publication status and date: Stable (no update expected for reasons given in What s new ), published in Issue 1, Review content assessed as up-to-date: 27 April Citation: Wild R, Pettit TACL, Burns A. Cholinesterase inhibitors for dementia with Lewy bodies. Cochrane Database of Systematic Reviews 2003, Issue 3. Art. No.: CD DOI: / CD Background A B S T R A C T Dementia with Lewy bodies (DLB) was first described in 1983, and clinical diagnostic criteria were published in the early to mid 1990s. It has been suggested DLB may account for up to 15-25% of cases of dementia among people aged over 65, although autopsy suggests much lower rates. Characteristic symptoms are dementia, marked fluctuation of cognitive ability, early and persistent visual hallucinations and spontaneous motor features of Parkinsonism. Falls, syncope, transient disturbances of consciousness, neuroleptic sensitivity, and hallucinations in other modalities are also common. This combination of features can be difficult to manage as neuroleptics can make the Parkinsonian and cognitive symptoms worse. There is evidence to suggest that the cholinesterase inhibitors may be beneficial in this disorder; small case series indicate that cholinesterase inhibitors are safe, and will improve both cognitive deficits and neuropsychiatric symptoms in DLB. Objectives To assess the use of cholinesterase inhibitors in DLB. Search strategy The trials were identified from a search of the Specialized Register of the Cochrane Dementia and Cognitive Improvement Group on 25 February 2002 using the terms Lewy body, Lewy bodies and Lewy. This register contains records from all major health care databases and trial databases and is updated regularly. Selection criteria Randomized, double-blindtrials in which treatment with cholinesterase inhibitors was administered and compared with alternative interventions in patients with DLB are included. Data collection and analysis Two reviewers (TP, RW) independently assessed quality of trials according to criteria described in the Cochrane Collaboration Handbook. Each drug was to be examined separately, and together as a group. We also analysed data by time to outcome measurement; short-term (up to one month), medium term (one month up to six months) and long term (Six months and longer). The primary outcome measures of interest are in the following areas:neuropsychiatric features. i.e. psychiatric symptoms and behavioural disturbances, cognitive function, activities of daily living, global assessments, quality of life, including maintaining role and social functioning, effect on carers, safety as measured by incidence of adverse events and side effects, acceptability of treatment as measured by withdrawal from trials, and by patient/carer assessment, institutionalization and death. 1

4 Main results There was one included trial of rivastigmine compared with placebo on 120 patients. Neuropsychiatric Inventory The 10-item test found no significant difference between the two groups in change of scores from baseline using intention-to-treat (ITT) analysis at 20 weeks and last observation carried forward (LOCF) analysis. The treatment effect was statistically significant in favour of rivastigmine if only observed cases (OC) were analysed (WMD -6.94, 95% CI to -2.29, P=0.003). There were similar results for the NPI-4, with only the OC analysis showing a significant superiority of rivastigmine to placebo at 20 weeks (WMD -3.75, 95%CI to -0.88, P=0.01). MMSE: Analysis of these results showed no statistically significant difference between the two groups at 20 weeks. CGC-plus: Analysis of the proportion of patients who had no change or became worse found no statistically significant difference between the two groups at 20 weeks for the ITT, LOCK and OC analyses. Adverse Events: The placebo group experienced significantly fewer adverse events than the treatment group (54/59 vs 46/61,OR 3.52, 95%CI 1.19 to 10.43). However, using ITT analysis of 20-week data, there was no significant difference between the two groups when serious adverse events were considered. There were no significant differences in death rates between the two groups at 20 weeks. Drop-out Rates: Analysis of these results showed no difference between the two groups at 20 weeks using ITT analysis. Authors conclusions Patients with dementia with Lewy bodies who suffer from behavioural disturbance or psychiatric problems may benefit from rivastigmine if they tolerate it, but the evidence is weak. Further trials using rivastigmine are needed, as are trials of other cholinesterase inhibitors in dementia with Lewy bodies. P L A I N L A N G U A G E S U M M A R Y No convincing evidence from one trial of the efficacy of cholinesterase inhibitors for dementia with Lewy bodies The characteristic features of dementia with Lewy bodies are dementia, marked fluctuation of cognitive ability, early and persistent visual hallucinations and spontaneous motor features of Parkinsonism. Other symptoms are repeated falls, syncope, transient disturbances of consciousness, neuroleptic sensitivity, and hallucinations in other modalities. This combination of features can be particularly difficult to manage, as antipsychotic drugs used to treat hallucinations, delusions and agitation will worsen Parkinsonian symptoms. The one included trial (of rivastigmine compared with placebo on 120 patients) showed no statistically significant difference between the two groups at 20 weeks. A possible beneficial effect on neuropsychiatric features was found only in analysis of observed cases, and may therefore be due to bias. 2

