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Journal of Alzheimer’s Disease xx (20xx) x–xx DOI 10.3233/JAD-132690 IOS Press

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Efficacy and Safety of Donepezil, Galantamine, Rivastigmine, and Memantine for the Treatment of Alzheimer’s Disease: A Systematic Review and Meta-Analysis

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Chen-Chen Tana , Jin-Tai Yua,b,c,∗ , Hui-Fu Wangb , Meng-Shan Tanc , Xiang-Fei Menga , Chong Wanga , Teng Jiangb , Xi-Chen Zhub and Lan Tana,b,c,∗

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Handling Associate Editor: Francesco Panza

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of Neurology, Qingdao Municipal Hospital, School of Medicine, Qingdao University, China of Neurology, Qingdao Municipal Hospital, Nanjing Medical University, China c Department of Neurology, Qingdao Municipal Hospital, College of Medicine and Pharmaceutics, Ocean University of China, China

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Abstract. Background: The role of currently available drugs for Alzheimer’s disease (AD) has been controversial, with some national formularies restricting their use, and health economists questioning whether the small clinical effects are economically worthwhile. Objective: To estimate the efficacy and safety of donepezil, galantamine, rivastigmine, and memantine for the treatment of AD. Methods: Double-blind, placebo-controlled, with random assignment to a cholinesterase inhibitor or memantine trials were included into the pooled studies. Results: Cognitive effects were significant for all drugs, ranging from a −1.29 points mean difference (95% CI −2.30 to −0.28) in the 20 mg daily memantine trials to −3.20 points (95% CI −3.28 to −3.12) in the 32 mg daily galantamine group. Only memantine had no effect on the Clinicians’ Global Impression of Change scale. No behavioral benefits were observed, except for −2.72 (95% CI −4.92 to −0.52) in the 10 mg daily donepezil group and −1.72 (95% CI −3.12 to −0.33) for 24 mg daily galantamine trial. Only 5 mg daily donepezil had no effect on the function outcome. Compared with placebo, more dropouts and adverse events occurred with the cholinesterase inhibitors, but not with memantine. Conclusions: Cholinesterase inhibitors and memantine are able to stabilize or slow decline in cognition, function, behavior, and global change.

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Accepted 9 February 2014

Keywords: Alzheimer’s disease, donepezil, efficacy, galantamine, memantine, meta-analysis, rivastigmine, safety, systematic review

INTRODUCTION ∗ Correspondence

to: Dr. Lan Tan or Jin-Tai Yu, Department of Neurology, Qingdao Municipal Hospital, School of Medicine, Qingdao University, No.5 Donghai Middle Road, Qingdao, Shandong Province 266071, China. E-mail: [email protected]. (L. Tan); E-mail: [email protected]. (J.T. Yu)

Alzheimer’s disease (AD) is the most common cause of dementia, affecting more than 36 million people worldwide. It has been predicted that by 2050, this figure will more than 115 million [1]. This age-associated

ISSN 1387-2877/14/$27.50 © 2014 – IOS Press and the authors. All rights reserved

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Search strategy

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METHODS

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materials from professional society meetings. Reviews without original data, meeting abstracts, and case reports/series were excluded. Selection criteria and data retrieval

