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Bond M, Rogers G, Peters J, et al. The Effectiveness and Cost-Effectiveness of Donepezil, Galantamine, Rivastigmine and Memantine for the Treatment of Alzheimer's Disease (Review of Technology Appraisal No. 111): A Systematic Review and Economic Model. Southampton (UK): NIHR Journals Library; 2012 Apr. (Health Technology Assessment, No. 16.21.)

3Assessment of clinical effectiveness

The purpose of the systematic review of clinical effectiveness is to record the studies found by Loveman and colleagues2 in 2004 and to update their findings with the results of subsequent trials.

This chapter has been arranged as follows:

  1. methods for reviewing effectiveness
  2. results of the systematic review
  3. manufacturers' reviews of clinical effectiveness
  4. results – pair-wise comparisons
    1. donepezil versus placebo
    2. galantamine versus placebo
    3. rivastigmine versus placebo
    4. memantine versus placebo
  5. head-to-head comparisons
  6. combination therapy
  7. results – multiple treatment comparisons
    1. cognitive
    2. functional
    3. behavioural
    4. global
  8. summary of clinical effectiveness.

Methods for reviewing effectiveness

The clinical effectiveness of donepezil, galantamine, rivastigmine and memantine for AD was assessed by a systematic review of research evidence. The review was undertaken following the principles published by the NHS Centre for Reviews and Dissemination (CRD).77 The study protocol can be viewed on the NICE website: www.nice.org.uk.

Identification of studies

Electronic databases were searched for systematic reviews and/or meta-analyses, randomised controlled trials (RCTs) and ongoing research in November 2009 and updated in March 2010; this updated search revealed no includable new studies. Appendix 2 shows the databases searched and the strategies in full. These included The Cochrane Library (2009 Issue 4, Cochrane Database of Systematic Reviews and Cochrane Central Register of Controlled Trials), MEDLINE, MEDLINE In-Process & Other Non-Indexed Citations, EMBASE, PsycINFO, EconLit, ISI Web of Science Databases – Science Citation Index, Conference Proceedings Citation Index, and BIOSIS, and the CRD databases – NHS Economic Evaluation Database (NHS EED), Health Technology Assessment, and Database of Abstracts of Reviews of Effects databases. Where possible, a controlled trials and human filter was added. As this is an update of a previous review the searches were run in the time frame 2004 to current. The meta-register of controlled trials and ‘clinicaltrials.gov’ were searched for ongoing trials. Bibliographies of included studies were searched for further relevant studies. The reference lists of the industry submissions were also scrutinised for additional studies. Owing to resource limitations the search was restricted to English-language papers only. All references were managed using Reference Manager (Professional Edition, version 11; Thomson ISI ResearchSoft, Thomson Reuters, New York, NY, USA) and Microsoft Access 2003 software (Microsoft Corporation, Redmond, WA, USA).

Relevant studies were identified in two stages. Titles and abstracts returned by the search strategy were examined independently by two researchers (GR and MB) and screened for possible inclusion. Disagreements were resolved by discussion. Full texts of the identified studies were obtained. Two researchers (GR and MB) examined these independently for inclusion or exclusion, and disagreements were again resolved by discussion. A third reviewer was available to resolve disagreements, but this was not necessary.

Inclusion and exclusion criteria

Study design

Inclusion criteria

For the review of clinical effectiveness, only systematic reviews of RCTs and RCTs were considered. The review protocol made provision for broadening the search criteria to include some observational evidence if insufficient systematic reviews or RCTs were identified; however, this proved unnecessary in view of the reasonable yield of evidence of a preferred design (see below).

Systematic reviews were used as a source for finding further RCTs and to compare with our systematic review. For the purpose of this review, a systematic review7779 was defined as a review that has:

  • a focused research question
  • explicit search criteria that are available to review, either in the document or on application
  • explicit inclusion/exclusion criteria, defining the population(s), intervention(s), comparator(s) and outcome(s) of interest
  • a critical appraisal of included studies, including consideration of internal and external validity of the research
  • a synthesis of the included evidence, whether narrative or quantitative.
Exclusion criteria

Studies were excluded if they did not match the inclusion criteria, and in particular:

  • non-randomised studies [except for adverse events (AEs)]
  • animal models
  • preclinical and biological studies
  • narrative reviews, editorials, opinions
  • non-English-language papers
  • reports published as meeting abstracts only, where insufficient methodological details were reported to allow critical appraisal of study quality.
Population

Studies were included if they reported a population comprising adults with AD. Following the 2004 review, trials that included participants with mixed dementia were included if the predominant dementia was AD.

Participants in included trials were required to meet the definitions of disease severity specified in the technologies' UK marketing authorisations (MMSE 26–10 for donepezil, galantamine and rivastigmine; MMSE 20–0 for memantine).

The exact inclusion criterion adopted for MMSE scores was defined as an approximation of the principle that at least 80% of a study's participants should be within the specified range. This approach relied on the assumption that reported baseline MMSE scores were normally distributed. On this basis, studies were included if the predefined thresholds were not exceeded by the reported mean baseline MMSE score ± 0.8416 standard deviation (SD), where 0.8416 is the inverse of the standard normal distribution corresponding to a probability of 0.8.

Interventions and comparators

Studies were included if the technologies they assessed fulfilled the following criteria:

  • Interventions The four technologies under review were considered within their UK marketing authorisations:

    mild-to-moderately severe AD (measured by the MMSE 26–10) – donepezil, galantamine and rivastigmine

    moderate-to-severe AD (measured by the MMSE 20–0) – memantine.

  • Comparators For people with mild AD the comparators of interest were placebo and/or BSC (i.e. treatment without AChEIs and without memantine). For people with moderate AD the comparators were donepezil, galantamine, rivastigmine, memantine and placebo and/or BSC (i.e. treatment without AChEIs). For people with severe AD the comparator was treatment without memantine.
Outcomes

Studies were included if they reported data on one or more of the following outcomes:

  • measures of severity and response to treatment
  • behavioural symptoms
  • mortality
  • ability to remain independent
  • likelihood of admission to residential/nursing care
  • HRQoL of patients and carers
  • adverse events of treatment.

Data extraction strategy

Data were extracted by GR into forms in bespoke software and checked by MB. Disagreements were resolved by discussion. The items extracted can be found in the data extraction forms of included studies which are available in Appendix 3.

Critical appraisal strategy

Assessments of study quality were performed according to the instrument developed for the 2004 review (which was based on criteria recommended by the NHS CRD77). The instrument is summarised below; for full details, see Appendix 5 of the 2004 review.2 Results were tabulated and the relevant aspects described in the data extraction forms.

Internal validity

The instrument sought to assess the following considerations:

  1. Was the assignment to the treatment groups really random?
  2. Was the treatment allocation concealed?
  3. Were the groups similar at baseline in terms of prognostic factors?
  4. Were the eligibility criteria specified?
  5. Were outcome assessors blinded to the treatment allocation?
  6. Was the care provider blinded?
  7. Was the patient blinded?
  8. Were point estimates and a measure of variability presented for the primary outcome measure?
  9. Did the analyses include an intention-to-treat (ITT) analysis?
  10. Were withdrawals and dropouts completely described?

In addition, methodological notes were made for each included study, including the reviewer's observations on sample size and power calculations, participant attrition, methods of data analysis, and conflicts of interest.

External validity

External validity was judged according to the ability of a reader to consider the applicability of findings to a patient group and service setting. Study findings can only be generalisable if they describe a cohort that is representative of the affected population at large. Studies that appeared representative of the UK AD population with regard to these considerations were judged to be externally valid.

Methods of quantitative synthesis

Where data permitted, the results of individual trials were pooled using the methods described in the following section.

Pair-wise meta-analysis

We used random-effects meta-analyses (DerSimonian and Laird model80) only, regardless of any statistical evidence of interstudy homogeneity. Heterogeneity was explored by visualisation of results and, in statistical terms, both Cochran's Q-test (compared with a chi-squared distribution)81 and the I2-statistic.82,83 Small-study effects (including publication bias) were visualised using funnel plots and quantified using Egger's test84 (see Appendix 4). Analyses were conducted using bespoke software, written in Microsoft Visual basic for Applications (version 6) and applied in both Microsoft Access 2003 and Microsoft Excel 2003 (Microsoft Corporation, Redmond, WA, USA). Stata 10.1 (StataCorp LP, College Station, TX, USA) was used to generate forest plots (‘metan’ command) and to assess small-study effects (‘metabias’ command).

Where more than one arm of a contributing trial was relevant to any analysis, data were pooled to form a single meta-arm as the unit of analysis, as recommended in the Cochrane Handbook for Systematic Reviews of Interventions (section 16.5.4).85 For the continuous outcome measures reported in this review, the mean for the combined arm is estimated as the weighted mean from the multiple separate arms (where the numbers in each arm provide the weights), and the SD for the combined arm is calculated according to the usual formula:

sc=i=1k(ni1)si2i=1k(ni1)
[Equation 1]

where i indexes a total of k arms being combined, ni is the number of participants in each arm, and si is the SD for that arm.

All meta-analyses were stratified according to the measurement population. Where multiple-measurement populations were reported in an individual study, we used the highest ranking according to a prespecified hierarchy:

  1. true ITT
  2. last observation carried forward (LOCF)
  3. observed cases (OCs) only.

The issue of how to deal with missing data point from dropouts in ITT analysis of dementia patients is a contentious one. Owing to the natural course of this degenerative disease, the assumption of LOCF that disease progression stops at the last data point clearly does not reflect reality. Similarly, to use OCs only (i.e. not estimating any data points after dropout) may give misleading results. A better solution may be to apply the rate of decline found in the control group to all dropouts.86

We performed separate analyses for different periods of follow-up. The two lengths of follow-up for which data were generally available were approximately 3 months (12–16 weeks of treatment) and approximately 6 months (21–28 weeks) (figures showing these results are in the body of the text).

Where different dosages of drugs were found in various studies, we meta-analysed comparable groups separately (figures for commonly used doses in the UK are in the body of the text). We also performed a single analysis in which all dosages were combined (figures from these analyses are in Appendix 5). For continuous outcomes measured over a longitudinal period of follow-up, it is possible for investigators to report outcomes in two ways: the mean of each participant's observed change from a measured baseline score (mean change from baseline) or absolute measurements at the relevant juncture (absolute value). If randomisation is adequate, the difference between these values should be the same (i.e. the mean of the differences will be the same as the difference in the means). However, the dispersion of each measure may vary. It is stated in the Cochrane Handbook for Systematic Reviews of Interventions (section 9.4.5.2) that ‘[t]here is no statistical reason why studies with change-from-baseline outcomes should not be combined in a meta-analysis with studies with final measurement outcomes’.85 However, exploratory analyses showed that the inclusion of both types of data led to large differences in the results of meta-analyses, although this may be because the studies that only report final measurement data tend to be of a lower methodological standard (and, therefore, may also be more susceptible to biases that would distort reported treatment effect). As a result, we were not prepared to pool the two types of measurement, and all of our meta-analyses rely on studies reporting mean change from baseline only.

Pooling of multiple outcome measures

In addition to pair-wise meta-analyses of treatment effect pooled on each outcome's natural scale [weighted mean difference (WMD)], we combined outcomes in a series of broad domains – cognitive, functional, behavioural and global – to investigate the overall characteristics of reported effectiveness evidence in each area (see figures in the body of the text and data sets used in the meta-analysis of pooled multiple outcome measures in Appendix 6).

In order to combine studies using different outcome measures within each domain, effect sizes were expressed as a standardised mean difference (SMD). The SMD expresses the size of the treatment effect in each trial relative to the variability observed in that trial. Accordingly, for a given trial i,

di=m1im2isi
[Equation 2]

where m1i and m2i represent the reported means in active treatment and control cohorts, respectively, and si is the pooled SD across both groups, estimated as

si=(n1i1)SD1i2+(n2i1)SD2i2Ni2
[Equation 3]

where n1i, n2i and Ni represent the sample sizes of treated, control and combined cohorts, respectively, and the reported SDs of measurements in treated and control groups are SD1i and SD2i. In order to pool SMDs, it is necessary to derive the standard error (SE), which is estimated as follows:

SE(di)=Nin1in2i+di22(Ni2)
[Equation 4]

The method assumes that the differences in SDs between studies reflect differences in measurement scales and not real differences in variability among study populations.

Where studies reported more than one outcome contributing to the same domain, a weighted average of all SMDs was calculated, using the precision of the estimates as the weighting factor (this could be seen as a submeta-analysis, adopting a fixed-effects model with inverse variance weighting). So that such studies were not given spurious weight, the sample size for each outcome measure was divided by the total number of outcomes.

This approach has the advantage of enabling a broader evidence base to be combined, but it has the disadvantage of requiring estimates to be pooled on a scale that has no direct clinical meaning. Accordingly, we used these analyses solely to explore the characteristics of the evidence base, and not to draw direct conclusions about the magnitude of relative effectiveness of the comparators. In particular, we used the analyses as a basis for metaregression (see below), and for assessing small-study effects.

Metaregression

Where there was sufficient evidence (at least five individual data points in a meta-analysis), study-level regression (‘metaregression’) was used to explore the statistical heterogeneity across studies. Three prespecified covariates were explored: population gender, population gender, and baseline disease severity (as measured by MMSE). Because of inconsistencies in the evidence base, it was not possible to undertake multivariate analyses, so regressions were conducted solely on a univariate basis. Metaregression was undertaken in Stata 10.1 (‘metareg’ command), using the restricted maximum likelihood estimator, as recommended.87,88 These figures are in Appendix 7.

Mixed-treatment comparison: indirect comparison

In addition to pair-wise meta-analyses, where sufficient data were available, we synthesised information on all technologies and their comparators simultaneously, in a mixed-treatment comparison (MTC) using Bayesian Markov Chain Monte Carlo (MCMC) sampling.8992 The analyses were performed using WinBUGS 1.4.1 (MRC Biostatistics Unit, Cambridge UK) (model code is reproduced in Appendix 8).

Vague prior distributions were used in the analyses (Normal[0, 0.000001] for mean difference between treatments; Uniform[0,2] for SD of random-effects distribution). Point estimates and 95% credible intervals were calculated from 100,000 simulated draws from the posterior distribution after a burn-in of 10,000 iterations.