5 B A C K G R O U N D Dementia with Lewy bodies was first described as a pathologically distinct entity in 1983, (Yoshimura 1983, Kosaka 1984), and was originally called Diffuse Lewy Body Disease. Lewy bodies were discovered by Frederick Lewy in the basal ganglia of people with Parkinson s disease, but in dementia with Lewy bodies they are found also in the cerebral cortex. Lewy bodies are intracytoplasmic aggregates formed from damaged cytoskeletal components. They stain pink with standard haematoxylin and eosinophil staining but are more readily seen using the more recently developed antiubiquitin immunohistochemistry. Clinical diagnostic criteria for DLB were published in the early to mid-1990s (Luis 1999). Dementia affects approximately 5% of people over the age of 65, and the limited evidence on clinical prevalence suggests DLB accounts for 15 to 25% of cases of dementia in older people (Ballard 1995; Holmes 1999; Shergill 1994; Rahkonen 2003), which would make it the second most common form of dementia after Alzheimer s Disease (AD). Diagnostic criteria are subject to considerable observer error and much lower estimates of prevalence have been reported from autopsy studies (MRC CFAS 2001). Its characteristic features are dementia, marked fluctuation of cognitive ability, early and persistent visual hallucinations and spontaneous motor features of Parkinsonism. Dementia also occurs concomitantly in some cases of Parkinson s disease, and the relationship between this syndrome and DLB remains uncertain. Other symptoms that support the diagnosis are repeated falls, syncope, transient disturbances of consciousness, neuroleptic sensitivity, and hallucinations in other modalities. This combination of features can be particularly difficult to manage, as antipsychotic drugs used to treat hallucinations, delusions and agitation will worsen Parkinsonian symptoms through the mechanism of dopamine blockade, and possibly worsen cognitive functioning by their anticholinergic activity. Enhancing cholinergic activity using cholinesterase inhibitors may be beneficial in DLB for a number of reasons; Cholinesterase inhibitors improve cognitive functioning and clinicians global ratings in mild to moderate AD when compared with placebo (Birks 2001a, Birks 2001b, Olin 2001). Some of the patients in these clinical trials met the diagnostic criteria for DLB (Del Ser 2000a). DLB patients have a marked decrease in cholinergic functioning, which is greater than that seen in AD (Langlais 1993, Perry 1994), and the enzyme choline acetyltransferase is lower in DLB than AD (Samuel 1997). Therefore, the key neuropathological defect that is targeted by cholinesterase inhibitors is present in both AD and DLB. Moreover, the lower cholinergic functioning in DLB may indicate a greater potential improvement from these drugs than that seen in AD. There are fewer neurofibrillary tangles and neuritic plaques, and less neuronal loss in DLB than AD (Lippa 1998, Lippa 1994). This suggests that cortical neurons in DLB are more viable than those in AD, and could be more responsive to cholinergic stimulation. Small case series indicate that cholinesterase inhibitors are safe, and will improve both cognitive deficits and neuropsychiatric symptoms in DLB (McKeith 2000, Shea 1998). O B J E C T I V E S To assess the efficacy, safety and tolerability of cholinesterase inhibitors in DLB. M E T H O D S Criteria for considering studies for this review Types of studies Randomized, double-blind trials in which treatment with cholinesterase inhibitors was administered and compared with alternative interventions in patients with DLB were included. Types of participants All patients diagnosed with DLB by established diagnostic criteria or by clinical interview. Types of interventions This review considered studies comparing any cholinesterase inhibitors at any dose with placeboor other psychotropic medication. The current cholinesterase inhibitors are donepezil, rivastigmine, galantamine and tacrine. Types of outcome measures The primary outcome measures of interest were in the following domains; 1. Neuropsychiatric features. i.e. psychiatric symptoms and behavioural disturbances 2. Cognitive function 3. Activities of daily living 4. Global assessments 5. Quality of life, including maintaining role and social functioning 6. Effect on carers 7. Safety as measured by incidence of adverse events and side effects 3

6 8. Acceptability of treatment as measured by withdrawal from trials, and by patient/carer assessment. 9. Institutionalization 10.Death; numbers during the trials and time to death. Search methods for identification of studies The trials were identified from a search of the Specialized Register of the Cochrane Dementia and Cognitive Improvement Group on 25 February 2002 using the terms Lewy body, Lewy bodies and Lewy. The Specialized Register at that time contained records from the following databases: CCTR/CENTRAL:October 2001 (issue 4); MEDLINE: 1966 to October 2001; EMBASE: 1980 to October 2001; PsycINFO 1887 to October 2001; CINAHL: 1982 to October 2001; SIGLE (Grey Literature in Europe): 1980 to December 2000; ISTP (Index to Scientific and Technical Proceedings): to May 2000; INSIDE (BL database of Conference Proceedings and Journals): to June 2000; Aslib Index to Theses (UK and Ireland theses): 1970 to June 2001; Dissertation Abstract (USA): 1861 to June 2001; ADEAR (Alzheimer s Disease Clinical Trials Database): to November 2001; National Research Register (including the MRC Clinical Trials Directory): July 2001 (issue 3) Alzheimers Society Trials Database: to November 2001; Glaxo-Wellcome Trials Database: to November 2001; Centerwatch Trials Database: to December The search strategies used to identify relevant records in MED- LINE, EMBASE, PsycINFO and CINAHL can be found in the Group s module. Relevant pharmaceutical companies were invited to release any published or unpublished data they have on file. The references of all identified studies were inspected for other studies, and the first authors asked if they knew of other relevant studies. Data collection and analysis Selection of studies: Two reviewers (TP, RW) independently discarded citations judged irrelevant on the basis of the title of the publication and its abstract. The criteria for exclusion were: the studies did not use a cholinesterase inhibitor, were not clinical trials, or did not relate to DLB. Two reviewers (TP, RW) independently selected the trials from the culled citation list for initial inclusion in the review, and reasons for exclusion were presented in the review. Disagreements were resolved by discussion. Further information was sought from authors of the studies when required. Assessment of methodological quality: Reviewers (TP, RW) independently assessed quality of trials according to criteria described in the Cochrane Collaboration Handbook (Clarke 2001). The reviewers regarded selection bias as particularly important. Studies were only included if participants were truly randomized, or stratified then randomized, to the treatment groups to be compared. Studies that did not conceal assignment were excluded, as lack of concealment can be associated with bias (Chalmers 1983, Moher 1998, Shulz 1995). Inadequate concealment includes; randomization by alternation, the use of case record numbers, dates of birth or day of the week, and any procedure transparent before allocation (such as an open list of random numbers). We indicated whether allocation concealment was adequate, unclear, inadequate, or not used. If this information was unclear from the study reports, we contacted the authors for clarification. Disagreements between the two reviewers (TP, RW) were resolved by discussion among all three reviewers (TP, RW, AB). Other sources of bias were considered on a trial by trial basis, and studies excluded if all three reviewers (TP, RW, AB) agreed that there was likelihood of significant bias. In these instances, the reasons for exclusion were specified. Types of bias include; performance bias (systematic differences in care provided apart from the intervention being evaluated), attrition bias (systematic differences in withdrawals from the trial) and detection bias (systematic differences in outcome assessment). We conducted sensitivity analysis on any included trials where there was possible bias. Data extraction: Data were extracted from the published reports. The summary statistics required for each trial and each outcome for continuous data are the mean change from baseline, the standard error of the mean change, and the number of patients for each treatment group at each assessment. Where changes from baseline are not reported, the mean, standard deviation and the number of patients for each treatment group at each time point were extracted if available. For binary data the numbers in each treatment group and the numbers experiencing the outcome of interest were sought. The baseline assessment is defined as the latest available assessment prior to randomization, but no longer than two months earlier. Data from titration phases prior to the randomized phase, or from open-label follow-up periods, were not used to assess safety or efficacy because patients were not randomized or treatments concealed. TP and RW extracted data independently and resolved disagreement by discussion. Rating scales: A wide range of rating scales is available to measure outcomes in mental health trials. These scales vary in quality and many are 4