Trials that were included met the following criteria: (1) double-blind, parallel-group, placebo-controlled, with random assignment to a cholinesterase inhibitor (donepezil, rivastigmine, galantamine) or memantine; (2) inclusion of patients who have a diagnosis of probable or possible AD consistent with the Diagnostic and Statistical Manual of Mental Disorders—Fourth Edition (DSM-IV)13 and the criteria of the National Institute of Neurological and Communicative Disorders and Stroke/Alzheimer’s Disease and Related Disorders Association (NINCDS-ADRDA) [8, 9]; (3) inclusion of treatments which last at least 20 weeks and contain at least one measure reflecting the following: cognition, function, behavior, or global assessment of change; (4) specification of medication doses and formulations. Studies with fatal flaws in study design or data analysis were excluded, as were trials whose data were not readily available. We obtained the following baseline variables from each study: sample size, age, gender, race, design, medication doses, blinding, trial durations, baseline cognitive scores (Mini-Mental State Examination, MMSE), numbers randomized, primary and secondary outcomes, adverse events, and all cause dropouts during the double-blind trial. We recorded intentionto-treat (ITT) population results if available, and if not, then extracted observed case or per protocol outcome. Data abstraction was accomplished under the cooperation between two investigators by use of a standardized data extraction. Any discrepant data were reviewed by discussion with other team members or contact with original investigators, who were all sent emails with requests for the exact data. For missing data (standard deviations), we sought missing information and essential clarification from the author. For the measures variation there is an approximate or direct algebraic relationship with the standard deviation (SD), we obtained it from standard errors, confidence intervals, t values or p values that relate to the difference between means in two groups. Measurement scales that has used in the trials were different each other. Hence, we recorded measurement scales according to the general domain being assessed: cognition, function, behavior, and global assessment of change. Then we attempted to determine a single measurement scale that was most commonly used

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neurodegenerative disorder has an insidious onset with progressive deterioration in cognition, functional ability, behavior, and mood. Current available nonpharmacologic and pharmacologic interventions can provide benefits, although none prevents or cures the disease [2, 3]. Non-pharmacologic therapy primarily includes physical exercise, social support, cognitive rehabilitation, assistance with activities of daily living, multidisciplinary programs, and providing support to caregivers [4]. Pharmacological interventions that have been approved in the US and most of Europe for AD include the cholinesterase inhibitors donepezil, galantamine, and rivastigmine, and the N-methyl-Daspartate receptor antagonist memantine, with the primary goal of slowing clinical progression [5, 6]. The role of currently available drugs for AD has been controversial, with some national formularies restricting their use, and health economists questioning whether the small clinical effects are economically worthwhile. Moreover, the place of N-methyl-Daspartic acid (NMDA) receptors and memantine in the treatment of AD has also been heavily debated [7]. In addition, high dropout rates and numerous adverse events have been observed in randomized clinical trials of these agents. Hence, safety concerns have been raised about the cholinesterase inhibitors and memantine. We conducted this systematic review and metaanalysis of donepezil, galantamine, rivastigmine, and memantine for the treatment of AD to clarify the efficacy and safety of these drugs. We sought to elaborate on previous reviews articles by including a broad spectrum of outcome measures, and determine whether these drugs have different degrees of efficacy on the cognitive, behavioral, and functional impairment of AD patients in progressive different stages of severity.

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We searched PubMed (1966 to November 2013), EMBASE (1980 to November 2013), International Pharmaceutical Abstracts (1970 to November 2013), clinicaltrials.gov, the Cochrane Controlled Trials Register, the Cochrane Database of Systematic Reviews, and the Cochrane Cognitive Improvement Group specialized registry with the terms “Alzheimer’s disease” or “AD”, “cholinesterase inhibitors”, “donepezil”, “galantamine”, “rivastigmine”, and “memantine”. Other sources searched were conference proceedings, abstracts, thesis dissertations, poster presentations, and

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Statistical analysis

Literature search findings

As the nearly identical trial designs, inclusion criteria, and outcomes within each drug assessed, the outcomes and the numbers of patients for each trial were statistically combined by use of the YousefPeto fixed effects model by use of Review Manager Version 5.2 software. For continuous data collected using the same measurement scale (e.g., cognition and behavior), we calculated a weighted mean differences (WMD) or standardized mean differences and its 95% confidence intervals (CIs) for changes from baseline or final values. For dichotomous clinical outcomes, dropouts, and adverse events, we conducted an analysis of the risk ratio (RR), absolute risk differences with 95% CI and p values to assess the efficacy and safety of the study drug. When meta-analysis is conducted, we assessed for clinical, statistical, and methodological heterogeneity. We quantitatively tested the heterogeneity between the trials using the visual inspection, and a χ²-test combined with the I² method. I2 approximates the proportion of total variation in the effect size estimates that is due to heterogeneity rather than sampling error. An ␣ error p < 0.20 and an I2 statistic greater than 50% was taken as indicators of heterogeneity of outcomes. Subgroup analyses based on medication doses were done for there still were a few differences between groups of varied doses. To establish the robustness of the primary outcome, we used a fixed effects model, and excluded studies in which the standard deviations were absent and estimated by Cochrane Handbook to conduct sensitivity analyses. Funnel plots of the WMD of the main outcomes of each trial against the standard errors of the WMDs were used to assess potential retrieval bias. We also conducted trial sequential analyses [10, 11], in which monitoring boundaries are used to determine whether clinical trials could be terminated early when a p value is small enough to detect the expected effect. We initially calculated the required information size