Outputs are presented in terms of treatment effect compared with a common baseline. In each case in the presented analyses, the available evidence networks included at least one placebo arm; therefore, the baseline treatment is always placebo. This is helpful, as it enables all MTC outputs to be interpreted on a common level. In addition to treatment effect relative to placebo, the posterior probability that each treatment is most effective is presented, simply calculated as the proportion of MCMC trials in which the given treatment had the highest (or lowest, for negative scales) estimated treatment of all comparators.

This approach assumes ‘exchangeability’ of treatment effect across all included trials, such that the observed treatment effect for any comparison could have been expected to arise if it had been measured in the populations reported in all other included trials. Exchangeability was judged through examination of the trial populations and comparability of outcomes in the common treatment group facilitating the comparison. Figures representing these analyses are in the body of the text.

As for pair-wise syntheses, we generated separate MTCs for different periods of follow-up (12–16 weeks and 21–28 weeks). We also generated separate analyses according to measurement population: LOCF only; ITT plus LOCF; OC only; and all measurement populations combined (see Appendix 9). Where multiple measurement populations were reported in an individual study and more than one was pertinent to one of these analyses, we used the highest ranking according to the hierarchy given above. Multiple relevant arms within a single study were pooled according to the methods detailed above (see Pair-wise meta-analysis), before being entered into the MTC.

Graphical representation of summary trial information

We present a novel approach to summarising the complex information relating to each trial at the end of each comparison section. These figures graphically represent the location, size, MMSE score at baseline, gender, age, study quality and results in a format that allows quick comparison between trials. A key to understanding the graphics is presented below in Figure 5.

FIGURE 5. Key to graphical summaries.

FIGURE 5

Key to graphical summaries. aSignificance displayed if mean change scores reported show significance of p < 0.05. In the case of multiple analyses, ITT is favoured over LOCF, which is, in turn, favoured over OC analyses. ADCS-CGIC, Alzheimer's (more...)

Results of the systematic review: identification of evidence

From screening the titles and abstracts of the 1843 references identified by our searches and additional sources, we retrieved 191 papers for detailed consideration, of which 21 were judged to meet the inclusion criteria for the review. The process is illustrated in detail in Figure 6. In assessing the titles and abstracts, agreement between the two reviewers was moderately good (κ = 0.642). At the full-text stage, agreement was moderate (κ = 0.538). At both stages, initial disagreements were easily resolved by consensus.

FIGURE 6. Identification of published evidence for review.

FIGURE 6

Identification of published evidence for review. IPD, individual patient data; SR, systematic review.

The submissions from Eisai/Pfizer and Lundbeck contained a number of published and unpublished items that we have excluded from our review because they did not meet our inclusion criteria. A list of these items, with reasons for their exclusion, can be found in Appendix 10. A list of ongoing trials can be found in Appendix 11.

Results: systematic reviews

Our searches found four systematic reviews that met our inclusion criteria. These were critically appraised using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement checklist, which describes 27 items that a report of a systematic review or meta-analysis should contain.78 A summary table of whether or not these quality indicators were present in these systematic reviews can be found in Appendix 12. The references of each systematic review were checked to see if they held any includable additional trials, no further includable studies were found. A brief summary of each systematic review can be seen below.

Summary of included systematic reviews and meta-analyses

Donepezil

No systematic reviews of donepezil were found that matched our inclusion criteria.

Galantamine

No systematic reviews of galantamine were found that matched our inclusion criteria.

Rivastigmine

Birks and colleagues94 conducted a Cochrane review of rivastigmine compared with placebo for people with mild-to-moderate AD. They found nine trials with a total of 4775 participants. The review found that the use of rivastigmine (6–12 mg daily) was associated with a two-point improvement on the ADAS-cog compared with placebo [ITT WMD −1.99 (95% CI −2.49 to −1.50)] and a 2.2-point improvement on the Progressive Deterioration Scale (PDS) for ADL [ITT WMD −2.15 (95% CI −3.16 to −1.13)] at 26 weeks. The authors concluded that rivastigmine gave benefit to people with mild-to-moderate AD when compared with placebo. The review also considered delivery of the drug by transdermal patch. It found that the lower dose patch (9.6 mg/day) was associated with fewer side effects than the capsules or the higher dose patch (17.4 mg/day), and produced similar efficacy. The main AEs were gastrointestinal (nausea and vomiting), usually occurring during the titration phase.

All cholinesterase inhibitors

The German Institute for Quality and Efficiency in Health Care (IQWiG) conducted a systematic review and meta-analysis of all of the cholinesterase inhibitors included in this report for people with mild-to-moderate AD.95 They included RCTs up to June 2006 in their systematic review, and found 27 studies with a total of 9883 participants. Only four of these trials met our inclusion criteria.9699 The IQWiG concluded that all the AChEIs provided benefit in improving or maintaining cognitive function and ADLs, and that galantamine alleviated psychological symptoms. However, none of the studies provided evidence of improvement in QoL. A summary table of these results can be found in Appendix 13.

Memantine

A systematic review of memantine for dementia was carried out by Raina and colleagues.100 Their inclusion criteria were broader than ours and included all major types of dementia, patients with mild-to-moderate disease severity and all drugs for treating dementia. Of the 59 studies they included, only two met our inclusion criteria for trials.96,101 The data syntheses from this systematic review are not relevant to this TAR and will not be discussed.

All included drugs

Hansen and colleagues102 conducted a systematic review and meta-analysis of functional outcomes from the use of donepezil, galantamine, rivastigmine and memantine for people with mild-to-moderate AD. They included 13 RCTs, 12 of which were included in the previous TAR (No. 111). The new study, which is included in this review, is Brodaty and colleagues.93 Overall, they found a small effect size (d = 0.1–0.4) favouring drug treatment. A metaregression showed that this effect was not affected by disease severity, age, gender and drug dose. AEs were most commonly gastrointestinal.

Manufacturers' reviews of clinical effectiveness

Three reviews were presented summarising evidence on the effectiveness of donepezil, galantamine and memantine by the manufacturers of each of the drugs. Although not part of the Peninsula Technology Assessment Group (PenTAG)'s systematic review they are presented here for convenience and because their findings are compared with our own review. Each submission is briefly discussed in the sections below.

Donepezil

Eisai and Pfizer submitted a systematic review as part of their joint submission on donepezil. It included both RCTs and targeted non-RCT/observational studies. Concerning the effect of donepezil relative to placebo the reported results of effect on cognition, function, behaviour and global impact were consistent with the results of the PenTAG review. There was, however, limited information on any summary estimates of effect in the manufacturer submission. Challenges to the validity of the AD2000 trial103 were re-emphasised.

Published meta-analyses were used to explore whether or not the effect of donepezil varied depending on the severity of AD, particularly the effectiveness in patients with mild AD. These suggested that a beneficial effect of donepezil relative to placebo on cognition, global impact and behaviour was present for patients with mild AD. The summary estimates quoted for mild AD were broadly similar to the overall summary estimates calculated in the PenTAG systematic review.

Results from non-RCT and observational data were presented to support the following additional aspects of the effectiveness of donepezil:

  • duration of effectiveness extending beyond 6 months up to at least 3 years
  • worsening of symptoms following withdrawal of treatment
  • emergence of benefit after initial absence of changes suggesting response
  • impact on carers, particularly caregiver stress and carer time
  • trends towards reductions in antipsychotic medication use
  • reductions in mortality.

Galantamine

Shire Pharmaceuticals presented a summary of all available RCTs (not just those from 2004 onwards) comparing galantamine with placebo, but did not indicate how the review had been conducted. They emphasised the importance of newer dosing regimens and highlighted deficiencies in the previous systematic review by the Southampton Health Technology Assessment Centre (SHTAC), particularly concerning failure to include a study directly comparing galantamine with donepezil.

The pooled summary estimates presented for the effect of galantamine on cognition, behaviour and function were consistent with the summary estimates in the PenTAG systematic review. The Shire Pharmaceuticals submission provided additional analyses, indicating an increase in effect with increasing severity of disease. Similar analyses could not be done in the PenTAG systematic review because of the requirement for individual patient data (IPD).

Memantine

Lundbeck presented a meta-analysis of pivotal trials as part of its submission. Although some details on the methods of analysis were provided, there was no information on how the pivotal trials were ascertained. The inclusion criteria were given and in essence the included studies were double-blind RCTs comparing memantine with placebo measuring cognition, disability, global health state and behaviour at 3 or 6 months. The need for IPD was further stipulated to allow subgroup analysis. There were six included studies in the main analysis covering all periods, not just 2004 onwards. The reasons why some studies were included in the Lundbeck analysis but not included in the PenTAG meta-analysis are documented in Appendix 10. Briefly, these were that Lundbeck's pooling methods relied on the availability of IPD to which PenTAG did not have access, and Lundbeck were prepared to pool data from trials of memantine plus AChEIs versus AChEIs alone with data from trials of memantine monotherapy versus placebo to produce a single estimate of memantine effect. PenTAG were not comfortable with the assumptions necessary to justify such a single analysis. Notwithstanding this, the direction and size of effect of memantine relative to placebo on cognition, disability, global health state and behaviour are consistent between the Lundbeck and PenTAG analyses. In this, account needs to be taken of the fact that the results in the Lundbeck submission are presented as SMDs, whereas those in the PenTAG analysis were WMDs. Approximate interconversion is achieved by multiplying or dividing by the pooled SD. The 95% CIs are narrower in the Lundbeck analysis because of the greater number of included studies. The submission identified no evidence that the effectiveness varied by severity of AD, by past use of AChEIs or by concurrent use AChEIs. These analyses could not be repeated in the PenTAG systematic review because they depend on IPD.

Lundbeck also examined whether or not there was evidence of a difference in effectiveness depending on the presence of agitation/aggression and/or psychotic symptoms (APS), defined by the baseline NPI score being ≥ 3 (as opposed to the definition of > 0 used in the last the submission for the last NICE guidance). The results suggested that there is greater effectiveness in patients with APS but, again, these analyses could not be repeated in the PenTAG systematic review because they depend on IPD.

Unavailable evidence

Subgroup analyses

The study protocol specified that if evidence allowed subgroups based on disease severity, response to treatment, behavioural disturbance and comorbidities should be considered. However, none of the included trials reported any of these subgroup analyses. Therefore, we are unable to comment on them.

Outcomes

None of the included trials reported mortality or institutionalisation outcomes, or reported on outcomes beyond 28 weeks.

Results: pair-wise comparisons

Donepezil versus placebo

Identified evidence

The 2004 review2 identified 14 RCTs investigating the effectiveness of donepezil compared with placebo.93,103116

Notes:

  • The Nunez and colleagues trial111,112 was reviewed in poster form in 2003; a full publication, authored by Johannsen and colleagues,112 is now available, from which we have extracted data; however, for consistency with the 2004 review, we continue to refer to this RCT as ‘Nunez and colleagues’.
  • The Seltzer and colleagues trial115 was reviewed on a commercial-in-confidence (CiC) basis using information supplied by the manufacturer in 2004 – a full publication, authored by Seltzer and colleagues.115
  • Winblad and colleagues,116 with additional information contained in the trial of Wimo and colleagues.117

Our searches identified an additional five RCTs.118122 A summary of their design characteristics can be found in Table 2 and the interventions, comparators and baseline characteristics of the participants in Table 3. Critical appraisal of these small studies showed that none was of good quality; neither study was reporting adequate randomisation nor allocation concealment. A summary of the markers of internal validity is presented in Table 4.

TABLE 2. Design of included studies: donepezil vs placebo.

TABLE 2

Design of included studies: donepezil vs placebo.

TABLE 3. Interventions, comparators and baseline characteristics of participants in included studies: donepezil vs placebo.

TABLE 3

Interventions, comparators and baseline characteristics of participants in included studies: donepezil vs placebo.

TABLE 4. Markers of internal validity of included studies: donepezil vs placebo.

TABLE 4

Markers of internal validity of included studies: donepezil vs placebo.

Evidence of clinical effectiveness

Cognition

In 2004, Loveman and colleagues2 summarised the evidence they found for donepezil versus placebo for cognitive outcomes as follows:

Six RCTs showed that donepezil appears to confer a statistically significant benefit to participants on the ADAS-cog scale when compared to placebo. The benefit varies according to the dose of donepezil with higher doses of donepezil tending to show increasing benefit. Because the mean change scores varied quite considerably between the included studies, this dose-related trend can particularly be seen within individual trials, although no direct statistical comparisons were made in any of these. The mean change scores were however varied between the included studies. Eight RCTs showed trends towards better MMSE score in the donepezil treated groups when compared to the placebo groups, although this was not always demonstrated to be statistically significant. These trends were mirrored in one unpublished trial of people with mild Alzheimer's disease.

New data In the studies we found published since 2004, four showed significant cognitive benefit for donepezil versus placebo.118121 However, only two of these trials118,122 estimated the missing values from dropouts using ITT analysis. The others made estimates using OCs only, thus potentially magnifying any benefit from donepezil and biasing their results in favour of the intervention. A summary of the results from cognitive measures can be seen in Table 5.

TABLE 5. Measures of cognition in included studies: donepezil vs placebo.

TABLE 5

Measures of cognition in included studies: donepezil vs placebo.

Synthesis with existing evidence base The data from the new trials were synthesised with those from Loveman and colleagues report2 by random-effects meta-analysis. This was conducted considering ADAS-cog and then MMSE as the outcomes, measuring differences between donepezil (all doses) and placebo at 12 and 24 weeks post randomisation. The results can be seen in Figures 7 and 8. We also meta-analysed the data by 5 mg/day and all doses combined; these results can be found in Appendix 5. We then went on to explore the effect of pooling the entire cognitive outcome measures at 24–26 weeks; the results of this can be seen below (see Figure 11).

FIGURE 7. Random-effects meta-analysis: ADAS-cog at 12 weeks (mean change from baseline): donepezil (10 mg/day) vs placebo.

FIGURE 7

Random-effects meta-analysis: ADAS-cog at 12 weeks (mean change from baseline): donepezil (10 mg/day) vs placebo.