7 poorly validated. The reviewers excluded data generated by the use of unpublished rating scales or from scales without established reliability and validity. In addition, the rating scales were either a self-report or completed by an independent rater or relative. The standards for instruments may become more stringent in future editions of this review. Intention-to-treat analysis: For each outcome measure, data were sought on every patient assessed. To allow an intention-to-treat analysis, the data were sought irrespective of compliance, whether or not the patient was subsequently deemed ineligible, or otherwise excluded from treatment or follow-up. If intention-to-treat data were not available in the publications, on-treatment or the data of those who complete the trial were sought and indicated as such. Data analysis: The outcomes measured in clinical trials of dementia and cognitive impairment often arise from ordinal rating scales. Where the rating scales used in the trials have a reasonably large number of categories (more than 10) the data were treated as continuous outcomes arising from a normal distribution. Summary statistics (n, mean and standard deviation) were required for each rating scale at each assessment time for each treatment group in each trial for change from baseline. The meta-analysis requires the combination of data from the trials that may not use the same rating scale to assess an outcome. The measure of the treatment difference for any outcome is the weighted mean difference when the pooled trials use the same rating scale or test, and the standardised mean difference, which is the absolute mean difference divided by the standard deviation when they use different rating scales or tests. For binary outcomes, such as clinical improvement or no clinical improvement, the odds ratio is used to measure treatment effect. For a meta-analysis a weighted estimate of the typical treatment effect across trials is calculated and an overall estimates of the treatment difference is presented. In all cases the overall estimate from a fixed effects model is presented and a test for heterogeneity using a standard chi-square statistic performed. If, however, there is evidence of heterogeneity of the treatment effect between trials then either only homogeneous results are pooled, or a random-effects model is used. If, however, there is evidence of heterogeneity of the treatment effect between trials then either only homogeneous results are pooled, or a random-effects model used (in which case the confidence intervals are broader than those of a fixed-effects model). We intended to carry out meta-analyses for each cholinesterase inhibitors separately and pooled. We also analysed data by time to outcome measurement; short-term (up to one month), medium term (one month up to six months) and long term (Six months and longer). R E S U L T S Description of studies See: Characteristics of included studies; Characteristics of excluded studies. One trial was included (McKeith 2000), comparing rivastigmine with placebo. Rivastigmine was started at a dose of 1.5 mg twice a day, titrated to a maximum of 6mg twice daily. The titration lasted up to 8 weeks. The mean daily stable dose at was 9.4 mg. The total period of randomised treatment was 20 weeks. The baseline demographic characteristics were similar in treatment and placebo groups. The mean age was 74 years, 52% male in the rivastigmine group and 61% in the placebo group. The mean MMSE scores were 17.9 and 17.8 in the rivastigmine and placebo groups respectively. Most patients had one or more co-existing medical conditions; musculoskeletal (28%), cardiovascular (28%), gastrointestinal (21%) and psychiatric (18%). The most common concomitant drugs were neurotropic agents, including dopaminergic drugs (30%), hypnotics and sedatives (25% in the rivastigmine group, 15% in the placebo group), and antidepressants (19% and 23% in rivastigmine and placebo groups respectively). For other details of the trial, see the table of included studies. SCALES Neuropsychiatric Inventory (NPI) (Cummings 1994). The NPI is a relatively brief interview assessing 10 behavioural disturbances; delusions, hallucinations, dysphoria, anxiety, agitation/aggression, euphoria, disinhibition, irritability/lability, apathy, and aberrant motor behaviour. Scores range from 1 (normal) to 144 (severely disturbed). The NPI-4 is a four item version, which is the sum of scores for dysphoria, apathy, delusions and hallucinations. This cluster of symptoms was identified as being characteristic of Lewy Body Dementia. (Del Ser 2000a). Mini Mental State Examination (MMSE) (Folstein 1975). The MMSE evaluates cognition in five areas: orientation, immediate recall, attention and calculation, delayed recall and language. The test takes fifteen minutes to administer, and the scores range from 0 (severe impairment) to 30 (normal). Clinical Global Change - plus (CGC-plus) (Guy 1976). The CGC-plus is a 7 point scale rating all domains of a patient s current condition in comparison with baseline. Both assessments should be conducted by the same clinician with input from relatives or carers. Unified Parkinson s Disease Rating Scale (UPDRS) (Fahn 1987). The motor examination section was used to assess changes in motor function and the symptoms of parkinsonism. Speed Score. This was a measure of reaction time on computer based tests, that was used in the included study (McKeith 2000). However, we did not analyse it in our results as there is no data regarding its validity or reliability, and its clinical relevance is unclear. 5