The search strategy yielded 1,351 citations in PubMed, EMBASE, International Pharmaceutical Abstracts, clinicaltrials.gov, the Cochrane Controlled Trials Register, the Cochrane Database of Systematic Reviews, and the Cochrane Cognitive Improvement Group specialized registry. Of these, ten donepezil trials [12–21], four galantamine trials [22–25], three rivastigmine trials [26–28], and six memantine trials [29–34] were included in the review. The search procedure and reasons for exclusion of other studies are shown in Fig. 1.

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RESULTS

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Characteristics of included trials The included trials each required a diagnosis of probable or possible AD by use of the NINCDSADRDA, but varied on dementia severity. Four donepezil trials [12, 13, 18, 21], three memantine trials [32–34], and one galantamine trial [23] were done to ascertain their effectiveness in patients with severe AD,

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and ␣-spending monitoring boundaries to detect or reject an intervention effect of relative risk reduction of low bias trials in efficacy analysis, and an effect of relative risk reduction of 30% in safety analysis, with a power of 80%. Trial sequential analyses were performed in TSA version 0.9 beta. We applied GRADE Profiler 3.6 to produce a summary table of outcomes. All analyses were two-tailed, with 5% risk of a type I error (␣ of 0.05).

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as a primary outcome measure within each domain. We focus on the Alzheimer’s Disease Assessment Scale (ADAS-cog), Alzheimer’s Disease Cooperative Study-Activities of Daily Living (ADCS/ADL), Neuropsychiatric Inventory (NPI), and the Clinician’s Interview Based Assessment of Change-Plus (CIBIC plus) as the primary measure of cognition, function, behavior, and global assessment of change, respectively. In addition, we recorded the discontinuations from the trials for adverse events to assess the benefits and risks of these drugs.

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Fig. 1. Flowchart describing the approach used to identify all eligible studies of meta-analysis.

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Table 1 Summary of the cholinesterase inhibitor or memantine trials Study

Patients (n)

Age Years Gender Race Disease (SD) (% men) (% white) severity

Donepezil Black et al., 2007 10 mg daily (167) 78.0 (8.20) Placebo (176) 78.0 (8.04) Burns et al., 1999 Placebo (274) 71.0 (0.50)

Homma et al., 2008

Homma et al., 2000

5 mg daily (271) 72.0 (0.50) 10 mg daily (273) 72.0 (0.50) Placebo (146) 74 10 mg daily (144) 73.3 Placebo (102) 79.7 (7.5)

76.1 76.1 99

39 43 39

100 99 ...

7.4 (3.57) Fixed 7.5 (3.25) Mild to moderately 20 (0.3) Fixed severe 20 (0.3) 20 (0.2) Moderate to severe 11.9 (0.3) Flexible

38.9 17.6

...

Severe

...

7.9 (3.3) 7.4 (3.4) Mild to moderately 16.6 (3.9) Fixed

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Behavior

Global

ADL

NPI

CIBIC+

...

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SIB

CIBIC+

34.9 24.7 20.1

24

ADAS-cog IDDD

20

CIBIC+

22.1 26.4 13.7

21

ADCS-ADL BEHAVE-AD CIBIC+

16.0 20.0

13

24

MMSE SIB DAD

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SIB

5 mg daily (96) 78.0 (8.90) 10 mg daily (92) 76.9 (7.9) Placebo (112) 69.4 (8.8)

20.8 20.7 34

5 mg daily (116) 70.1 (7.6) Placebo (61) 71.6 (6.72)

32 30

... ...