FIGURE 8. Random-effects meta-analysis: ADAS-cog at 24 weeks (mean change from baseline): donepezil (10 mg/day) vs placebo.

FIGURE 8

Random-effects meta-analysis: ADAS-cog at 24 weeks (mean change from baseline): donepezil (10 mg/day) vs placebo.

FIGURE 11. Random-effects meta-analysis: cognitive outcomes (SMD) at 24–26 weeks: donepezil (all dosages) vs placebo.

FIGURE 11

Random-effects meta-analysis: cognitive outcomes (SMD) at 24–26 weeks: donepezil (all dosages) vs placebo.

Alzheimer's Disease Assessment Scale – Cognitive Subscale We found no new studies reporting the ADAS-cog at 12 or 24 weeks. The meta-analyses presented below are of studies included in the previous assessment report. The overall pooled estimates shows a benefit from donepezil compared with placebo, which increases over time: 12 weeks' WMD = −1.97 (95% CI −3.38 to −0.56), p = 0.006; 24 weeks' WMD = −2.90 (95% CI −3.61 to −2.18), p < 0.001 (Figures 7 and 8).

Similarly, no new evidence was found for the outcome measure MMSE at 12 weeks post randomisation, but one new study was found with measures at 24 weeks' follow-up. The meta-analyses below show an overall benefit from donepezil versus placebo when measured on the MMSE: 12 weeks' (10 mg/day) WMD = −1.17 (95% CI 0.88 to 1.45), p < 0.001; 24 weeks' (5 and 10 mg/day) WMD = 1.21 (95% CI 0.84 to 1.57), p < 0.001 (Figures 9 and 10).

FIGURE 9. Random-effects meta-analysis: MMSE at 12 weeks (mean change from baseline): donepezil (10 mg/day) vs placebo.

FIGURE 9

Random-effects meta-analysis: MMSE at 12 weeks (mean change from baseline): donepezil (10 mg/day) vs placebo.

FIGURE 10. Random-effects meta-analysis: MMSE at 24 weeks (mean change from baseline): donepezil (all dosages) vs placebo.

FIGURE 10

Random-effects meta-analysis: MMSE at 24 weeks (mean change from baseline): donepezil (all dosages) vs placebo. a, WMD and error bars provided in publication; SE estimated on assumption that error bars represent 95% CIs; b, Pooled 5 and 10 mg/day arms. (more...)

Pooled multiple outcome measures Two new studies were found to add to this combined meta-analysis of cognitive outcome measures at 24–26 weeks. The overall pooled estimate showed a significant cognitive benefit from donepezil compared with placebo: SMD = 0.40 (95% CI 0.29 to 0.50), p < 0.001 (Figure 11). The data set used in this meta-analysis can be found in Appendix 6.

Functional

The 2004 assessment report2 found that:

A variety of functional measures were used in eight RCTs. Donepezil had some effect in improving or limiting further deterioration on ADLs when compared with placebo, but this was not always statistically significant, particularly over longer durations of follow-up. One trial reported time to loss of ADL and/or time to institutional care and found that donepezil conferred no advantage to placebo.

New data We found only one new RCT measuring functional outcomes for this comparison. This small, poorly reported trial showed a significant benefit from donepezil (5 mg/day) for ADLs in an OC-measured population at 12 weeks' follow-up – mean difference: I = 40.5 (SD 7.6), C = 49.5 (SD 6.3), p < 0.01 (Table 6).

TABLE 6. Measures of functional ability in included studies: donepezil vs placebo.

TABLE 6

Measures of functional ability in included studies: donepezil vs placebo.

Synthesis with existing evidence base When the 2004 and post-2004 evidence bases were collected together, there was an extremely heterogeneous collection of outcome measures for this domain. As a result, we have not been able to perform any quantitative synthesis of individual outcome measures on a natural scale.

Pooled multiple outcome measures There were no new studies that measured functional outcomes at 24 weeks; therefore, we pooled the functional outcome data from the studies in the previous assessment. This showed a significant benefit for donepezil at all doses compared with placebo: SMD = 0.30 (95% CI 0.14 to 0.45), p < 0.001 (Figure 12). The data set used for this meta-analysis can be found in Appendix 6.

FIGURE 12. Random-effects meta-analysis: functional outcomes (SMD) at 24 weeks: donepezil (all dosages) vs placebo.

FIGURE 12

Random-effects meta-analysis: functional outcomes (SMD) at 24 weeks: donepezil (all dosages) vs placebo.

Behavioural and mood

In 2004 the assessment group2 reported that:

The NPI was used as a measure of mood and behaviour in four RCTs. Data were varied but suggested that donepezil may have some effect in improving or limiting further deterioration on the NPI scale compared to placebo, at least over shorter durations of follow-up.

New data None of the newly identified studies provided any additional data on the effect of donepezil as indicated by measures of behavioural function. Therefore, we conducted random-effects meta-analysis of the studies included in 2004 for the NPI at 12 and 24 weeks, which showed no significant benefit from donepezil measured by the NPI (Figures 13 and 14).

FIGURE 13. Random-effects meta-analysis: NPI at 12 weeks (mean change from baseline): donepezil [all dosages (all are 10 mg/day)] vs placebo.

FIGURE 13

Random-effects meta-analysis: NPI at 12 weeks (mean change from baseline): donepezil [all dosages (all are 10 mg/day)] vs placebo. a, Score inverted from published figure to reflect usual direction of NPI; b, WMD and error bars provided in publication (more...)

FIGURE 14. Random-effects meta-analysis: NPI at 24 weeks (mean change from baseline): donepezil [all dosages (all are 10 mg/day)] vs placebo.

FIGURE 14

Random-effects meta-analysis: NPI at 24 weeks (mean change from baseline): donepezil [all dosages (all are 10 mg/day)] vs placebo. a, Score inverted from published figure to reflect usual of direction NPI; b, WMD and error bars provided in publication (more...)

Pooled multiple outcome measures Because NPI is the only outcome measure used in this domain of the evidence base, it was not necessary to pool outcomes on a standardised level.

Global effect

Loveman and colleagues2 summarised their findings on global outcomes comparing donepezil and placebo as:

Seven RCTs assessed the effect of donepezil compared with placebo on the Clinical Global Impression of Change (CGIC) or CIBIC plus, showing overall that CGIC/CIBIC-plus scores were statistically significantly better with donepezil. The range of scores varied between the included studies. Higher proportions of participants receiving donepezil were considered as responders to treatment, although this was not compared statistically in many cases. On the CDR scale trends were also demonstrated towards improved global function in the donepezil-treated groups compared with the placebo groups in five trials but statistical significance was not demonstrated. In one unpublished trial with participants with mild Alzheimer's disease, no benefit on the CDR was noted in the donepezil treated group.

New data Only one of the new studies measured global outcomes.121 They also found significant benefit on the CDR: I = 1.2 (SD 0.2), C = 2.0 (SD 0.2), p < 0.01 (Table 7).

TABLE 7. Measures of global effect in included studies: donepezil vs placebo.

TABLE 7

Measures of global effect in included studies: donepezil vs placebo.

Synthesis with existing evidence base

Clinician interview-based impression of change-plus Only the previously included studies had data for meta-analysis of the CIBIC-plus. We pooled studies at 12 and 24 weeks and found that at both time points there was a significant overall pooled estimate of benefit from donepezil at 10 mg/day compared with placebo [12 weeks' WMD = −0.38 (95% CI −0.49 to −0.26), p < 0.001; 24 weeks' WMD = −0.43 (95% CI −0.55 to −0.31), p < 0.001] (Figures 15 and 16). Meta-analyses of CIBIC-plus results for 5 mg/day and all doses combined can be found in Appendix 5.

FIGURE 15. Random-effects meta-analysis: CIBIC-plus at 12 weeks (mean change from baseline): donepezil (10 mg/day) vs placebo.

FIGURE 15

Random-effects meta-analysis: CIBIC-plus at 12 weeks (mean change from baseline): donepezil (10 mg/day) vs placebo.

FIGURE 16. Random-effects meta-analysis: CIBIC-plus at 24 weeks (mean change from baseline): donepezil (10 mg/day) vs placebo.

FIGURE 16

Random-effects meta-analysis: CIBIC-plus at 24 weeks (mean change from baseline): donepezil (10 mg/day) vs placebo.

Clinical Dementia Rating The pooled results on the CDR scale showed a significant advantage from taking donepezil at 12 and 24 weeks' follow-up: 12 weeks' WMD = −0.26 (95% CI −0.44 to −0.09), p < 0.003 and 24 weeks' WMD = −0.57 (95% CI −0.85 to −0.29), p < 0.001 (Figures 17 and 18).

FIGURE 17. Random-effects meta-analysis: CDR at 12 weeks (mean change from baseline): donepezil (all dosages) vs placebo.

FIGURE 17

Random-effects meta-analysis: CDR at 12 weeks (mean change from baseline): donepezil (all dosages) vs placebo. a, Pooled 5- and 10 mg/day arms.

FIGURE 18. Random-effects meta-analysis: CDR at 24 weeks (mean change from baseline): donepezil (all dosages) vs placebo.

FIGURE 18

Random-effects meta-analysis: CDR at 24 weeks (mean change from baseline): donepezil (all dosages) vs placebo. a, 5 and 10 mg/day arms pooled.

Pooled multiple outcome measures We did not find any new studies that measured global outcomes at 24–26 weeks; therefore, we pooled the global outcome data from the studies in the previous assessment. This showed a significant benefit for donepezil at all doses compared with placebo: SMD = 0.38 (95% CI 0.27 to 0.48), p < 0.001 (Figure 19). The data set used in this meta-analysis can be found in Appendix 6.

FIGURE 19. Random-effects meta-analysis: global outcomes (SMD) at 24–26 weeks: donepezil (all dosages) vs placebo.

FIGURE 19

Random-effects meta-analysis: global outcomes (SMD) at 24–26 weeks: donepezil (all dosages) vs placebo.

Metaregression We also conducted metaregression analysis to explore the statistical heterogeneity across studies, looking at age, age and baseline MMSE (as a proxy for disease severity). Only one graph showed a significant relationship; this was between baseline MMSE and functional outcomes at 24 weeks for all doses of donepezil giving a metaregression estimate of α = 1.456, β = −0.065, p = 0.009. However, owing to the small number of studies in each analysis and the fact that the data were assessed at a population level (which may not reflect the individual level) we felt that these results may be ambiguous and so have placed them in Appendix 7 in case they are of interest.

Quality of life

None of the included studies provided any additional data on QoL with donepezil compared with placebo. Accordingly, the data presented in the 2004 review2 (p. 32) represent a complete and current summary of the randomised evidence on this subject.

Safety

None of the five newly identified studies118122 provide data on AEs observed under randomised conditions.

Peng and colleagues121 present limited safety data conflating their randomised study with data from a parallel observational study. Among the total of 145 individuals who took donepezil, seven (4.8%) experienced an AE (it appears that one each experienced dizziness, nausea, inappetence, mild diarrhoea, constipation, fatigue and agitation). Four of these seven patients stopped taking medicine. Among patients in the placebo group of the randomised trial, two (4.7%) experienced dizziness and stopped medication for this reason.

Summary: donepezil versus placebo

We found an additional five RCTs118122 to add to the 14 previously found by Loveman and colleagues;2 none of the new studies was of good quality or had a follow-up of longer than 6 months.

Pooled cognitive outcomes showed a significant benefit from donepezil measured by the ADAS-cog and MMSE with greater benefit shown at 24 weeks [ADAS-cog: WMD = −2.90 (95% CI −3.61 to −2.18), p < 0.001; MMSE: WMD = 1.21 (95% CI 0.84 to 1.57), p < 0.001]. The pooled estimates of all cognitive outcomes likewise showed a benefit from donepezil at 24–26 weeks' follow-up.

Only one new study looked at functional outcomes for this comparison; at 12 weeks this showed a significant gain for those taking donepezil [mean difference: I = 40.5 (SD 7.6), C = 49.5 (SD 6.3), p < 0.01)]. At 24 weeks there were data from only the 2004 assessment trials, and the results from all the studies reporting functional outcomes were pooled; this analysis again showed a significant benefit from taking donepezil.

None of the new studies measured behavioural outcomes; the pooled estimates from the previous assessment, using the NPI, failed to show a significant gain on behavioural outcomes at either 12 or 24 weeks.

Just one new study121 looked at global outcomes; this showed a benefit from taking donepezil on the CDR [I = 1.2 (SD 0.2), C = 2.0 (SD 0.2), p < 0.01)]. The pooled results for the CIBIC-plus scale were only from the previous TAR and they showed a significant advantage from donepezil at 12 and 24 weeks' follow-up [24 weeks: WMD = −0.43 (95% CI −0.55 to −0.31), p < 0.001]. When both the global outcome measures were pooled at 24–26 weeks, the results again showed a significant benefit from donepezil.

None of the new studies provided additional data on QoL or safety under randomised conditions.

The new studies found have added to the body of evidence showing a benefit from donepezil compared with placebo for cognitive, functional and global outcomes. However, there is no new or pooled evidence to show a behavioural benefit from donepezil versus placebo in people with mild-to-moderate AD. All but two of the studies included in these meta-analyses calculated their missing data points using LOCF or OC methods, thereby potentially biasing their results in favour of donepezil.

Graphical summary of donepezil versus placebo

The first thing that is noticeable when comparing Figures 2022 is that no new large studies have been undertaken since 2004 and that only one study was multicentre. Closer examination shows that the quality of trials has not improved and, with the exception of Peng and colleagues, studies measured only cognitive abilities. As in the previous review, these outcomes showed that patients benefited from taking donepezil. Although the new trials add to the precision of our knowledge of the effects of donepezil on cognitive measures in mixed mild/moderate AD populations, none of the new studies was in the mild AD population. This means that we are still dependent on one moderately sized RCT from the 2004 review that looked at cognitive outcomes in the mild AD population, which showed a cognitive benefit for this group from taking 10 mg/day donepezil.

FIGURE 20. Summary of studies included in the 2004 review: donepezil vs placebo.

FIGURE 20

Summary of studies included in the 2004 review: donepezil vs placebo. ADCS-ADL, Alzheimer's Disease Cooperative Study – Activities of Daily Living Inventory; ADCS-CGIC, Alzheimer's Disease Cooperative Study – Clinical Global Impression (more...)