8 Risk of bias in included studies The included study (McKeith 2000) used a computer generated block-randomization technique; the investigator and patient were blind to allocation. There was a 23% drop-out rate, the main cause being adverse events. The analysis was either on an intention-totreat basis or used the last observation carried forwards (see table of results for details). A number of neuropsychological tests were excluded from the analysis, owing to the large number of patients unable to complete the tests (e.g. Digit Symbol Substitution Task, Trail making test, Stroop congruent test, Block Design Test), which would have led to biased results. Effects of interventions There was one included trial (McKeith 2000) of rivastigmine compared with placebo on 120 patients. Neuropsychiatric Inventory The 10-item test found no significant difference between the two groups in change of scores from baseline using intention-to-treat (ITT) analysis at 20 weeks [WMD -3.30, 95% CI to1.54, P=0.18], and last observation carried forward (LOCF) analysis [WMD -4.16, 95% CI to 1.17, P=0.13]. The treatment effect was statistically significant in favourofrivastigmine if only observed cases (OC) were analysed [WMD -6.94, 95% CI to -2.29, P=0.003). There were similar results for the NPI-4, with only the OC analysis showing a significant superiority of rivastigmine compared with placebo at 20 weeks [WMD -3.75, 95%CI to -0.88, P=0.01]. MMSE Analysis of these results showed no statistically significant difference between the two groups at 20 weeks: ITT analysis [WMD +1.24, 95% CI to 2.76, P=0.11], LOCF analysis [WMD 1.18, 95% CI to 2.96, P=0.19] and OC analysis [WMD 1.6, 95% CI to 3.29, P=0.06]. CGC-plus. Analysis of the proportion of patients who had no change or became worse found no statistically significant difference between the rivastigmine compared with placebo at 20 weeks: ITT analysis [29/48 vs 41/56OR 0.56, 95% CI 0.24 to 1.28, P=0.07], LOCF analysis [25/40 vs 40/55, OR 0.62, 95% CI 0.26 to 1.5, P=0.29] and OC analysis [22/36 vs 34/46, OR 0.55, 95% CI 0.22 to 1.42, P=0.22]. ADVERSE EVENTS The placebo group experienced significantly fewer adverse events than the treatment group [54/59 vs 46/61,OR 3.52, 95%CI 1.19 to 10.43, P=0.02]. However, using ITT analysis of 20-week data, there was no significant difference between the two groups when serious adverse events were considered [10/59 vs 8/61,OR 1.35, 95%CI 0.49 to 3.70, P=0.56]. There were no significant differences in death rates between the two groups at 20 weeks [0/59 vs 2/61, OR 0.20, 95%CI 0.01 to 4.26, P=0.30]. DROP OUT RATES Analysis of these results showed no difference between the two groups at 20 weeks using ITT analysis [18/59 vs 10/61, OR 2.24, 95% CI 0.93 to 5.37, P=0.07]. The results for the NPI-4 and NPI-10 outcomes are not entirely consistent with the trial results as published (McKeith 2000). The published p-values for the comparisons between treatment groups refer to the results of nonparametric analyses using Koch s method (Koch 1982), and not to the comparisons between treatment resulting from the parametric analyses of covariance. It is not possible to estimate the magnitude of treatment effects from the nonparametric analyses, and the published treatment effects arise from the parametric analyses. The two sets of p-values are presented intable 1. Although the p- values for the completers analyses are similar, the p-values for the non-parametric analyses are much smaller for the ITT and LOCF analyses.the use of Koch s method was not reported and discussed inmckeith 2000but the nonparametric method was considered the more appropriate method for the analysis of the NPI data (personal communication Novartis) Table 1. P-values for comparisons between groups Outcome (20 weeks) parametric non-parametric NPI-4 ITT NPI-4 LOCF NPI-4 OC NPI-10 ITT NPI-10 LOCF

9 Table 1. P-values for comparisons between groups (Continued) NPI-10 OC KOCH S METHOD FOR NONPARAMETRIC ANALYSIS OF COVARIANCE Parametric analysis of covariance depends on several assumptions, normality of error terms, equality of error variances for the treatment groups, equality of the regression slopes for the regression lines of the dependent variable on the covariate for each treatment group, linearity of regression. Rank analysis of covariance is used when these assumptions may not be satisfied. The method has been described by Koch The technique is used to carry out nonparametric comparisons between treatments, after adjusting for one or more covariates. The dependent variable and covariate are replaced by the rank scores. The residuals from the regression of the dependent variable on the covariate are saved. A Mantel-Haenszel statistic is calculated from the contingency table of treatment group x residuals. This statistic allows the mean values of the treatment groups to be compared, but the magnitude of a treatment effect cannot be calculated. D I S C U S S I O N At the beginning of this review we outlined the physiological reasons why cholinesterase Inhibitors might be useful in the treatment of dlb and set out to look for evidence of efficacy in controlled clinical trials. At the present time there is only one RCT reported. This investigated the effectiveness of rivastigmine only and therefore we have not been able to include data about the other cholinesterase Inhibitors. The report of the trial paper explored 6 of the 10 outcome measures that we had identified. The only positive finding was that taking rivastigmine was associated with a significant improvement in neuropsychiatric features of DLB when analysis was restricted to observed cases. However, this result was not significant when all patients entering the study were included in the analysis (intention-to-treat analysis, ITT). The two alternative explanations are that taking the drug has a beneficial effect that is too weak so be detected in the ITT analysis, or that there was a disproportionate number of non-responders in the group of patients who dropped out of the treatment arm of the trial. The former explanation is possible, as there was no significant difference in acceptability, as indicated by dropout rates, between rivastigmine and placebo. The rate of serious adverse events showed no significant differences, although overall there were more adverse events in the rivastigmine group. It is difficult to interpret the differences between the non-parametric and parametric analyses of the NPI outcomes. These mostly affect the LOCF analyses, and our conclusions are not changed. Rivastigmine did not show a significant benefit on cognitive functioning compared with placebo. We found no data on the effect of rivastigmine in DLB on activities of daily living, quality of life, effect on carers or institutionalization. A U T H O R S C O N C L U S I O N S Implications for practice There is weak evidence that patients with DLB who suffer from neuropsychiatric symptoms may benefit from a trial of rivastigmine, and it is reasonably well tolerated. We are not aware of any other controlled trials that demonstrate the efficacy of other medication for these problems in DLB. Neuroleptics are often used for psychotic symptoms in dementia, but need to be given with caution to people with DLB owing to their high sensitivity to extrapyramidal side effects. Rivastigmine may provide an alternative. Implications for research Results from measures of neuropsychiatric symptoms were compatible with somesuperiority of rivastigmine over placebo, but were not statistically significant using intention-to-treat analysis. This could suggest that the effects are so small that the included study lacked sufficient power to show a significant result. Further studies using rivastigmine would be helpful to see if this interpretation is sustained by a future meta-analysis. Trial evidence for the effects of the other cholinesterase inhibitors on LBD is not available, and as we cannot assume the results will be similar to rivastigmine, studies using these drugs are needed. Trials of longer duration are also required, as the implications for longer term use of cholinesterase inhibitors are unclear. Future trials should consider including outcome measures for activities of daily living, quality of life, effect on carers, and institutionalization. A C K N O W L E D G E M E N T S We are grateful to Dr Jo McShane, a carer and member of the Alzheimer s Society who acted as the lay reviewer for his comments 7