10 mg daily (67) 71.1 (8.39) Placebo (162) 72.6 (0.6)

37 39

... 94

5 mg daily (154) 72.9 (0.6) 10 mg daily (157) 74.6 (0.6) Placebo (57) 73.3 (8.8)

37 38 50

95 96 ...

73.3 (9.6) 85.9 85.4 85.3 (5.9)

40 18 17 26

... ... ... 99

84.5 (6.0)

21

100

76.3 (8.03)

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90

Mild to moderate

18.1 (4.1) Fixed

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ADAS-cog ADL

76.5 (7.77) 83.5 (5.8) 83.7 (5.7)

36 19 19

90 ... ...

Severe

17.8 (4.1) 9.1 (2.4) Fixed 8.8 (2.4)

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SIB

severe Maher-Edwards et al., 2011

11.7 (0.3) 8.0 (3.3) Flexible

10 mg daily (96) Tariot et al., 2001 Placebo (105) 10 mg daily (103) Winblad et al., Placebo (120) 2006 10 mg daily (128) Galantamine Brodaty et al., Placebo (320) 2005 24 mg daily (326) Burns et al., 2009 Placebo (200) 24 mg daily (207)

Mild to moderate

Mild to moderately 19.0 (0.4) Flexible severe 19.2 (0.4) 18.9 (0.4) Mild 24.3 (1.3) Fixed

... Severe

24.1 (1.1) 14.4 (5.8) Fixed 14.4 (5.4) 6.2 (3.0) Fixed

NPI

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Dropout Ref. rate (%)

Function

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ADAS-cog . . .

...

CGIC

...

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24

ADAS-cog DAD

NPI

CIBIC+

... 23.8

19

24

ADAS-cog . . .

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CIBIC+

14.9 19.8

15

...

14.9 31.8 19.3

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ADAS-cog . . .

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MMSE

PSMS

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SIB

ADL

Pr ...

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27.1 ... ... 17.5

NPI

CIBIC+

16.9

22

...

...

23.0 19.5 18.8

23

NPI ...

6.0 (3.0)

ADL

CDR

CGIC

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Baseline Type of Duration Outcomes MMSE (SE) drug dosing (weeks) Cognition

Table 1 (Continued) Study Tariot et al., 2000 Wilcock et al., 2000

Patients (n)

Age Years Gender Race (SD) (% men) (% white) 38 33 38.6

93 91 ...

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24 mg daily (220) 71.9 (8.3) 32 mg daily (218) 72.1 (8.6) Rivastigmine Feldman et al., 2007

Placebo (222)

12 mg daily (227) Rosler et al., 1999 Placebo (239) 12 mg daily (243) Winblad et al., Placebo (302) 2007 12 mg daily (297) Memantine Bakchine and Placebo (152) Loft, 2008 20 mg daily (318) Herrmann et al., Placebo (187) 2013 20 mg daily (182) Peskind et al., Placebo (202) 2006 20 mg daily (201) Reisberg et al., Placebo (84) 2003 20 mg daily (97) Tariot et al., 2004 Placebo (201) 20 mg daily (203) van Dyck et al., Placebo (172) 2007 20 mg daily (178)

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Baseline Type of Duration Outcomes MMSE (SE) drug dosing (weeks) Cognition 17.7 (0.2) 17.7 (0.2) 19.3 (3.5)

Dropout Ref. rate (%)

Function Behavior Global

Flexible

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ADAS-cog

ADL

NPI

CIBIC+

Flexible

24

ADAS-cog

DAD

...

CIBIC+

19.5 (3.4) 19.0 (3.8)

15.7 18.7 13.5

71.7 (8.7)

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...

Mild to moderate

71.4 (7.9) 72

40 41

... 97

73.9 (7.3)

33.4

75.2

72.8 (8.2)

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20.0 25.2

18.7 (4.6)

Fixed

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ADAS-cog

PDS

...

CIBIC+

Mild to moderate

Flexible

26

ADAS-cog

PDS

...

CIBIC+

Mild to moderate

16.4 (3.0)

Fixed

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ADAS-cog

ADL

NPI

CGIC

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18.3 (4.5) 10–26

74.5

73.3 (6.9)

40

...