FIGURE 21. Summary of studies included in the 2004 review: donepezil vs placebo (cont.).

FIGURE 21

Summary of studies included in the 2004 review: donepezil vs placebo (cont.). ADCS-ADL, Alzheimer's Disease Cooperative Study – Activities of Daily Living Inventory; ADCS-CGIC, Alzheimer's Disease Cooperative Study – Clinical Global Impression (more...)

FIGURE 22. Summary of new studies included in the 2010 review: donepezil vs placebo.

FIGURE 22

Summary of new studies included in the 2010 review: donepezil vs placebo. ADCS-ADL, Alzheimer's Disease Cooperative Study – Activities of Daily Living Inventory; ADCS-CGIC, Alzheimer's Disease Cooperative Study – Clinical Global Impression (more...)

Galantamine versus placebo

Identified evidence

For the pair-wise comparison between galantamine and placebo, the 2004 review included six RCTs.123129 However, it is apparent that two of these publications124,129 report the same population. Accordingly, we have entered only Rockwood and colleagues' primary publication124 in syntheses, below.

We identified an additional three moderately good-to-poor-quality RCTs, meeting few of the quality criteria indicated above (see Critical appraisal strategy).

The primary publication of the GAL-INT-6 study, written by Erkinjuntti and colleagues in 2002,130 was correctly excluded from the 2004 review because it conflated participants with multiple forms of dementia. However, we were able to include a subsequent paper – Bullock and colleagues 2004101 – reporting the AD-specific subgroup of this trial. A summary of their design characteristics can be found in Table 8 and the interventions, comparators and baseline characteristics of the participants in Table 9. A summary of the markers of internal validity is presented in Table 10.

TABLE 8. Design of included studies: galantamine vs placebo.

TABLE 8

Design of included studies: galantamine vs placebo.

TABLE 9. Interventions, comparators and baseline characteristics of participants in included studies: galantamine vs placebo.

TABLE 9

Interventions, comparators and baseline characteristics of participants in included studies: galantamine vs placebo.

TABLE 10. Markers of internal validity of included studies: galantamine vs placebo.

TABLE 10

Markers of internal validity of included studies: galantamine vs placebo.

Evidence of clinical effectiveness

Cognition

The previous review2 summarised the evidence from cognition outcomes thus:

Six published RCTs showed that galantamine appears to confer a statistically significant benefit to participants on the ADAS-cog scale when compared to placebo, whether reducing the deterioration or leading to some improvement in their condition. The benefit varies depending upon the dose of galantamine. The galantamine–placebo differences in ADAS-cog for 8 mg/day was 1.3 points, 16 mg/day 3.1 points, 18 mg/day 1.7 points, 16 or 24 mg/day 2.5 to 2.8 points; 24 to 32 mg/day 1.7 to 3.4 points and 36 mg/day 2.3 points. The one unpublished RCT mirrored these positive effects of galantamine versus placebo. In addition, some 14–17% more of galantamine participants were classified as responders (improving by 4 or more points on the ADAS-cog) than those on placebo.

New data The results from the three new studies96,101,131 show that overall those treated with galantamine had improved scores on the ADAS-cog, whereas those in the control group remained stable or declined. However, missing data were accounted for using LOCF and OC methods, leading to a potential overestimate of the treatment effect.86 Table 11 summarises the cognitive results from the new studies.

TABLE 11. Measures of cognition in included studies: galantamine vs placebo.

TABLE 11

Measures of cognition in included studies: galantamine vs placebo.

Synthesis with existing evidence base We pooled data from the new studies96,101,131 with those of the 2004 assessment2 by random-effects meta-analysis using the ADAS-cog as the outcome measure for ≤ 24 mg/day at 12–16 weeks and 21–26 weeks post randomisation. No studies reported the MMSE. We also meta-analysed the data by > 12 mg/day and all doses combined; these results can be found in Appendix 5.

Alzheimer's Disease Assessment Scale Cognitive Subscale Two new studies were included in the meta-analysis. The overall pooled estimates showed a benefit from galantamine compared with placebo at 12–16 and 21–26 weeks: 12–16 weeks WMD = −2.39 (95% CI −2.80 to −1.97), p < 0.001; 21–26 weeks WMD = −2.96 (95% CI −3.41 to −2.51), p < 0.001 (Figures 23 and 24).

FIGURE 23. Random-effects meta-analysis: ADAS-cog at 12–16 weeks (mean change from baseline) – galantamine (maximum dose ≤ 24 mg/day) vs placebo.

FIGURE 23

Random-effects meta-analysis: ADAS-cog at 12–16 weeks (mean change from baseline) – galantamine (maximum dose ≤ 24 mg/day) vs placebo. a, 18 and 24 mg/day arms pooled; b, once daily prolonged-release formulation and twice daily (more...)

FIGURE 24. Random-effects meta-analysis: ADAS-cog at 21–26 weeks (mean change from baseline) – galantamine (maximum dose ≤ 24 mg/day) vs placebo.

FIGURE 24

Random-effects meta-analysis: ADAS-cog at 21–26 weeks (mean change from baseline) – galantamine (maximum dose ≤ 24 mg/day) vs placebo. a, 8, 16 and 24 mg/day arms pooled; b, once daily prolonged-release formulation and twice daily (more...)

Pooled multiple outcome measures Because ADAS-cog is the only outcome measure used to assess cognitive effect in the placebo-controlled trials of galantamine, it was not necessary to pool outcomes on a standardised level for this domain.

Functional

In 20042 the assessment group reported for functional outcomes that:

Three RCTs assessed mean changes from baseline on the DAD scale, all reporting statistically significantly slower deterioration for those receiving galantamine 24–32 mg/day compared to placebo. Two RCTs found that participants receiving 16 mg/day and/or 24 mg/day galantamine experienced a statistically significantly smaller deterioration on the ADCS/ADL compared to placebo.

New data All three new RCTs measured functional outcomes.96,101,131 They found that functional abilities had improved significantly more in the treatment group. Table 12 summarises the results.

TABLE 12. Measures of functional effect in included studies: galantamine vs placebo.

TABLE 12

Measures of functional effect in included studies: galantamine vs placebo.

Synthesis with existing evidence base The data from the new trials96,101,131 were pooled, by random-effects meta-analysis, with those of the studies found in 2004. The outcome measures considered were the Alzheimer's Disease Cooperative Study – Activities of Daily Living (ADCS-ADL) Inventory and the Disability Assessment of Dementia (DAD) Scale.

Alzheimer's Disease Cooperative Study – Activities of Daily Living Results from the ADCS-ADL were pooled at 12–13 weeks' follow-up and at 21–26 weeks' follow-up. The overall pooled estimates showed functional benefit from galantamine compared with placebo: 12–13 weeks' WMD = 1.39 (95% CI 0.59 to 2.20), p < 0.001; 21–26 weeks WMD = 2.23 (95% CI 1.33 to 3.14), p < 0.001 (Figures 25 and 26).

FIGURE 25. Random-effects meta-analysis: ADCS-ADL at 12–13 weeks (mean change from baseline): galantamine (≤ 24 mg/day]) vs placebo.

FIGURE 25

Random-effects meta-analysis: ADCS-ADL at 12–13 weeks (mean change from baseline): galantamine (≤ 24 mg/day]) vs placebo. a, 8, 16 and 24 mg/day arms pooled; b, once daily prolonged-release formulation and twice daily standard formulation (more...)

FIGURE 26. Random-effects meta-analysis: ADCS-ADL at 21–26 weeks (mean change from baseline): galantamine (≤ 24 mg/day]) vs placebo.

FIGURE 26

Random-effects meta-analysis: ADCS-ADL at 21–26 weeks (mean change from baseline): galantamine (≤ 24 mg/day]) vs placebo. a, 8, 16 and 24 mg/day arms pooled; b, once daily prolonged-release formulation and twice daily standard formulation (more...)

Disability Assessment for Dementia Scale The results from the DAD were pooled at 21–26 weeks' follow-up. They again showed a significant benefit from galantamine compared with placebo: WMD = 3.76 (95% CI 1.66 to 5.86), p < 0.001 (Figure 27).

FIGURE 27. Random-effects meta-analysis: DAD at 21–26 weeks (mean change from baseline): galantamine (≤ 24 mg/day) vs placebo.

FIGURE 27

Random-effects meta-analysis: DAD at 21–26 weeks (mean change from baseline): galantamine (≤ 24 mg/day) vs placebo. a, 24 and 32 mg/day arms pooled.

Pooled multiple outcome measures Two new studies were added to the meta-analysis of combined functional outcome measures at 21–26 weeks. The overall pooled estimate showed a significant functional benefit from galantamine compared with placebo: SMD = 0.27 (95% CI 0.18 to 0.34), p < 0.001 (Figure 28). The data set used in this meta-analysis can be found in Appendix 6. With only four data points in this evidence base, it would not be informative to perform metaregression.

FIGURE 28. Random-effects meta-analysis: functional outcomes (SMD) at 21–26 weeks: galantamine (all dosages) vs placebo.

FIGURE 28

Random-effects meta-analysis: functional outcomes (SMD) at 21–26 weeks: galantamine (all dosages) vs placebo.

Behavioural and mood

In 2004, Loveman and colleagues2 summarised the behavioural results from this comparison as:

Two published and one unpublished RCTs found that galantamine had some effect in improving or limiting further deterioration on the NPI scale compared to placebo. Differences in the mean change from baseline were statistically significant for doses of 16 mg/day or over in one of the three studies.

New data Only one included study96 provided additional data on the effectiveness of galantamine in relieving behavioural symptoms of AD when compared with placebo. However, this failed to show any statistically significant benefit. Data are shown in Table 13.

TABLE 13. Measures of behavioural effect and mood in included studies: galantamine vs placebo.

TABLE 13

Measures of behavioural effect and mood in included studies: galantamine vs placebo.

Synthesis with existing evidence base

Neuropsychiatric Inventory Only one new study added evidence to this meta-analysis. We looked for estimates of effectiveness at 13 and 21–26 weeks; at 13 weeks no significant benefit was found. However, at 21–26 weeks the overall pooled estimate favoured galantamine: WMD = −1.46 (95% CI −2.59 to −0.34), p = 0.012 (Figures 29 and 30).

FIGURE 29. Random-effects meta-analysis: NPI at 13 weeks (mean change from baseline) – galantamine (all dosages) vs placebo.

FIGURE 29

Random-effects meta-analysis: NPI at 13 weeks (mean change from baseline) – galantamine (all dosages) vs placebo. a, 8, 16 and 24 mg/day arms pooled.

FIGURE 30. Random-effects meta-analysis: NPI at 21–26 weeks (mean change from baseline) – galantamine (all dosages) vs placebo.

FIGURE 30

Random-effects meta-analysis: NPI at 21–26 weeks (mean change from baseline) – galantamine (all dosages) vs placebo. a, 8, 16 and 24 mg/day arms pooled; b, once daily prolonged-release formulation and twice daily standard formulation pooled. (more...)

Pooled multiple outcome measures Because the NPI is the only outcome measure used in this domain of the evidence base, it was not necessary to pool outcomes on a standardised level.

Global effect

The previous assessment in 20042 summarised the effectiveness of galantamine on global outcomes:

Five published and one unpublished RCT assessed the effect of galantamine compared to placebo on the CIBIC plus, individually showing that higher proportions of participants receiving galantamine experience improvement in their condition compared to those on placebo (0% to 6.5% more participants). In contrast, a higher proportion of placebo participants tend to deteriorate (4% to 18% more participants). Also, a higher proportion of galantamine compared to placebo participants were considered to be responders to treatment with differences of between 4% (8 mg/day) and 17% (24 mg/day). When studies are pooled there are no statistically significant effects demonstrated.

New data Two new studies were found that measured global outcomes.96,131 Rockwood and colleagues131 found a benefit from galantamine measured by the CIBIC-plus compared with placebo at 13–16 weeks (Table 14).

TABLE 14. Measures of global effect in included studies: galantamine vs placebo.

TABLE 14

Measures of global effect in included studies: galantamine vs placebo.

Synthesis with existing evidence base

Clinician's Interview-based Impression of Change When the new studies' data were pooled with the existing evidence base, the overall pooled estimates of the CIBIC-plus at 26 weeks showed a benefit from galantamine compared with placebo: WMD = −0.20 (95% CI −0.30 to −0.09), p < 0.001 (Figure 31).

FIGURE 31. Random-effects meta-analysis: CIBIC-plus at 26 weeks – galantamine (maximum dose ≥ 24 mg/day) vs placebo.

FIGURE 31

Random-effects meta-analysis: CIBIC-plus at 26 weeks – galantamine (maximum dose ≥ 24 mg/day) vs placebo. a, once daily prolonged-release formulation and twice daily standard formulation pooled.

Pooled multiple outcome measures Because CIBIC-plus is the only outcome measure used to assess global effect in the placebo-controlled trials of galantamine, there was no reason to pool outcomes on a standardised level for this domain.

Quality of life

None of the included studies provided any randomised evidence on QoL with galantamine compared with placebo and no such data were identified in the 2004 review.2

Safety

Overall, there was a high percentage of any AE in both studies in treatment and control groups (any AE: Brodaty,96 once a day treatment = 79%, placebo = 70%; Rockwood,131 treatment = 84%, placebo = 62%). The main AEs were gastrointestinal. A summary of all the AEs reported can be found in Table 15.

TABLE 15. Adverse events in included studies: galantamine vs placebo.

TABLE 15

Adverse events in included studies: galantamine vs placebo.

Summary: galantamine versus placebo

We found an additional three RCTs96,101,131 to add to the five reported in the 2004 review.2

Overall cognitive results from the new studies using ADAS-cog showed improvements for those taking galantamine. When these studies were pooled with the existing evidence the benefit remained and increased with time, with greater benefit seen at 21–26 weeks [WMD = −2.96 (95% CI −3.41 to −2.51), p < 0.001] than 12–16 weeks [WMD = −2.39 (95% CI −2.80 to −1.97), p < 0.001].