10 on the background and outcome measures. Jaqueline Birks, from the Cochrane Dementia and Cognitive Improvement Group, has provided invaluable statistical advice and analysis. Professor Ian McKeith provided additional unpublished data from the included trial. R E F E R E N C E S References to studies included in this review McKeith 2000 {published data only} Byrne J. Treatment of Lewy body dementia with Exelon. National Research Register [MEDLINE: Del Ser T. Efficacy of cholinesterase inhibitors in lewy body dementia. Sixth International Stockholm/Springfield Symposium on Advances in Alzheimer Therapy; April 5-8, 2000; Stockholm, Sweden 2000:51. Del Ser T, McKeith I, Anand R, Cicin-Sain A, Ferrara R, Spiegel R. Dementia with Lewy bodies: findings from an international multicentre study. Int J Geriatr Psychiatry 2000;15(11): McKeith I, Del Ser T, Anand R, et al.rivastigmine provides symptomatic benefit in dementia with lewy bodies: findings from a placebo-controlled international multicenter study. Neurology 2000e; Vol. 54, issue suppl 3:A450. McKeith I, Del Ser T, Spano P, Emre M, Wesnes K, Anand R, Cicin-Sain A, Ferrara R, Spiegel R. Efficacy of rivastigmine in dementia with Lewy bodies: a randomised, double-blind, placebocontrolled international study. Lancet 2000f; Vol. 356, issue 9247: Rossor MN. A prospective, multicentre, randomised double blind placebo controlled exploratory study to evaluate the safety, tolerability and efficacy of a new drug in patients suffering from probable dementia with Lewy bodies. National Research Register Wesnes K, McKeith I, Ferrara R, Emre M, Del Ser T, Spano P, Cicin-Sain A, Anand R, Spiegel R. Effects of rivastigmine on cognitive function in dementia with lewy bodies: A randomised placebo controlled international study using the Cognitive Drug Research Computerised Assessment system.. Dementia and Geriatric Cognitive Disorders 2002;13(3): References to studies excluded from this review Anand 2000 {published data only} Anand R, Enz A, Novartis Pharmaceuticals Corporation. Effects of rivastigmine extend beyond symptomatic treatment in patients with alzheimer s disease(ad): new clinical studies. Sixth International Stockholm/Springfield Symposium on Advances in Alzheimer Therapy; April 5-8, 2000; Stockholm, Sweden 2000:29. McKeith 2000a {published data only} McKeith IG, Grace JB, Walker Z, Byrne EJ, Wilkinson D, Stevens T, Perry EK. Rivastigmine in the treatment of dementia with Lewy bodies: preliminary findings from an open trial. Int-J-Geriatr- Psychiatry 2000d; Vol. 15, issue 5: McKeith 2000b {published data only} McKeith IG. A pilot study into the effects of donepezil on cognitive impairment and neuropsychiatric features in patients with dementia with Lewy bodies and Parkinson s disease. National Research Register 2000g. [MEDLINE: Samuel 2000 {published data only} Samuel W, Caligiuri M, Galasko D, Lacro J, Marini M, McClure FS, Warren K, Jeste DV. Better cognitive and psychopathologic response to donepezil in patients prospectively diagnosed as dementia with Lewy bodies: A preliminary study. International Journal of Geriatric Psychiatry 2000; Vol. 15, issue 9: Walker 2000b {published data only} Walker Z. Lewy body dementia: The investigation of pre and post synaptic dopaminergic receptors with SPET. NRR [MEDLINE: Wilcock 2000 {published data only} Wilcock GK. A double-blind, placebo-controlled, randomised, parallel group phase IIa study of the efficacy and safety of a novel therapy in the treatment of behavioural and psychological symptoms in subjects with dementia with Lewy bodies. National Research Register 2000e. Additional references Ballard 1995 Ballard CG, Mohan RNC, Patel A, Bannister C. Idiopathic clouding of consciousness - do patients have cortical Lewy Body Disease?. Int J Geriatr Psychiat 1995;8: Birks 2001a Birks J, Grimley Evans J, Iakovidou V, Tsolaki M. Rivastigmine for Alzheimer s disease. Cochrane Database of Systematic Reviews 2001, Issue 4. [: / CD001191][Art. No.: CD DOI: / CD pub2] Birks 2001b Birks JS, Harvey RJ. Donepezil for dementia due to Alzheimer s disease. Cochrane Database of Systematic Reviews 2006, Issue 1. [: / CD pub2][Art. No.: CD DOI: / CD pub2] Chalmers 1983 Chalmers TC, Celano P, Sacks HS, Smith H. Bias in treatment assignment in controlled clinical trials. N Engl J Med 1983;309: Clarke 2001 Clarke M, Oxman AD. Cochrane Reviewers Handbook [updated March 2001]. Vol. issue 2, Oxford: Update Software,