Mild to moderate

18.9 (3.2)

Fixed

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ADAS-cog

ADL

NPI

CIBIC+

9.2

29

74.0 (7.4) 75.1 (6.9)

35 41.2

... ...

Mild to moderate

18.6 (3.3) 11.8 (2·9)

Fixed

24

SIB

ADL

NPI

...

1.3 17.1

30

74.7 (7.9) 77.0 (8.2)

42.3 42.6

... ...

Mild to moderate

11.9 (3.1) 17.2 (3.4)

Fixed

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ADAS-cog

ADL

NPI

CIBIC+

17.0 17.3

31

78.0 (8.3) 75.8 (7.28)

39.8 34.5

... 89.3

Moderate to severe

17.4 (3.7) 8.1 (3.6)

Fixed

24

SIB

CIBIC+

17.9 33.3

32

75.5 (8.16) 75.5 (8.73) 75.5 (8.45) 78.3 (7.6)

27.8 33 37 29.7

87.6 92.5 90.1 82

Fixed

24

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ADL

SIB

ADL

NPI

CIBIC+

Fixed

24

SIB

ADL

NPI

CIBIC+

78.1 (8.2)

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Moderate to severe Moderate to severe

9.0

16.4 (3.1)

10.6 13.0 32.5 11.9

10.0 (2.8)

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21.2

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7.8 (3.76) 10.2 (2.9) 9.9 (3.13) 10.3 (3.1)

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Placebo (286) 77.1 (0.5) 24 mg daily (273) 77.7 (0.4) Placebo (215) 72.7 (7.6)

Disease severity

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ADAS-cog, Alzheimer’s Disease (AD) Assessment Scale, cognitive subscale (possible range 0–70); ADCS-ADL, AD Cooperative Study Activities of Daily Living Inventory; BEHAVE-AD, Behavioral Pathology in Alzheimer’s Disease Rating Scale; CDR, Clinical Dementia Rating; CGIC, Clinical Global Impression of Change; CIBIC+, Clinicians’ Interview-Based Impression of Change with Caregiver’s Input (possible range 1–7); DAD, Disability Assessment in Dementia; MMSE, Mini-Mental State Examination. NPI, Neuropsychiatric Inventory; PDS, Progressive Deterioration Scale; PSMS, Physical Self-Maintenance Scale; SIB, Severe Impairment Battery;. . . Not available.

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Fig. 2. Cognitive outcomes on the ADAS-cog subscale (change from baseline) in AD patients in cholinesterase inhibitors and memantine trials by drug and dose.

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screening the patients were required to have a MMSE score between 1 and 12. While another donepezil trial [16] whose inclusion criteria included an MMSE score of 21 to 26 focused on the effectiveness in patients with mild AD. The rest of trials investigated their efficacy and tolerability in patients with mild to moderate AD with an MMSE score of 10 to 26. All studies were randomized, double-blind, placebo-controlled trials and were done mainly in the US and European countries. Reported baseline

characteristics were similar between intervention and placebo groups in all the trials. The allocation concealment and randomization methods in all the trials were adequate. Trial durations ranged from 20 weeks to 26 weeks. Three donepezil trials [13, 15, 21], two galantamine trials [24, 25], and one rivastigmine trials [27] were dose ranging; the rest of trials used fixed doses. Design and population characteristic of cholinesterase inhibitor or memantine trials are shown in Table 1.

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Efficacy

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Cognitive function Eleven studies measured and reported the mean change in ADAS-cog score from baseline to endpoint for intervention compared with placebo: four on donepezil [14, 15, 19, 21]; three on galantamine [22, 24, 25]; three on rivastigmine [26–28]; and two on memantine [29, 31]. All of these studies included participants with mild to moderate dementia, with mean age 73.9 years and 34.1% male. Cognitive effects were significant for all drugs by meta-analysis in the available data, and the pooled weighted mean difference in change between intervention and placebo varied from −1.29 points (95% CI −2.30 to −0.28) in the 20 mg daily memantine trials to −3.20 points (95% CI −3.28 to −3.12) in the 32 mg daily galantamine group. In the donepezil trials, the differences by meta-analysis were −1.95 (95% CI −2.60 to −1.29) for 5 mg daily group and −2.48 (95% CI −3.23 to −1.73) for 10 mg daily group. In addition, the difference between 24 mg daily galantamine group and placebo was −3.03 (95% CI −3.66 to −2.41). In the rivastigmine trials, the difference by meta-analysis was −2.01 (95% CI −2.69 to −1.32). The low (0% to 39%) I2 statistic showed mild heterogeneity for the pooled studies. Funnel plots of outcome scores were non-informative with regard to retrieval bias (Fig. 2).