All of the new studies reported functional outcomes. Those measured by the DAD and ADCS-ADL scales generally showed significant improvement; those measured by the Goal Attainment Scale (GAS) were rather more ambiguous. Pooled results of the ADCS-ADL and the DAD at 21–26 weeks continued to show benefit from galantamine compared with placebo [WMD = 2.23 (95% CI 1.33 to 3.14), p < 0.001; WMD = 3.76 (95% CI 1.66 to 5.86), p < 0.001, respectively]. When data from both these outcome measures were pooled, results still favoured galantamine.

Behavioural outcomes from one new study, measured by the NPI, failed to show a benefit from galantamine. This lack of benefit was also seen from the pooled results at 13 weeks from follow-up. However, when the new data were pooled with those of the previous assessment2 a significant difference favouring galantamine was found at 21–26 weeks [WMD = −1.46 (95% CI −2.59 to −0.34), p = 0.012].

Two of the new studies measured global outcomes; one found that it produced a significant benefit on the CIBIC-plus. When these data were pooled with the data from the previous review, significant benefit was found on the CIBIC-plus at 26 weeks' follow-up: WMD = −0.20 (95% CI −0.30 to −0.09), p < 0.001, with doses of ≤ 24 mg/day.

No QoL data were reported in either the new or the old studies for this comparison. The main AEs found were gastrointestinal.

The evidence from the new studies confirmed the benefits from galantamine for cognitive outcomes and, although there was some ambiguity with functional measures, the overall pooled estimates were favourable. Although none of the new studies showed significant benefit for behavioural outcomes, when these data were pooled with existing evidence, gains were shown at later follow-up times. Again, although the new trial data varied in its significance, pooling suggested that there were gains to be made on global outcomes. However, it should be noted that in all these studies estimates for missing data were calculated using LOCF or OC methods and may therefore have inflated the benefits from galantamine.

Graphical summary of galantamine versus placebo

In contrast with the donepezil research, one large study has been conducted since 2004 (comparing two different methods of delivery versus placebo), and the quality of the studies has improved overall (Figures 32 and 33). As in the previous review, the larger studies are more likely to show a benefit from galantamine on cognitive outcomes. The evidence for an effect on functional outcomes continues to be mixed: previously there appeared to be a relationship to the size of the dose – in the new study by Brodaty and colleagues96 effectiveness at 24 mg/day was linked to mode of delivery, with the prolonged-release capsule (PRC) showing a significant gain over placebo, which the regular capsule did not. Similar to the 2004 review,2 the results on global outcomes were mixed; thus it remains unclear what effect galantamine has on these outcomes.

FIGURE 32. Summary of studies included in the 2004 review: galantamine vs placebo.

FIGURE 32

Summary of studies included in the 2004 review: galantamine vs placebo. ADCS-CGIC, Alzheimer's Disease Cooperative Study – Clinical Global Impression of Change; Analy, analysis; be, behavioural; Blind, blinding; Char, characteristics of patients; (more...)

FIGURE 33. Summary of new studies included in the 2010 review: galantamine vs placebo.

FIGURE 33

Summary of new studies included in the 2010 review: galantamine vs placebo. a, Significant only for ‘clinician-rated’ outcome measure, not for ‘patient/caregiver rated’. ADCS-CGIC, Alzheimer's Disease Cooperative Study (more...)

Rivastigmine versus placebo

Identified evidence

The 20042 review included four RCTs.134137

Our searches identified three additional relevant trials,138140 details of which are tabulated in Table 16. Table 17 contains information about studies' interventions, comparators and baseline characteristics and Table 18 gives key markers of internal validity for the included studies, which were moderately good to poor quality.

TABLE 16. Design of included studies: rivastigmine vs placebo.

TABLE 16

Design of included studies: rivastigmine vs placebo.

TABLE 17. Interventions, comparators, and baseline characteristics of participants in included studies: rivastigmine vs placebo.

TABLE 17

Interventions, comparators, and baseline characteristics of participants in included studies: rivastigmine vs placebo.

TABLE 18. Markers of internal validity of included studies: rivastigmine vs placebo.

TABLE 18

Markers of internal validity of included studies: rivastigmine vs placebo.

Evidence of clinical effectiveness

Cognition

The 2004 assessment report by Loveman and colleagues2 summarised the evidence they found on cognitive outcomes as:

Statistically significant differences between the 6–12 mg/day treatment groups and placebo were reported by two of three published trials which reported ADAS-cog and MMSE. No statistically significant effects were seen in the low-dose treatment groups in these studies. However, sample sizes were very low (< 30 participants in each group) and this study presented no information on power calculations.

The unpublished studies both found statistically better mean changes from ADAS-cog baseline scores in participants taking rivastigmine compared with placebo groups, a statistically significantly higher percentage of participants receiving t.i.d. (× 3 daily). Rivastigmine showed an improvement of at least four points compared with the placebo group, but there was no statistically significant difference between the b.i.d. (× 2 daily) group and placebo. One of the studies also reported on ADAS-cogA, and found statistically significant differences in both mean change from baseline and percentage of improvers for both b.i.d. and t.i.d. treatment groups compared with placebo.

Both unpublished studies reported MMSE as an outcome measure and found a statistically significant improvement in participants receiving rivastigmine compared with those receiving a placebo, with the exception of the 9 mg/day rivastigmine group.

New data In the three studies138140 we found that had been published since 2004, comparing rivastigmine with placebo for mild-to-moderate AD, all studies reported benefits for the treatment group on cognitive outcome measures. These results appear to be dose dependent (as in the previous report), with doses ≥ 12 mg/day showing a greater effect (see Appendix 5). However, only one study measured missing outcomes with an ITT population.138 Table 19 shows the summary results for cognition in the included studies. It should be noted that in the study by Winblad and colleagues140 only the 10-cm patch is currently licensed in the UK.

TABLE 19. Measures of cognition in included studies: rivastigmine vs placebo.

TABLE 19

Measures of cognition in included studies: rivastigmine vs placebo.

Synthesis with existing evidence base The data from the new trials were synthesised with those of the previous assessment using random-effects meta-analysis. The measures of ADAS-cog and MMSE were first considered separately and then combined in a pooled multiple outcome measure analysis at ≥ 12 mg/day. We also meta-analysed the data by ≤ 10 mg/day, 4 mg/day and combined doses; results can be found in Appendix 5.

Alzheimer's Disease Assessment Scale – Cognitive Subscale The meta-analyses of ADAS-cog scores at 24–26 weeks showed a significant benefit from rivastigmine (≥ 12 mg/day) compared with placebo: WMD = −2.46 (95% CI −3.37 to −1.56), p < 0.001 (Figure 34).

FIGURE 34. Random-effects meta-analysis: ADAS-cog at 24–26 weeks (mean change from baseline) – rivastigmine (≥ 12 mg/day) vs placebo.

FIGURE 34

Random-effects meta-analysis: ADAS-cog at 24–26 weeks (mean change from baseline) – rivastigmine (≥ 12 mg/day) vs placebo. a, b.i.d. (twice a day) and t.i.d. (three times a day) arms pooled; b, the 17.4 mg/day patch and 12 mg/day (more...)

Mini Mental State Examination At 24–26 weeks' follow-up the pooled estimate of effect showed a benefit from rivastigmine: WMD = 1.02 (95% CI 0.63 to 1.41), p < 0.001 (Figure 35).

FIGURE 35. Random-effects meta-analysis: MMSE at 24–26 weeks (mean change from baseline) – rivastigmine (≥ 12 mg/day) vs placebo.

FIGURE 35

Random-effects meta-analysis: MMSE at 24–26 weeks (mean change from baseline) – rivastigmine (≥ 12 mg/day) vs placebo. a, b.i.d. (twice a day) and t.i.d. (three times a day) arms pooled; b, the 20-cm2 patch and 12 mg/day capsule (more...)

Pooled multiple outcome measures When we pooled all the results for the cognitive outcomes from the new and existing studies, we found that the overall pooled estimate showed a significant benefit from rivastigmine compared with placebo: SMD = 0.28 (95% CI 0.14 to 0.42), p < 0.001 (Figure 36). The data set used in this meta-analysis can be found in Appendix 6.

FIGURE 36. Random-effects meta-analysis – cognitive outcomes (SMD) at 24–26 weeks: rivastigmine (all dosages) vs placebo.

FIGURE 36

Random-effects meta-analysis – cognitive outcomes (SMD) at 24–26 weeks: rivastigmine (all dosages) vs placebo.

With only four data points in this evidence base, it would not be informative to perform metaregression.

Functional

In 2004 Loveman and colleagues2 reported that:

Two published studies reported the PDS as a functional outcome measure. One of these found a statistically significant improvement in participants treated with 6–12 mg/day rivastigmine compared with placebo, and the other reported that a statistically significantly higher percentage of these high dose participants than placebo participants showed an improvement of at least 10%.

New data Two of the three new studies found since 2004 reported significant functional benefit from rivastigmine compared with placebo. These used PDS and ADCS-ADL as their outcome measures. A summary table of results can be found below in Table 20.

TABLE 20. Measures of functional ability in included studies: rivastigmine vs placebo.

TABLE 20

Measures of functional ability in included studies: rivastigmine vs placebo.

Synthesis with existing evidence base Data from the existing evidence were synthesised with the new data in a meta-analysis of the PDS scores.

Progressive Deterioration Scale The overall pooled estimate at 24–26 weeks showed a significant benefit from rivastigmine: WMD = 3.10 (95% CI 1.81 to 4.40), p = 0.001 (Figure 37).

FIGURE 37. Random-effects meta-analysis – PDS at 24–26 weeks (mean change from baseline): rivastigmine (12 mg/day) vs placebo.

FIGURE 37

Random-effects meta-analysis – PDS at 24–26 weeks (mean change from baseline): rivastigmine (12 mg/day) vs placebo. a, b.i.d. (twice a day) and t.i.d. (three times a day) arms pooled.

Pooled multiple outcome measures Two new studies were found to add to this combined meta-analysis of functional outcomes at 24–26 weeks. Again, the overall pooled estimate showed a benefit from rivastigmine compared with placebo: SMD = 0.21 (95% CI 0.12 to 0.29), p < 0.001 (Figure 38). The data set used in this meta-analysis can be found in Appendix 6.

FIGURE 38. Random-effects meta-analysis: functional outcomes (SMD) at 24–26 weeks: rivastigmine (all dosages) vs placebo.

FIGURE 38

Random-effects meta-analysis: functional outcomes (SMD) at 24–26 weeks: rivastigmine (all dosages) vs placebo.

With only three data points in this evidence base, it would not be informative to perform metaregression.

Behavioural and mood

The 2004 systematic review2 summarised the behavioural results as:

On measures of behaviour and mood no statistically significant benefit was demonstrated in the rivastigmine treated groups compared to the placebo groups.

New data Two new studies139,140 were found that measured behavioural outcomes. One small study by Mowla and colleagues139 found a significant benefit from rivastigmine; the other much larger study did not.140 Table 21 below shows the summary outcome data.

TABLE 21. Measures of behavioural effect and mood in included studies: rivastigmine vs placebo.

TABLE 21

Measures of behavioural effect and mood in included studies: rivastigmine vs placebo.

Synthesis with existing evidence base

The data identified by this review and the 2004 review2 are sparse and too heterogeneous to permit meaningful quantitative synthesis.

Global effect

The evidence from the 2004 assessment2 was summarised thus:

Both of the published studies which included CIBIC-plus as a global outcome measure reported a statistically significant improvement in high dose participants (6–12 mg/day) compared with placebo participants. One study also reported a statistically significantly greater proportion of ‘responders’ among participants treated with rivastigmine compared against placebo participants. Another study reported that a greater proportion of high dose rivastigmine participants than placebo participants had a ‘successful’ CIGIC assessment, i.e. scoring one or two on the scale. Two trials found a statistically significant improvement on the Global Deterioration Scale (GDS) measure in participants treated with 6–12 mg/day of rivastigmine compared with placebo participants.

New data The two new studies138,140 in this comparison that reported global outcomes had conflicting results. Feldman and Lane138 found mostly significantly favourable results with the CIBIC-plus and the Global Deterioration Scale (GDS), whereas Winblad and colleagues' results were mostly non-significant140 (Table 22).

TABLE 22. Measures of global effect in included studies: rivastigmine vs placebo.

TABLE 22

Measures of global effect in included studies: rivastigmine vs placebo.

Synthesis with existing evidence base Data from the new studies were pooled with the existing evidence in random-effects meta-analyses using the CIBIC-plus at 26 weeks and the GDS at 26 weeks. The results can be seen in Figures 39 and 40.

FIGURE 39. Random-effects meta-analysis – CIBIC-plus at 26 weeks: rivastigmine (12 mg/day) vs placebo.

FIGURE 39

Random-effects meta-analysis – CIBIC-plus at 26 weeks: rivastigmine (12 mg/day) vs placebo. a, b.i.d. (twice a day) and t.i.d. (three times a day) arms pooled.

FIGURE 40. Random-effects meta-analysis – GDS at 26 weeks (mean change from baseline): rivastigmine (12 mg/day) vs placebo.

FIGURE 40

Random-effects meta-analysis – GDS at 26 weeks (mean change from baseline): rivastigmine (12 mg/day) vs placebo. a, b.i.d. (twice a day) and t.i.d. (three times a day) arms pooled.

Clinician's Interview-based Impression of Change The meta-analysis showed a significant benefit from rivastigmine at 26 weeks: WMD = −0.42 (95% CI −0.55 to −0.29), p < 0.001.

Global Deterioration Scale This meta-analysis also showed a significant benefit from rivastigmine at 26 weeks: WMD = 0.20 (95% CI 0.12 to 0.27), p < 0.001.

Pooled multiple outcome measures We then pooled the results from both outcomes; the results from this can be seen in Figure 41 and showed an overall pooled estimate of SMD = 0.23 (95% CI 0.16 to 0.31), p < 0.001. The data set that was used in this meta-analysis can be found in Appendix 6.

FIGURE 41. Random-effects meta-analysis – global outcomes (SMD) at 24–26 weeks: rivastigmine (all dosages) vs placebo.

FIGURE 41

Random-effects meta-analysis – global outcomes (SMD) at 24–26 weeks: rivastigmine (all dosages) vs placebo.

With only four data points in this evidence base, it would not be informative to perform metaregression.