11 Cummings 1994 Cummings JL, Mega M, Gray K, Rosenberg-Thompson S, Carusi DA, Gornbein J. The neuropsychiatric inventory: Comprehensive assessment of psychopathology in dementia. Neurology 1994;44: Del Ser 2000a Del Ser T, McKeith I, Anand R, Cicin-Sain A, Ferrara R, Spiegel R. Dementia with Lewy bodies: findings from an international multicentre study. Int J Geriatr Psychiatry 2000;15(11): Fahn 1987 Fahn S, Elton RL. Members of the UPDRS development committe: Unified Parkinson s Disease Rating Scale. In: Fahn S, Marsden CD, Calne DB, Goldstein M editor(s). Recent Developments in Parkinson s Disease. Florhan Park, NJ: MacMillan Healthcare Information, 1987: Folstein 1975 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: Guy 1976 Guy W (ed). ECDEU Assessment manual for psychopharmacology. Rockville: National Institute of Mental Health, Holmes 1999 Holmes C, Cairns N, Lantos P, Mann A. Validity of current clinical criteria for Alzheimer s disease, vascular dementia and dementia with Lewy bodies. Br J Psychiatry 1999;174: Koch 1982 Koch GG, Amara IA, Davis GW, Gillings DB. A review of some statistical methods for covariance analysis of categorical data. Biometrics 1982;38: Kosaka 1984 Kosaka K, Yoshimura M, Ikeda K, Budka H. Diffuse type of Lewy body disease: progressive dementia with abundant cortical Lewy bodies and senile changes of varying degree - a new disease?. Clin Neuropathol 1984;3(5): Langlais 1993 Langlais PJ, Thal L, Hansen L, Galasko D, Alford M, Masliah E. Neurotransmitters in basal ganglia and cortex of Alzheimer s disease with and without Lewy bodies. Neurology 1993;43(10): Lippa 1994 Lippa CF, Smith TW, Swearer JM. Alzheimer s disease and Lewy body disease: a comparative clinicopathological study. Ann Neurol 1994;35(1):81 8. Lippa 1998 Lippa CF, Johnson R, Smith TW. The medial temporal lobe in dementia with Lewy bodies: a comparative study with Alzheimer s disease. Ann Neurol 1998;43(1): Luis 1999 Luis CA, Barker WW, Gajaraj K, et al.sensitivity and specificity of three clinical criteria for dementia with Lewy bodies in an autopsyverified sample. Int J Geriatr Psychiatry 1999;14(7): McKeith 2000c McKeith IG, Grace JB, Walker Z, et al.rivastigmine in the treatment of dementia with Lewy bodies: preliminary findings from an open trial. Int J Geriatr Psychiatry 2000;15(5): Moher 1998 Moher D, Phan B, Jones A, et al.does quality of reports of randomized trials affect estimates of intervention efficacy reported in meta-analyses?. Lancet 1998;352: MRC CFAS 2001 Neuropathology Group of the Medical Research Council cognitive function and Ageing Study (MRC CFAS). Pathological correlates of late-onset dementia in a multicentre, community-based population in England and Wales. Lancet 2001;357: Olin 2001 Loy C, Schneider L. Galantamine for Alzheimer s disease and mild cognitive impairment. Cochrane Database of Systematic Reviews 2006, Issue 1. [: / CD pub3.][Art. No.: CD DOI: / CD pub3] Perry 1994 Perry EK, Haroutunian V, Davis KL, et al.neocortical cholinergic activities differentiate Lewy body dementia from classical Alzheimer s disease. Neuroreport 1994;5(7): Rahkonen 2003 Rahkonen T, Eloniemi-Sulkava U, Rissanen S, Vatanen A, Viramo P, Sulkava R. Dementia with Lewy bodies according to the consensus criteria in a general population aged 75 years or older. J Neurol Neurosurg Psychiatry 2003;74(6): Samuel 1997 Samuel W, Alford M, Hofstetter CR, Hansen L. Dementia with Lewy bodies versus pure Alzheimer disease: differences in cognition, neuropathology, cholinergic dysfunction, and synapse density. J Neuropathol Exp Neurol 1997;56(5): Shea 1998 Shea C, MacKnight C, Rockwood K. Donepezil for treatment of dementia with Lewy bodies: a case series of nine patients. Int Psychogeriatr 1998;10(3): Shergill 1994 Shergill S, Mullan E, D Ath P, Katona C. What is the clinical prevalence of Lewy Body Dementia?. Int J Geriatr Psychiat 1994;9: Shulz 1995 Shulz KF, Chalmers I, Hayes RJ, Altman D. Empirical evidence of bias. JAMA 1995;273: Yoshimura 1983 Yoshimura M. Cortical changes in the parkinsonian brain: a contribution to the delineation of diffuse Lewy body disease. J Neurol 1983;229(1): References to other published versions of this review Wild 2003 Wild R, Pettit T, Burns A. Cholinesterase inhibitors for dementia with Lewy bodies. Cochrane Database of Systematic Reviews 2003, Issue 3. [DOI: / CD003672] Indicates the major publication for the study 9

12 C H A R A C T E R I S T I C S O F S T U D I E S Characteristics of included studies [ordered by study ID] McKeith 2000 Methods Allocation: Block randomisation Blindness: Triple - clinician, patient and assessors. Duration: 23 weeks. 20 weeks treatment followed by 3 weeks rest. Participants Diagnosis: Lewy-body dementia. N = 120. Age: Mean 73.9, SD 6.5, Range Sex: F 68, M 52. Setting: Dementia assessment clinics in Spain, UK and Italy. Inclusion: Clinical diagnosis of DLB. MMSE > 9. With regular carer. Exclusion: Severe extrapyramidal symptoms, asthma, taking neuroleptics, anticholinergics, selegiline or similar drugs. Interventions 1. Rivastigmine. Started at 1.5 mg twice daily, titrated to 6mg twice daily (or maximum tolerated) over 8 weeks maximum. Outcomes Notes Neuropsychiatric Inventory, 10 and 4 item versions (NPI-10 & NPI-4). Speed of response to selected tests. Clinical Global Change plus (CGC-plus). Mini Mental State Examination (MMSE). Unified Parkinsons Disease Rating Scale (UPDRS). Data on speed of response was not used in this Cochrane review, as we viewed it as a proxy measure rather than a direct measure of a clinically important feature of DLB. We were unable to include the UPDRS, as data was not presented in the published paper. Risk of bias Item Authors judgement Description Allocation concealment? Yes A - Adequate Characteristics of excluded studies [ordered by study ID] Study Anand 2000 McKeith 2000a McKeith 2000b Reason for exclusion Conference presentation. Review, not a clinical trial. Case series. Case series. Trial ongoing. 10

13 (Continued) Samuel 2000 Walker 2000b Wilcock 2000 Lewy Body Dementia patients compared with Alzheimer s Disease patients regarding response to donepezil. Investigation of pathophysiological changes. Project abandoned. 11