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Although all included trials were randomized, double blinded, and placebo controlled, reporting of allocation concealment and randomization methods were different with each other. Fourteen reports of studies explicitly mentioned use of placebo and drug pills or capsules that were visually identical for allocation concealment. The randomization was conducted according to a computerized randomization schedule among ten trials. Another six repots specified the varied methods of randomization. As the intervention in all trials was limited to use of drug or placebo, there was no indication of performance bias. Moreover, primary outcomes were analyzed by ITT data in all trials, thus minimizing effects of attrition bias. The quality of reporting of all included studies was appraised with GRADE (Supplementary Figs. 1, 2).

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five on donepezil [12, 13, 15, 19, 20]; three on galantamine [22, 24, 25]; two on rivastigmine [26, 27]; and two on memantine [29, 33]. Nine of these studies included participants with mild to moderate dementia, but one memantine trial and two donepezil trials included patients with severe dementia. Across the studies, the average of participants was 74.5 years, and 23.6% were male. Only 20 mg daily memantine (RR 1.18, 95% CI 0.88 to 1.57) and 32 mg daily galantamine (RR 1.49, 95% CI 1.00 to 2.22) had no effect on the Clinicians’ Global Impression of Change scale. Therapeutic benefits of drugs with all available data were observed on donepezil 5 mg (RR 1.45, 95% CI 1.19 to 2.00) (Heterogeneity: I2 = 61%), donepezil 10 mg (RR 1.66, 95% CI 1.38 to 2.00) (Heterogeneity: I2 = 26%), 24 mg galantamine (RR 1.18, 95% CI 1.03 to 1.35) (Heterogeneity: I2 = 0%), and rivastigmine 12 mg (RR 1.72, 95% CI 1.36 to 2.16) (Heterogeneity: I2 = 0%). The statistical heterogeneity was of a mild degree among most pooled analysis (Fig. 3). Trial sequential analysis showed that the heterogeneity adjusted required information size was 1,889 patients in donepezil 5 mg trials at a relative risk reduction of low bias trials, and the cumulative Z curve crossed ␣-spending monitoring boundary (trial sequential analysis adjusted 95% CI 1.07 to 2.24) (Supplementary Fig. 3). Similarly, the heterogeneity adjusted required information size was 1,908 patients in donepezil 10 mg trials at a relative risk reduction of low bias trials, and the cumulative Z curve also crossed ␣-spending monitoring boundary (trial sequential analysis adjusted 95% CI 1.32 to 2.09) (Supplementary Fig. 4). The significant effects on rivastigmine 12 mg were also confirmed in trial sequential analysis (required information size 1,278, trial sequential analysis adjusted 95% CI 1.28 to 2.30) (Supplementary Fig. 5). However, trial sequential analysis showed that the information fraction of 24 mg galantamine trials was too small to produce inner wedge futility area.

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Global assessment For global assessment of change, 17 studies measured the CIBIC+ scale and 12 of these trials reported the number of patients with improvement on CIBIC+:

Behavioral symptoms For behavioral outcome, eleven studies used the NPI: three on donepezil [12, 17, 21]; one on rivastigmine [28]; two on galantamine [22, 24]; and five on memantine [29–31, 33, 34]. Seven of these studies included participants with mild to moderate dementia, but two donepezil trials [12, 21] and two memantine trials included patients with severe dementia. The average of participants was 76.7 years, and 34.5% were male. No behavioral benefits were observed on NPI

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Fig. 3. Global change outcomes in AD patients in cholinesterase inhibitors and memantine trials based on CIBIC-plus improvement versus no change or worsening compared to baseline by drug and dose. 330 331 332

scale, except for −2.72 (95% CI −4.92 to −0.52) in the 10 mg daily donepezil group and −1.72 (95% CI −3.12 to −0.33) for 24 mg daily galantamine trial

(Fig. 4). There was larger heterogeneity (I2 = 75%) among pooled memantine studies. Funnel plots of outcome scores indicated one donepezil trial [12] with

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Fig. 4. Behavior outcomes on the NPI scale (change from baseline) in AD patients in cholinesterase inhibitors and memantine trials by drug and dose.