Quality of life

None of the included studies provided any randomised evidence on QoL with rivastigmine compared with placebo, and no such data were identified in the 2004 review.2

Safety

Overall, there was a high percentage of any AEs, ranging from 51% to 91% in the treatment groups and from 46% to 76% in control groups. The main AEs were gastrointestinal: the lower dose (9.5 mg/day) transdermal patch produced fewer side effects than the capsule (12 mg/day). A summary of all the AEs reported can be found in Table 23.

TABLE 23. Adverse events in included studies: rivastigmine vs placebo.

TABLE 23

Adverse events in included studies: rivastigmine vs placebo.

Summary: rivastigmine versus placebo

Our update searches identified three new RCTs138140 to add to the four134137 included in the previous review.2

All three studies138140 showed benefits from rivastigmine on the ADAS-cog and MMSE, although these benefits were dependent on dose, with greater benefits seen at 12 mg/day than at 6 mg/day. When these data were pooled with the existing evidence, significant differences favouring rivastigmine continued to be seen on the ADAS-cog at 24–26 weeks (≥ 12 mg/day), WMD = −2.46 (95% CI −3.37 to −1.56), p < 0.001. However, the benefits from rivastigmine were not apparent on MMSE scores until 24–26 weeks' follow-up [WMD = 1.02 (95% CI 0.63 to 1.41), p < 0.001]; this may be due to the MMSE's difficulties with detecting change. When the outcomes from both cognitive measures were combined they continued to show an advantage from taking rivastigmine on cognitive outcomes.

Two of the three new studies reporting functional outcomes showed significant gains for these measures. When these new data were synthesised with existing evidence using the PDS, significant gains were shown at 24–26 weeks [WMD = 3.10 (95% CI 1.81 to 4.40), p = 0.001].

The data on behavioural outcomes from the new studies were unclear, with the smaller study139 showing a benefit from rivastigmine that the larger one140 did not. The existing evidence was too heterogeneous for meta-analysis, so the overall effectiveness of rivastigmine for behavioural outcomes is unknown.

The results for global outcomes were also mixed. Results from the CIBIC-plus were almost universally significant, whereas those measured by the Alzheimer's Disease Cooperative Study–Clinical Global Impression of Change (ADCS-CGIC) were almost universally not; those using the GDS showed no significant gain from rivastigmine. However, when these data were pooled with the existing evidence, the overall estimates favoured rivastigmine on the CIBIC-plus [WMD = −0.42 (95% CI −0.55 to −0.29), p < 0.001] and the GDS [WMD = 0.20 (95% CI 0.12 to 0.27), p < 0.001]. When results from both these outcome measures were combined, the result continued to show significant benefit from rivastigmine, these results are based on a robust ITT population.

When rivastigmine patches were compared with capsules, the results showed that the 9.5 mg/day patch was similarly effective as the 12.5 mg/day capsule, but with fewer side effects.

None of the included studies in either the updated or the original review reported QoL outcomes.

As in the other AChEIs, the main AEs were gastrointestinal.

Overall, pooled estimates of cognitive benefits from rivastigmine were favourable, but were shown to be dose dependent as in the previous review. The results from functional and global outcomes also showed significant gains. However, the results from individual trials of behavioural outcomes were mixed (pooling was not possible owing to heterogeneity). The lower dose transdermal patch (9.5 mg/day) was shown to be as effective as the capsule (12 mg/day), but with fewer side effects.

Graphical summary of rivastigmine versus placebo

The graphical summary in Figure 42 shows that two large studies138,140 and one small study139 have been added to the evidence for rivastigmine since 2004. The figure illustrates how the new studies have added to the precision of our knowledge of the effects of rivastigmine in AD. Previously, the results for cognitive outcomes were ambiguous; however, the results from the new trials all show cognitive benefits. The smaller new study139 showed a gain on behavioural outcomes that had not been seen in the previous studies, but the results for functional and global outcomes continued to be mixed.

FIGURE 42. Summary of all included studies in the 2004 and 2010 reviews: rivastigmine vs placebo.

FIGURE 42

Summary of all included studies in the 2004 and 2010 reviews: rivastigmine vs placebo. *Significant only for ‘TMT’, not ‘ten-point clock-drawing test’. Analy, analysis; be, behavioural; b.i.d., twice a day; Blind, blinding; (more...)

Memantine versus placebo

Differing approaches to pooling data

A key difference to our memantine findings and Lundbeck's lies in our differing approaches to pooling data. In particular, Lundbeck have pooled together memantine plus AChEI versus placebo plus AChEI trials with memantine monotherapy versus placebo studies; we were not comfortable with this approach owing to the heterogeneity of the data. Nevertheless, we have followed this approach for completeness and present the results in Appendix 14. The effect of pooling data in this way is to show a more favourable response to memantine.

Identified evidence

The 2004 review2 lists two RCTs141,142 as investigations into the effectiveness of memantine in AD. However, one of those studies141 addressed the effectiveness of memantine in combination with donepezil; accordingly, this study is considered as part of our assessment of combination therapy (see Summary: head-to-head comparisons).

We identified one additional RCT143 of relevance to this comparison, details of which are presented in Table 24. This study's interventions, comparators and baseline characteristics can be seen in Table 25 and the markers of internal validity in Table 26.

TABLE 24. Design of included studies: memantine vs placebo.

TABLE 24

Design of included studies: memantine vs placebo.

TABLE 25. Interventions, comparators and baseline characteristics of participants in included studies: memantine vs placebo.

TABLE 25

Interventions, comparators and baseline characteristics of participants in included studies: memantine vs placebo.

TABLE 26. Markers of internal validity of included studies: memantine vs placebo.

TABLE 26

Markers of internal validity of included studies: memantine vs placebo.

Evidence of clinical effectiveness

Cognition

The 2004 report by Loveman and colleagues2 found two studies of memantine; they summarised their results as follows:

Both studies used the SIB as a measure of cognitive outcome. Statistically significant differences in favour of the use of memantine over placebo were apparent in the two studies. MMSE scores deteriorated in both the memantine group and the placebo group and the degree of deterioration was not statistically significantly different between the two groups.

New data The data from the new trial143 showed a significant effect only from memantine on one of six analyses. However, this was in an OCs-only analysis that may have biased the results; Table 27 summarises the results.

TABLE 27. Measures of cognition in included studies: memantine vs placebo.

TABLE 27

Measures of cognition in included studies: memantine vs placebo.

Synthesis with existing evidence base

Severe Impairment Battery The data from the new trial were pooled with that of the existing studies in random-effects meta-analyses of the Severe Impairment Battery (SIB) at 12 weeks and 24–28 weeks. The results showed a significant effect at 12 weeks [WMD = 4.15 (95% CI 0.52 to 7.78), p = 0.025], but not at 24–28 weeks (Figures 43 and 44).

FIGURE 43. Random-effects meta-analysis – SIB at 12 weeks (mean change from baseline): memantine vs placebo.

FIGURE 43

Random-effects meta-analysis – SIB at 12 weeks (mean change from baseline): memantine vs placebo.

FIGURE 44. Random-effects meta-analysis – SIB at 24–28 weeks (mean change from baseline): memantine vs placebo.

FIGURE 44

Random-effects meta-analysis – SIB at 24–28 weeks (mean change from baseline): memantine vs placebo.

Functional

The previous assessment report2 summarised the findings about the effects of memantine on functional outcomes as:

Both studies demonstrated that memantine appears to show a statistically significant benefit to participants on the ADCS-ADL when compared to placebo, with a reduction in the level of deterioration.

New data The results from the new study showed no significant benefit on functional outcomes for memantine compared with placebo (Table 28).

TABLE 28. Measures of functional ability in included studies: memantine vs placebo.

TABLE 28

Measures of functional ability in included studies: memantine vs placebo.

Synthesis with existing evidence base The data from the new studies were synthesised with the existing evidence in a random-effects meta-analysis.

Alzheimer's Disease Cooperative Study – Activities of Daily Living Index Two studies provide data on functional effect as measured by ADCS-ADL; both report the modified ADCS-ADL19 version of the instrument, consisting of 19 items that have been individually validated in cases of more severe dementia. The data were meta-analysed at 12 weeks' and 24–28 weeks' follow-up. The results were not significant at 12 weeks and barely significant at 24–28 weeks, especially considering that the population analysed were LOCF: WMD = 1.41 (95% CI 0.04 to 2.78), p = 0.044 (Figures 45 and 46).

FIGURE 45. Random-effects meta-analysis – ADCS-ADL19 at 12 weeks (mean change from baseline): memantine vs placebo.

FIGURE 45

Random-effects meta-analysis – ADCS-ADL19 at 12 weeks (mean change from baseline): memantine vs placebo.

FIGURE 46. Random-effects meta-analysis – ADCS-ADL19 at 24–28 weeks (mean change from baseline): memantine vs placebo.

FIGURE 46

Random-effects meta-analysis – ADCS-ADL19 at 24–28 weeks (mean change from baseline): memantine vs placebo.

Functional Assessment Staging Tool Another meta-analysis was conducted with data from existing and new studies using the Functional Assessment Staging Tool (FAST) at 24–28 weeks' follow-up. The overall pooled estimate showed a significant benefit from memantine compared with placebo, WMD = −0.34 (95% CI −0.55 to −0.13), p = 0.002 (Figure 47).

FIGURE 47. Random-effects meta-analysis – FAST at 24–28 weeks (mean change from baseline): memantine vs placebo.

FIGURE 47

Random-effects meta-analysis – FAST at 24–28 weeks (mean change from baseline): memantine vs placebo.

Behavioural and mood

The 2004 assessment report2 summarised the finding for behavioural outcomes comparing memantine with placebo as:

It appears that participants receiving memantine and already receiving a steady dose of donepezil have a statistically significantly lower NPI score than placebo. Those on memantine only however, showed no statistically significant difference compared to placebo.

New data The study143 that was published after 2004 measured behavioural outcomes using the NPI and the Behavioural Rating Scale for Geriatric Patients (BGP). Neither measure showed a significant benefit from memantine (Table 29).

TABLE 29. Measures of behavioural effect and mood in included studies: memantine vs placebo.

TABLE 29

Measures of behavioural effect and mood in included studies: memantine vs placebo.

Synthesis with existing evidence base The NPI data from van Dyck and colleagues143 were pooled with the existing data at 24–28 weeks' follow-up in a random-effects meta-analysis. This analysis also failed to show a significant gain from memantine compared with placebo (Figure 48).

FIGURE 48. Random-effects meta-analysis – NPI at 24–28 weeks (mean change from baseline): memantine vs placebo.

FIGURE 48

Random-effects meta-analysis – NPI at 24–28 weeks (mean change from baseline): memantine vs placebo.

Global effect

In 2004, Loveman and colleagues2 summarised the results for global measures comparing memantine with placebo as:

Both studies used the CIBIC-plus as a measure of global outcome, and, in both cases, memantine appeared to be effective.

New data Van Dyck and colleagues143 also measured global outcomes with the CIBIC-plus; however, the differences they found were not significant (Table 30).

TABLE 30. Measures of global effect in included studies: memantine vs placebo.

TABLE 30

Measures of global effect in included studies: memantine vs placebo.

Synthesis with existing evidence base

Clinician's Interview-based Impression of Change When the new data were pooled with the existing studies in a random-effects meta-analysis the overall pooled estimate showed a significant beneficial effect from memantine compared with placebo: WMD = −0.30 (95% CI −0.47 to −0.13), p < 0.001 (Figure 49).

FIGURE 49. Random-effects meta-analysis – CIBIC-plus at 24–28 weeks: memantine vs placebo.

FIGURE 49

Random-effects meta-analysis – CIBIC-plus at 24–28 weeks: memantine vs placebo.

Quality of life

None of the included studies provided any randomised evidence on QoL with memantine compared with placebo and no such data were identified in the 2004 review.

Safety

The proportion of any AEs were similar in the treatment and control groups (T = 74%, C = 73%). The main AEs were agitation and hypertension in the memantine group, and agitation and falls in the control group (Table 31).

TABLE 31. Adverse events in included studies: memantine vs placebo.

TABLE 31

Adverse events in included studies: memantine vs placebo.

Summary: memantine versus placebo

One new moderate-to-poor-quality study was found to add to the existing evidence for memantine versus placebo.

The pooled results for cognitive abilities measured by the SIB showed a significant benefit from memantine at 12 weeks' follow-up [WMD = 4.15 (95% CI 0.52 to 7.78), p = 0.025]. However, at 24 weeks the data pooled with that of the previous review showed no significant benefit.

Similar to the previous review,2 the new study143 found a significant benefit from memantine from the FAST functional outcome, although not with the ADCS-ADL at 12 weeks. When the FAST data from new and existing studies were pooled, a significant relationship was found between memantine and an improvement in scores [WMD = −0.34 (95% CI −0.55 to −0.13), p = 0.002]. A marginally significant benefit was seen from memantine when pooled ADCS-ADL data were measured at 24–28 weeks [WMD = 1.41 (95% CI 0.04 to 2.78) p = 0.044].

The results from behavioural outcomes in the new study,141 similar to the previous review,2 failed to show a significant benefit from memantine, either singly or when the data were pooled.

Although the results of the CIBIC-plus failed to show a significant gain from memantine, when these data were pooled with that from the previous review a significant effect was found [WMD = −3.00 (95% CI −0.471 to −0.129), p < 0.001].

No studies reported QoL outcomes. The main AEs were agitation and hypertension.

The meta-analysis of memantine versus placebo studies showed benefit from memantine at 12 weeks' follow-up on the SIB. However, treatment gain, measured by functional outcome, depended on the type of instrument used, and no benefit was seen from behavioural outcomes. Nevertheless, pooled estimates of global outcomes showed a benefit from taking memantine at 24–28 weeks. Overall, the pooled results from these moderate-to-poor-quality studies showed inconclusive results for cognitive and behavioural outcomes. The results for functional outcomes were dependent on the measure used, but the pooled results of the new and existing evidence for global outcomes showed significant benefit from using memantine.

Graphical summary of memantine versus placebo

Figure 50, below, illustrates how little the evidence has changed for memantine versus placebo. The cognitive benefits found in 2004 failed to be replicated; indeed the new study143 favoured memantine on only one outcome measure. However, the quality of the new143 and existing study142 was not high; thus, these results cannot be considered conclusive.