14 D A T A A N D A N A L Y S E S Comparison 1. Rivastigmine versus placebo Outcome or subgroup title No. of studies No. of participants Statistical method Effect size 1 Neuropsychiatric Inventory (10 1 Mean Difference (IV, Fixed, 95% CI) Subtotals only items). Change from baseline. 20 weeks. 1.1 ITT analysis Mean Difference (IV, Fixed, 95% CI) -3.3 [-8.14, 1.54] 1.2 LOCF analysis Mean Difference (IV, Fixed, 95% CI) [-9.49, 1.17] 1.3 OC analysis 1 91 Mean Difference (IV, Fixed, 95% CI) [-11.59, -2.29] 2 Neuropsychiatric Inventory 1 Mean Difference (IV, Fixed, 95% CI) Subtotals only (4items). Change from baseline. 20 weeks. 2.1 ITT analysis Mean Difference (IV, Fixed, 95% CI) [-4.34, 1.02] 2.2 LOCF analysis Mean Difference (IV, Fixed, 95% CI) [-5.41, 0.69] 2.3 OC analysis 1 91 Mean Difference (IV, Fixed, 95% CI) [-6.62, -0.88] 3 Proportion with an Adverse Odds Ratio (M-H, Fixed, 95% CI) 3.52 [1.19, 10.43] Event. ITT analysis. 20 weeks. 4 Proportion with a serious Odds Ratio (M-H, Fixed, 95% CI) 1.35 [0.49, 3.70] Adverse Event. ITT analysis. 20 weeks. 5 Drop out Rate. ITT analysis Odds Ratio (M-H, Fixed, 95% CI) 2.24 [0.93, 5.37] weeks. 6 Death. ITT analysis. 20 weeks Odds Ratio (M-H, Fixed, 95% CI) 0.2 [0.01, 4.26] 7 Mini-Mental State Examination. 1 Mean Difference (IV, Fixed, 95% CI) Subtotals only Change from baseline. 20 weeks. 7.1 ITT analysis Mean Difference (IV, Fixed, 95% CI) 1.24 [-0.28, 2.76] 7.2 LOCF analysis 1 99 Mean Difference (IV, Fixed, 95% CI) 1.18 [-0.60, 2.96] 7.3 OC analysis 1 90 Mean Difference (IV, Fixed, 95% CI) 1.6 [-0.09, 3.29] 8 Clinician Global Change Plus. 1 Odds Ratio (M-H, Fixed, 95% CI) Subtotals only No change or worse. 20 weeks 8.1 ITT analysis Odds Ratio (M-H, Fixed, 95% CI) 0.56 [0.24, 1.28] 8.2 LOCF analysis 1 95 Odds Ratio (M-H, Fixed, 95% CI) 0.63 [0.26, 1.50] 8.3 OC analysis 1 82 Odds Ratio (M-H, Fixed, 95% CI) 0.55 [0.22, 1.42] 12

15 Analysis 1.1. Comparison 1 Rivastigmine versus placebo, Outcome 1 Neuropsychiatric Inventory (10 items). Change from baseline. 20 weeks.. Review: Cholinesterase inhibitors for dementia with Lewy bodies Comparison: 1 Rivastigmine versus placebo Outcome: 1 Neuropsychiatric Inventory (10 items). Change from baseline. 20 weeks. Study or subgroup Rivastigmine Placebo Mean Difference Weight Mean Difference N Mean(SD) N Mean(SD) IV,Fixed,95% CI IV,Fixed,95% CI 1 ITT analysis McKeith (13.51) (13.51) % [ -8.14, 1.54 ] Subtotal (95% CI) % [ -8.14, 1.54 ] Test for overall effect: Z = 1.34 (P = 0.18) 2 LOCF analysis McKeith (13.56) (13.56) % [ -9.49, 1.17 ] Subtotal (95% CI) % [ -9.49, 1.17 ] Test for overall effect: Z = 1.53 (P = 0.13) 3 OC analysis McKeith (11.25) (11.25) % [ , ] Subtotal (95% CI) % [ , ] Test for overall effect: Z = 2.93 (P = ) Test for subgroup differences: Chi 2 = 1.24, df = 2 (P = 0.54), I 2 =0.0% Favours Rivastigmine Favours Placebo 13

16 Analysis 1.2. Comparison 1 Rivastigmine versus placebo, Outcome 2 Neuropsychiatric Inventory (4items). Change from baseline. 20 weeks.. Review: Cholinesterase inhibitors for dementia with Lewy bodies Comparison: 1 Rivastigmine versus placebo Outcome: 2 Neuropsychiatric Inventory (4items). Change from baseline. 20 weeks. Study or subgroup Rivastigmine Placebo Mean Difference Weight Mean Difference N Mean(SD) N Mean(SD) IV,Fixed,95% CI IV,Fixed,95% CI 1 ITT analysis McKeith (7.48) (7.48) % [ -4.34, 1.02 ] Subtotal (95% CI) % [ -4.34, 1.02 ] Test for overall effect: Z = 1.22 (P = 0.22) 2 LOCF analysis McKeith (7.76) (7.76) % [ -5.41, 0.69 ] Subtotal (95% CI) % [ -5.41, 0.69 ] Test for overall effect: Z = 1.52 (P = 0.13) 3 OC analysis McKeith (6.96) (6.96) % [ -6.62, ] Subtotal (95% CI) % [ -6.62, ] Test for overall effect: Z = 2.56 (P = 0.011) Test for subgroup differences: Chi 2 = 1.11, df = 2 (P = 0.57), I 2 =0.0% Favours Rivastigmine Favours Placebo 14