FIGURE 50. Summary of all included studies in the 2004 and current reviews: memantine vs placebo.

FIGURE 50

Summary of all included studies in the 2004 and current reviews: memantine vs placebo. Analy, analysis; be, behavioural; Blind, blinding; Char, characteristics of patients; cog, cognitive; F, female; func, functional; glo, global; M, male; Rand, randomisation. (more...)

Head-to-head comparisons

Identified evidence

Alongside placebo-controlled trials, a certain amount of randomised evidence provides direct, head-to-head comparisons of two or more of the technologies under review. Three such RCTs were included in the 2004 review:2 donepezil versus rivastigmine,144 donepezil versus rivastigmine,145 and donepezil versus galantamine.146

Our searches identified a further four RCTs of this type.99,147149 Details of the design of these trials are tabulated in Table 32, and a summary of treatments and baseline characteristics of participants can be found in Table 33. Two of the new RCTs99,147 compared all three AChEIs (although Nordberg and colleagues' trial147 is of relevance to the current review only for its safety data). One trial investigated donepezil versus rivastigmine148 and the last was concerned with donepezil versus galantamine.149

TABLE 32. Design of included studies: head-to-head comparisons.

TABLE 32

Design of included studies: head-to-head comparisons.

TABLE 33. Interventions, comparators, and baseline characteristics of participants in included studies: head-to-head comparisons.

TABLE 33

Interventions, comparators, and baseline characteristics of participants in included studies: head-to-head comparisons.

The quality of the newly identified RCTs in this category (Table 34) tended to be low. Cumbo's three-way examination of donepezil, galantamine and rivastigmine99 is of especially dubious validity, with no description of randomisation or allocation, and an open-label treatment period. Moreover, most of the outcomes reported by this trial – concentrating on distribution of symptoms among participants experiencing behavioural disturbance – are of little help for our purpose of establishing the relative effectiveness of the technologies.

TABLE 34. Markers of internal validity of included studies: head-to-head comparisons.

TABLE 34

Markers of internal validity of included studies: head-to-head comparisons.

Of the RCTs we identified, Bullock and colleagues'148 2-year, double-blind comparison of donepezil and rivastigmine was judged to be much the least susceptible to bias. Robust randomisation, allocation and assessment methods are reported, and the study was of a good size, with each treatment arm comprising almost 500 individuals.

Evidence of clinical effectiveness

Cognition

New data Only one148 of the newly identified RCTs reports outcome measures assessing the cognitive function of participants. Bullock and colleagues148 report that, following 2 years of double-blind treatment, a similar cognitive decline was seen in individuals who had been randomised to donepezil or rivastigmine (Table 35).

TABLE 35. Measures of cognition in included studies: head-to-head comparisons.

TABLE 35

Measures of cognition in included studies: head-to-head comparisons.

Synthesis with existing evidence base It was not possible to amalgamate the new and existing evidence in quantitative synthesis, because the Bullock and colleagues trial148 featured much more extensive follow-up than the 12- to 30-week donepezil versus rivastigmine RCTs identified in 2004.144,145 Unfortunately, Bullock and colleagues148 do not report findings on cognitive measures over the course of their trial (one figure showing SIB decline is provided, but does not give any indication of dispersion at each juncture), so their findings cannot be combined at earlier follow-up either.

Functional

New data Again, Bullock and colleagues' RCT148 provides the only new evidence on the relative effectiveness of the technologies under review in the functional domain. In the primary – ITT LOCF – analysis, a significant advantage for rivastigmine over donepezil after 2 years' treatment was detected. Individuals who had been randomised to receive rivastigmine declined by around two fewer points on the ADCS-ADL instrument (Table 36). It should be noted, however, that this finding was not replicated in the secondary analyses, which relied on evaluable cases (all participants who were treated for at least 16 weeks, with LOCF imputation for subsequent missing values) and OCs.

TABLE 36. Measures of functional ability in included studies: head-to-head comparisons.

TABLE 36

Measures of functional ability in included studies: head-to-head comparisons.

Synthesis with existing evidence base Again, the much longer duration of the new trial, coupled with its lack of intermediate follow-up data, makes it impossible to perform quantitative synthesis combining Bullock and colleagues' data148 with that identified in 2004.144146

Behavioural and mood

New data Bullock and colleagues148 found no significant difference between donepezil and rivastigmine on the NPI scale, with participants in both groups declining by an average of between two and three points over 2 years' treatment (Table 37). Cumbo's trial99 is explicitly focused on behavioural disturbance in individuals taking AChEIs. However, the paper mostly concentrates on the profile of individuals who were adjudged to experience behavioural and psychological symptoms, rather than the incidence of such events in the whole population. It was found that most categories of behavioural event happened with lower frequency among those taking rivastigmine; however, no tests of the magnitude of such differences are presented. We have found that, in most cases, any discrepancy would be insufficient to fulfil conventional definitions of statistical significance (i.e. p < 0.05 by chi-squared test), with the exceptions of the night-time behaviour subdomain of the NPI and the diurnal cycle disturbances item of the Behavioral Pathology in Alzheimer's disease (BEHAVE-AD) scale (see Table 37). The high probability of type 1 error in the presence of multiple comparisons must clearly be borne in mind here.

TABLE 37. Measures of behavioural effect and mood in included studies: head-to-head comparisons.

TABLE 37

Measures of behavioural effect and mood in included studies: head-to-head comparisons.

Individuals taking rivastigmine were also reported to have a higher probability of remaining free of behavioural symptoms at 18 months than those taking donepezil in Cumbo's RCT,99 although the methods adopted in the time-to-event (TTE) analysis are unclear.

Synthesis with existing evidence base Once more, heterogeneity of measures reported and follow-up times at which data are available makes it impossible to perform meaningful synthesis within or between the newly identified evidence base and that reported in 2004.

Global effect

New data Bullock and colleagues148 used the GDS to measure overall effect. They found that, over the 2-year trial, individuals who had been randomised to donepezil deteriorated by around 0.1 points more than those taking rivastigmine. As with the difference found on their chosen functional measure, this discrepancy appeared significant in the ITT LOCF analysis (p < 0.05 by Wilcoxon's rank-sum test), but this finding was not repeated in secondary analyses based on evaluable and OCs.

In the Ancoli-Israel and colleagues RCT,149 none of the individuals taking galantamine experienced a global decline, according to the CIBIC-plus, over the 8 weeks of treatment, whereas 13% of those taking donepezil deteriorated on the same measure, although this difference does not appear to be a significant one (Table 38).

TABLE 38. Measures of global effect in included studies: head-to-head comparisons.

TABLE 38

Measures of global effect in included studies: head-to-head comparisons.

Synthesis with existing evidence base Quantitative synthesis combining the newly identified evidence and/or that reported in 2004 was not possible, owing to heterogeneity of measures reported and follow-up times at which data are available.

Quality of life

None of the newly identified,99,147149 head-to-head, randomised studies investigated QoL with the technologies under assessment, and no such data were identified in the 2004 review.2

Safety

A variety of AEs were reported in the included studies; the most common were nausea, diarrhoea, vomiting and headache (Tables 3941).

TABLE 39. Adverse events in included head-to-head studies: donepezil vs galantamine.

TABLE 39

Adverse events in included head-to-head studies: donepezil vs galantamine.

TABLE 40. Adverse events in included head-to-head studies: donepezil vs rivastigmine.

TABLE 40

Adverse events in included head-to-head studies: donepezil vs rivastigmine.

TABLE 41. Adverse events in included head-to-head studies: galantamine vs rivastigmine.

TABLE 41

Adverse events in included head-to-head studies: galantamine vs rivastigmine.

Summary: head-to-head comparisons

Four new head to head RCTs were found;99,147149 two compared all included AChEIs,99,147 one compared donepezil to rivastigmine148 and one compared donepezil to galantamine.149 Pooling of data from head-to-head trials was not possible owing to the heterogeneity of the data. The quality of the evidence they provide is limited because of the poor quality of most of the trials. The exception to this was Bullock and colleagues,148 whose good-quality study found no significant difference between donepezil and rivastigmine for cognitive or behavioural outcomes. However, when they looked at functional and global outcomes, patients taking rivastigmine fared significantly better than those taking donepezil in the primary analysis.

Graphical summary of head-to-head comparisons

Figure 51 clearly shows that this group of studies is dominated by the new comparison of rivastigmine with donepezil by Bullock and colleagues.148 The small studies from the previous review indicate that there is no difference between donepezil and galantamine on cognitive outcomes. These earlier results support those of the much larger study by Bullock and colleagues,148 which also shows that rivastigmine is significantly better than donepezil on functional and global outcomes. Previously, when donepezil and galantamine were compared in a small, poor-quality trial, the results favoured donepezil on cognitive and functional outcomes; no new evidence for this comparison for these outcomes was found. There was no good or even moderate evidence comparing all three AChEIs.

FIGURE 51. Summary of all included head-to-head studies in the 2004 and 2010 reviews.

FIGURE 51

Summary of all included head-to-head studies in the 2004 and 2010 reviews. Analy, analysis; be, behavioural; Blind, blinding; Char, characteristics of patients; cog, cognitive; F, female; glo, global effect; GvD, galantamine vs donepezil; M, male; Rand, (more...)

Combination therapy

Identified evidence

Our searches identified a single new randomised trial addressing the effectiveness of combination therapy consisting of two of the technologies under review.150 Details of the design and characteristics are presented in Tables 42 and 43, and an assessment of study quality in Table 44.

TABLE 42. Design of included studies: combination therapy.

TABLE 42

Design of included studies: combination therapy.

TABLE 43. Interventions, comparators and baseline characteristics of participants in included studies: memantine and cholinesterase inhibitors vs cholinesterase inhibitors.

TABLE 43

Interventions, comparators and baseline characteristics of participants in included studies: memantine and cholinesterase inhibitors vs cholinesterase inhibitors.

TABLE 44. Markers of internal validity of included studies: memantine and cholinesterase inhibitors vs cholinesterase inhibitors.

TABLE 44

Markers of internal validity of included studies: memantine and cholinesterase inhibitors vs cholinesterase inhibitors.

One included study in the 2004 review141 addressed the effectiveness of donepezil plus memantine versus donepezil plus placebo. In the 2004 review,2 this is considered among the evidence of effectiveness of memantine. We have not followed this approach, as we prefer to assess monotherapy and combination regimens separately, because the effect of multiple agents may or may not be straightforwardly additive.

Evidence of clinical effectiveness

Cognition

The new study by Porsteinsson and colleagues150 failed to show any benefit on cognitive outcomes from combining memantine with an AChEI (Table 45). One reason for this may be an underlying pharmacological interaction between galantamine and memantine that could neutralise their effects.

TABLE 45. Measures of cognition in included studies: combination therapy.

TABLE 45

Measures of cognition in included studies: combination therapy.

Synthesis with existing evidence base Because the previously identified study141 relies on SIB to estimate the effect of combination therapy on cognition, whereas Porsteinsson and colleagues150 report MMSE and ADAS-cog, it was not possible to combine the two studies in a WMD meta-analysis, nor would it have been informative to combine the two RCTs on a standardised scale.

Functional

New data Similarly, functional outcomes failed to show a significant difference between combination therapy and an AChEI plus placebo (Table 46).

TABLE 46. Measures of functional ability in included studies: combination therapy.

TABLE 46

Measures of functional ability in included studies: combination therapy.

Synthesis with existing evidence base Although both relevant studies use the ADCS-ADL to measure the functional effectiveness of combination therapy, different versions of the instrument are adopted: Porsteinsson and colleagues150 rely on the 23-item scale, whereas Tariot and colleagues141 use the 19-item version. Accordingly, it is not valid to synthesise these data on their original scales.

Behavioural and mood

New data Porsteinsson and colleagues150 also failed to show any benefit from combination therapy when behavioural outcomes were measured with the NPI (Table 47).

TABLE 47. Measures of behavioural effect and mood in included studies: combination therapy.

TABLE 47

Measures of behavioural effect and mood in included studies: combination therapy.

Synthesis with existing evidence base

Neuropsychiatric Inventory When the data from Porsteinsson and colleagues150 were pooled with the existing data from the NPI at 12 and 24 weeks, the overall pooled estimates showed no significant gain from combination therapy (Figures 52 and 53).

FIGURE 52. Random-effects meta-analysis – NPI at 12 weeks (mean change from baseline): AChEI + memantine vs AChEI + placebo.

FIGURE 52

Random-effects meta-analysis – NPI at 12 weeks (mean change from baseline): AChEI + memantine vs AChEI + placebo.

FIGURE 53. Random-effects meta-analysis – NPI at 24 weeks (mean change from baseline): AChEI + memantine vs AChEI + placebo.

FIGURE 53

Random-effects meta-analysis – NPI at 24 weeks (mean change from baseline): AChEI + memantine vs AChEI + placebo.

Global effect

New data Again, with global outcomes, no additional benefit was found from combination therapy (Table 48).

TABLE 48. Measures of global effect in included studies: combination therapy.

TABLE 48

Measures of global effect in included studies: combination therapy.

Synthesis with existing evidence base

Clinician's Interview-based Impression of Change-plus Caregiver Input (Figure 54) A synthesis of new and existing evidence for global outcomes showed no overall benefit from combination therapy (see Table 45).

FIGURE 54. Random-effects meta-analysis – CIBIC-plus at 24 weeks: AChEI + memantine vs AChEI + placebo.

FIGURE 54

Random-effects meta-analysis – CIBIC-plus at 24 weeks: AChEI + memantine vs AChEI + placebo.

Quality of life

The new included study did not provide any randomised evidence on QoL with combination therapy and no such data were identified in the 2004 review.2

Safety

The proportion of AEs did not significantly vary between groups. The most common AEs were falls and injury (Table 49).

TABLE 49. Adverse events in included studies: combination therapy.

TABLE 49

Adverse events in included studies: combination therapy.

Summary: combination therapy

Our searches found one new trial that compared memantine plus an AChEI with an AChEI.148 This failed to show any benefit from combining memantine with an AChEI on cognitive, functional, behavioural or global outcomes. Pooling these data with previous trails also failed to show any additional benefit from combination therapy.

Graphical summary of combination therapy

Figure 55 clearly illustrates the similarities between the new and existing evidence for combination therapy; what is striking is the difference in results. Some of the variation may be explained by the use of different outcome measures or versions of outcome measures. However, it is unclear why the behavioural and global outcome results are different. The designs of these studies differed in that Porsteinsson and colleagues150 combined memantine with any of the three included AChEIs, whereas Tariot and colleagues141 only combined memantine with donepezil. The other notable difference is that the 2004141 authors analysed a modified ITT population, whereas the 2008150 study authors analysed a full ITT population. Whether or not these differences are sufficient to account for these differences in apparently similar populations is unknown.

FIGURE 55. Summary of all studies included in the 2004 and 2010: combination therapy.

FIGURE 55

Summary of all studies included in the 2004 and 2010: combination therapy. Analy, analysis; be, behavioural; Blind, blinding; Char, characteristics of patients; cog, cognitive; F, female; glo, global effect; M, male; Rand, randomisation.

Mixed-treatment comparisons: indirect comparisons

Where there were sufficient data we pooled information on all technologies and their comparators simultaneously, in a MTC using Bayesian MCMC sampling.8992 The results are shown in terms of treatment effect compared with a common baseline. The evidence network shows the comparisons that were available and the quantity of those comparisons (by the thickness of the connecting lines). More details can be found in Methods of quantitative analysis/Mixed-treatment comparisons: indirect comparisons. MTCs of the technologies performed in specified measurement populations can be found in Appendix 9.

Cognitive

Alzheimer's Disease Assessment Scale – Cognitive Subscale

Table 50 shows the studies pooled in this MTC at 12–16 weeks' follow-up, with their evidence network and effectiveness estimates. The results in Table 51 give the relative effectiveness of each technology compared with placebo, indicating that donepezil and galantamine are certainly more effective than placebo and that donepezil is probably the most effective of these (0.48).

TABLE 50. Mixed-treatment comparison – ADAS-cog at 12–16 weeks (mean change from baseline; all measurement populations): input data.

TABLE 50

Mixed-treatment comparison – ADAS-cog at 12–16 weeks (mean change from baseline; all measurement populations): input data.

TABLE 51. Mixed-treatment comparison – ADAS-cog at 12–16 weeks (mean change from baseline; all measurement populations): results.

TABLE 51

Mixed-treatment comparison – ADAS-cog at 12–16 weeks (mean change from baseline; all measurement populations): results.

At 21–26 weeks' follow-up the MTC showed that all the treatments were more effective than placebo, with galantamine probably the most effective (0.89) (Tables 52 and 53).

TABLE 52. Mixed-treatment comparison – ADAS-cog at 21–26 weeks (mean change from baseline, all measurement populations): input data.

TABLE 52

Mixed-treatment comparison – ADAS-cog at 21–26 weeks (mean change from baseline, all measurement populations): input data.

TABLE 53. Mixed-treatment comparison – ADAS-cog at 21–26 weeks (mean change from baseline, all measurement populations): results.

TABLE 53

Mixed-treatment comparison – ADAS-cog at 21–26 weeks (mean change from baseline, all measurement populations): results.

Mini Mental State Examination

The data used for the 12- to 13-week MTC for MMSE can be seen in Table 54. The results in Table 55 show that at this early follow-up donepezil is the only treatment that is certainly more effective than placebo and consequently probably the most effective treatment overall (0.54).

TABLE 54. Mixed-treatment comparison – MMSE at 12–13 weeks (mean change from baseline, all measurement populations): input data.

TABLE 54

Mixed-treatment comparison – MMSE at 12–13 weeks (mean change from baseline, all measurement populations): input data.

TABLE 55. Mixed-treatment comparison – MMSE at 12–13 weeks (mean change from baseline, all measurement populations): results.

TABLE 55

Mixed-treatment comparison – MMSE at 12–13 weeks (mean change from baseline, all measurement populations): results.

At 24–26 weeks from baseline there is no evidence from galantamine, and donepezil continues to show that it is probably the most effective treatment (0.67) (Tables 56 and 57).

TABLE 56. Mixed-treatment comparison – MMSE at 24–26 weeks (mean change from baseline; all measurement populations): input data.

TABLE 56

Mixed-treatment comparison – MMSE at 24–26 weeks (mean change from baseline; all measurement populations): input data.

TABLE 57. Mixed-treatment comparison – MMSE at 24–26 weeks (mean change from baseline; all measurement populations): results.

TABLE 57

Mixed-treatment comparison – MMSE at 24–26 weeks (mean change from baseline; all measurement populations): results.

Functional

Alzheimer's Disease Cooperative Study – Activities of Daily Living Index

Mixed-treatment comparisons were conducted for the ADCS-ADL. At 12–16 weeks, galantamine and rivastigmine were shown to be almost equally effective compared with placebo, with rivastigmine possibly being the most effective (0.50) (Tables 58 and 59).

TABLE 58. Mixed-treatment comparison – ADCS-ADL at 12–16 weeks (mean change from baseline, all measurement populations): input data.

TABLE 58

Mixed-treatment comparison – ADCS-ADL at 12–16 weeks (mean change from baseline, all measurement populations): input data.

TABLE 59. Mixed-treatment comparison – ADCS-ADL at 12–16 weeks (mean change from baseline, all measurement populations): results.

TABLE 59

Mixed-treatment comparison – ADCS-ADL at 12–16 weeks (mean change from baseline, all measurement populations): results.

At 21–26 weeks' follow-up, the situation had changed, with galantamine showing a slightly greater probability of being the most effective technology (0.55) (Tables 60 and 61).

TABLE 60. Mixed-treatment comparison – ADCS-ADL at 21–26 weeks (mean change from baseline, all measurement populations): input data.

TABLE 60

Mixed-treatment comparison – ADCS-ADL at 21–26 weeks (mean change from baseline, all measurement populations): input data.

TABLE 61. Mixed-treatment comparison – ADCS-ADL at 21–26 weeks (mean change from baseline, all measurement populations): results.

TABLE 61

Mixed-treatment comparison – ADCS-ADL at 21–26 weeks (mean change from baseline, all measurement populations): results.

Behavioural

Neuropsychiatric Inventory

The MTC for behavioural outcomes were measured using the NPI. At 12–13 weeks from baseline, donepezil was probably more effective than galantamine at controlling behavioural symptoms (0.78) (Tables 62 and 63).

TABLE 62. Mixed-treatment comparison – NPI at 12–13 weeks (mean change from baseline, all measurement populations): input data.

TABLE 62

Mixed-treatment comparison – NPI at 12–13 weeks (mean change from baseline, all measurement populations): input data.

TABLE 63. Mixed-treatment comparison – NPI at 12–13 weeks (mean change from baseline; all measurement populations): results.

TABLE 63

Mixed-treatment comparison – NPI at 12–13 weeks (mean change from baseline; all measurement populations): results.

At 21–28 weeks' follow-up there were also data on rivastigmine and memantine to put into the MTC. However, donepezil was still probably the most effective treatment (0.57) (Tables 64 and 65).

TABLE 64. Mixed-treatment comparison – NPI at 21–28 weeks [mean change from baseline, all measurement populations (all are classic ITT or LOCF analysis)]: input data.

TABLE 64

Mixed-treatment comparison – NPI at 21–28 weeks [mean change from baseline, all measurement populations (all are classic ITT or LOCF analysis)]: input data.

TABLE 65. Mixed-treatment comparison – NPI at 21–28 weeks [mean change from baseline; all measurement populations (all are classic ITT or LOCF analysis)]: results.

TABLE 65

Mixed-treatment comparison – NPI at 21–28 weeks [mean change from baseline; all measurement populations (all are classic ITT or LOCF analysis)]: results.

Global

For global outcomes MTC was carried out using the CIBIC-plus and the GDS.

Clinician's Interview-based Impression of Change plus Caregiver Input

At 12–16 weeks post baseline, a MTC of all the treatments showed that galantamine was probably the most effective treatment (0.54) (Tables 66 and 67).

TABLE 66. Mixed-treatment comparison – CIBIC-plus at 12–16 weeks (all measurement populations): input data.

TABLE 66

Mixed-treatment comparison – CIBIC-plus at 12–16 weeks (all measurement populations): input data.

TABLE 67. Mixed-treatment comparison – CIBIC-plus at 12–16 weeks (all measurement populations): results.

TABLE 67

Mixed-treatment comparison – CIBIC-plus at 12–16 weeks (all measurement populations): results.

However, at 24–28 weeks' follow-up, donepezil was probably the most effective (0.55) (Tables 68 and 69).

TABLE 68. MTC – CIBIC-plus at 24–28 weeks (all measurement populations): input data.

TABLE 68

MTC – CIBIC-plus at 24–28 weeks (all measurement populations): input data.

TABLE 69. Mixed-treatment comparison – CIBIC-plus at 24–28 weeks (all measurement populations): results.

TABLE 69

Mixed-treatment comparison – CIBIC-plus at 24–28 weeks (all measurement populations): results.

Global Deterioration Scale

There were only data from the GDS at 24–28 weeks from baseline. This indicated that rivastigmine was probably more effective than donepezil or memantine for global outcomes (0.49) (Tables 70 and 71).

TABLE 70. Mixed-treatment comparison – GDS at 24–28 weeks (mean change from baseline; all measurement populations): input data.

TABLE 70

Mixed-treatment comparison – GDS at 24–28 weeks (mean change from baseline; all measurement populations): input data.

TABLE 71. Mixed-treatment comparison – GDS at 24–28 weeks (mean change from baseline; all measurement populations): results.

TABLE 71

Mixed-treatment comparison – GDS at 24–28 weeks (mean change from baseline; all measurement populations): results.

Summary: mixed-treatment comparisons

The MTC results for cognitive outcomes varied with follow-up time and the measure used. Donepezil was shown to be probably the most effective treatment at short-term follow-up on the ADAS-cog and MMSE, and this remained the case for the MMSE at 24–26 weeks; however, the ADAS-cog favoured galantamine at this later follow-up time. Functional outcomes measured with the ADCS-ADL showed equal effectiveness from galantamine and rivastigmine at 12–16 weeks, but by 21–26 weeks galantamine was probably the most effective treatment. For behavioural outcomes donepezil came out most favourably. For global outcomes the results were less clear, with galantamine probably the best treatment at 12–16 weeks when measured by the CIBIC-plus, but donepezil taking over by 24–28 weeks. However, when global outcomes were measured with the GDS, rivastigmine came out as the most effective.

Summary of clinical effectiveness evidence

  • From 1843 titles and abstracts screened, four systematic reviews and 17 RCTs were found that matched our inclusion criteria, which had been published since 2004.
  • Overall, the quality of the trials was disappointing, and there was insufficient evidence to suggest that one treatment is better than another. We, therefore, suggest that the AChEIs are taken as a class of drugs.
  • When combined with data from the previous review in 2004,2 donepezil was shown to provide gains on cognitive, functional and global outcomes when compared with placebo.
  • Similar pooling of data from galantamine studies was conducted, showing clear benefits from cognitive, functional and global outcomes. Additionally, results favouring treatment were seen for behavioural outcomes at later (6-month) follow-up.
  • Pooled estimates of cognitive benefits from rivastigmine were favourable, but were shown to be dose dependent as in the previous review in 2004.2 The results from functional and global outcomes also showed significant gains. However, results from individual trials of behavioural outcomes were mixed (pooling was not possible owing to heterogeneity). The lower dose transdermal patch (9.5 mg/day) was shown to be as effective as the capsule (12 mg/day), but with fewer side effects.
  • The meta-analysis of memantine versus placebo showed benefit from memantine at 12 weeks' follow-up on the SIB. However, treatment gain, measured by functional outcome, depended on the type of instrument used, and no benefit on behavioural outcomes was seen. Nevertheless, pooled estimates of global outcomes showed a benefit from taking memantine.
  • Pooling of data from head-to-head trials was not possible owing to the heterogeneity of the data. Results from the one reasonably good-quality trial showed no significant difference between donepezil and rivastigmine for cognitive or behavioural outcomes. However, when looking at functional and global outcomes, patients taking rivastigmine fared significantly better than those taking donepezil in the primary analysis.
  • Pooling data from trials combining memantine plus an AChEI versus an AChEI failed to show any additional benefit from combination therapy.
  • The MTC results for cognitive outcomes varied. Donepezil and galantamine were both probably the most effective for cognitive outcomes depending on the measure used and the length of follow-up. Similarly, depending on the follow-up time, galantamine and rivastigmine were either equally effective or galantamine was more effective on functional outcomes. For longer-term outcomes donepezil or rivastigmine were probably the most effective treatments, depending on the measure used.

As found in the previous review,2 the main AEs for the AChEIs were gastrointestinal, and agitation and hypertension for memantine. However, the source of this evidence was limited to the included RCTs. The trial populations and their experience of AEs may not reflect those of people with AD who were not in trials.

Table 72, summarising the change in the evidence of effectiveness, as measured by statistical significance at p < 0.05, should be interpreted with caution. The fewer the studies contributing to a category of outcome measure, for example cognitive, the more likely it is to have a positive or negative result, and the more studies there are in a category, the more likely it is that their results will go in different directions. Thus, there appears to be a possibly false sense of certainty about the memantine results when this may simply be an artefact of the number of studies.

TABLE 72. Summary of the change in clinical effectiveness evidence since the 2004 review.

TABLE 72

Summary of the change in clinical effectiveness evidence since the 2004 review.

© 2012, Crown Copyright.

Included under terms of UK Non-commercial Government License.

Cover of The Effectiveness and Cost-Effectiveness of Donepezil, Galantamine, Rivastigmine and Memantine for the Treatment of Alzheimer's Disease (Review of Technology Appraisal No. 111): A Systematic Review and Economic Model
The Effectiveness and Cost-Effectiveness of Donepezil, Galantamine, Rivastigmine and Memantine for the Treatment of Alzheimer's Disease (Review of Technology Appraisal No. 111): A Systematic Review and Economic Model.
Health Technology Assessment, No. 16.21.
Bond M, Rogers G, Peters J, et al.
Southampton (UK): NIHR Journals Library; 2012 Apr.

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