17 Analysis 1.3. Comparison 1 Rivastigmine versus placebo, Outcome 3 Proportion with an Adverse Event. ITT analysis. 20 weeks.. Review: Cholinesterase inhibitors for dementia with Lewy bodies Comparison: 1 Rivastigmine versus placebo Outcome: 3 Proportion with an Adverse Event. ITT analysis. 20 weeks. Study or subgroup Rivastigmine Placebo Odds Ratio Weight Odds Ratio n/n n/n M-H,Fixed,95% CI M-H,Fixed,95% CI McKeith /59 46/ % 3.52 [ 1.19, ] Total (95% CI) % 3.52 [ 1.19, ] Total events: 54 (Rivastigmine), 46 (Placebo) Test for overall effect: Z = 2.27 (P = 0.023) Favours Rivastigmine Favours Placebo Analysis 1.4. Comparison 1 Rivastigmine versus placebo, Outcome 4 Proportion with a serious Adverse Event. ITT analysis. 20 weeks.. Review: Cholinesterase inhibitors for dementia with Lewy bodies Comparison: 1 Rivastigmine versus placebo Outcome: 4 Proportion with a serious Adverse Event. ITT analysis. 20 weeks. Study or subgroup Rivastigmine Placebo Odds Ratio Weight Odds Ratio n/n n/n M-H,Fixed,95% CI M-H,Fixed,95% CI McKeith /59 8/ % 1.35 [ 0.49, 3.70 ] Total (95% CI) % 1.35 [ 0.49, 3.70 ] Total events: 10 (Rivastigmine), 8 (Placebo) Test for overall effect: Z = 0.59 (P = 0.56) Favours Rivastigmine Favours Placebo 15

18 Analysis 1.5. Comparison 1 Rivastigmine versus placebo, Outcome 5 Drop out Rate. ITT analysis. 20 weeks.. Review: Cholinesterase inhibitors for dementia with Lewy bodies Comparison: 1 Rivastigmine versus placebo Outcome: 5 Drop out Rate. ITT analysis. 20 weeks. Study or subgroup Rivastigmine Placebo Odds Ratio Weight Odds Ratio n/n n/n M-H,Fixed,95% CI M-H,Fixed,95% CI McKeith /59 10/ % 2.24 [ 0.93, 5.37 ] Total (95% CI) % 2.24 [ 0.93, 5.37 ] Total events: 18 (Rivastigmine), 10 (Placebo) Test for overall effect: Z = 1.80 (P = 0.071) Favours Rivastigmine Favours Placebo Analysis 1.6. Comparison 1 Rivastigmine versus placebo, Outcome 6 Death. ITT analysis. 20 weeks.. Review: Cholinesterase inhibitors for dementia with Lewy bodies Comparison: 1 Rivastigmine versus placebo Outcome: 6 Death. ITT analysis. 20 weeks. Study or subgroup Rivastigmine Placebo Odds Ratio Weight Odds Ratio n/n n/n M-H,Fixed,95% CI M-H,Fixed,95% CI McKeith /59 2/ % 0.20 [ 0.01, 4.26 ] Total (95% CI) % 0.20 [ 0.01, 4.26 ] Total events: 0 (Rivastigmine), 2 (Placebo) Test for overall effect: Z = 1.03 (P = 0.30) Favours Rivastigmine Favours Placebo 16

19 Analysis 1.7. Comparison 1 Rivastigmine versus placebo, Outcome 7 Mini-Mental State Examination. Change from baseline. 20 weeks.. Review: Cholinesterase inhibitors for dementia with Lewy bodies Comparison: 1 Rivastigmine versus placebo Outcome: 7 Mini-Mental State Examination. Change from baseline. 20 weeks. Study or subgroup Rivastigmine Placebo Mean Difference Weight Mean Difference N Mean(SD) N Mean(SD) IV,Fixed,95% CI IV,Fixed,95% CI 1 ITT analysis McKeith (4.26) (4.26) % 1.24 [ -0.28, 2.76 ] Subtotal (95% CI) % 1.24 [ -0.28, 2.76 ] Test for overall effect: Z = 1.59 (P = 0.11) 2 LOCF analysis McKeith (4.51) (4.51) % 1.18 [ -0.60, 2.96 ] Subtotal (95% CI) % 1.18 [ -0.60, 2.96 ] Test for overall effect: Z = 1.30 (P = 0.19) 3 OC analysis McKeith (4.07) (4.07) % 1.60 [ -0.09, 3.29 ] Subtotal (95% CI) % 1.60 [ -0.09, 3.29 ] Test for overall effect: Z = 1.86 (P = 0.063) Test for subgroup differences: Chi 2 = 0.14, df = 2 (P = 0.93), I 2 =0.0% Favours placebo Favours rivastigmine 17

20 Analysis 1.8. Comparison 1 Rivastigmine versus placebo, Outcome 8 Clinician Global Change Plus. No change or worse. 20 weeks. Review: Cholinesterase inhibitors for dementia with Lewy bodies Comparison: 1 Rivastigmine versus placebo Outcome: 8 Clinician Global Change Plus. No change or worse. 20 weeks Study or subgroup Rivastigmine Placebo Odds Ratio Weight Odds Ratio n/n n/n M-H,Fixed,95% CI M-H,Fixed,95% CI 1 ITT analysis McKeith /48 41/ % 0.56 [ 0.24, 1.28 ] Subtotal (95% CI) % 0.56 [ 0.24, 1.28 ] Total events: 29 (Rivastigmine), 41 (Placebo) Test for overall effect: Z = 1.38 (P = 0.17) 2 LOCF analysis McKeith /40 40/ % 0.63 [ 0.26, 1.50 ] Subtotal (95% CI) % 0.63 [ 0.26, 1.50 ] Total events: 25 (Rivastigmine), 40 (Placebo) Test for overall effect: Z = 1.06 (P = 0.29) 3 OC analysis McKeith /36 34/ % 0.55 [ 0.22, 1.42 ] Subtotal (95% CI) % 0.55 [ 0.22, 1.42 ] Total events: 22 (Rivastigmine), 34 (Placebo) Test for overall effect: Z = 1.23 (P = 0.22) Favours Rivastigmine Favours Placebo W H A T S N E W Last assessed as up-to-date: 27 April Date Event Description 28 April 2008 Review declared as stable This review does not need to be updated as it will be replaced by the new review on Cholinesterase inhibitors for dementia with Lewy bodies, Parkinson s disease dementia and cognitive impairment in Parkinson s disease, which is currently in progress 28 April 2008 Amended Converted to new review format 18