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Functional outcome

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For functional outcome, 12 studies measured and reported the mean change in ADCS/ADL score from baseline to endpoint for intervention compared with placebo: three on donepezil [12, 13, 18]; one on rivastigmine [28]; three on galantamine [22–24]; and five on memantine [29, 31–34]. Five of these studies included participants with mild to moderate dementia, but one galantamine trial, three donepezil trials, and three memantine trials included patients with severe dementia, who were more likely older and female than patients in other included trials. Across the studies, the average of participants was 76.2 years, and 33.5% were male. Only 5 mg daily donepezil (WMD 1.00, 95% CI −0.53 to 2.53) had no effect on the function out-

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regard to retrieval bias. Furthermore, we detected the significant effects on donepezil 10 mg (WMD −4.86, 95% CI −7.57 to −2.15) (I2 = 0%) in the sensitivity analysis that excluded the studies with regard to retrieval bias.

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come (Fig. 5). The pooled weighted mean difference in change between intervention and placebo with mild to moderate dementia participants was 1.80 (95% CI 0.20 to 3.40) for 12 mg daily rivastigmine trial, 0.68 (95% CI 0.04 to 1.32) for 24 mg daily galantamine group. The effect of donepezil 10 mg (1.03 [95% CI 0.21 to 1.85]) and memantine 20 mg (1.02 [95% CI 0.27 to 1.78]) on ADCS/ADL is statistically significant. The heterogeneity among most pooled studies was mild (0%). However, larger heterogeneity (I2 = 84%) was gained from the 24 mg daily galantamine pooled studies. We conducted sensitivity analysis that excluded the studies with in which the participants with severe dementia, and detected the more significant effects (WMD 1.85, 95% CI 0.93 to 2.77) on 24 mg daily galantamine with a mild heterogeneity (0%). Safety and tolerability RRs for dropouts from the trials for any reason were significantly greater in patients treated with 12 mg daily rivastigmine (1.90 [95% CI 1.50 to 2.41]) and

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32 mg daily galantamine (1.87 [95% CI 1.24 to 2.81]) than with placebo. Pooled proportions of patients withdrawing were 21.6% versus 11.4% for 12 mg daily rivastigmine, 25.2% versus 13.5% for 32 mg daily galantamine. All cause withdrawals were not higher with 24 mg daily galantamine (1.24 [95% CI 1.03 to 1.50]) and 10 mg daily donepezil group (1.31 [95% CI 1.12 to 1.53]). Pooled dropouts were 20.4% versus 16.4% for 24 mg daily galantamine, 25.9% versus 19.7% for 10 mg daily donepezil. However, subjects with donepezil 5 mg daily (0.91 [95% CI 0.71 to 1.17]) and memantine 20 mg daily (RR 0.89, 95% CI 0.75 to 1.05) did not significantly increase the risk on allcause dropouts compared to those with placebo. The

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Fig. 5. Functional outcomes on the ADCS/ADL subscale (change from baseline) in AD patients in cholinesterase inhibitors and memantine trials by drug and dose.

pooled discontinuation of are 14.1% versus 19.9% for 5 mg daily donepezil and 18.0% versus 21.2% for memantine. Heterogeneity was moderate for analysis of memantine (I2 = 55%), low (I2 = 0%) for analysis of 24 mg daily galantamine and donepezil, but large (I2 = 69%) for analysis of 12 mg daily rivastigmine (Fig. 6). Trial sequential analysis showed that the heterogeneity adjusted required information size was 1,444 patients in donepezil 10 mg trials at a relative risk reduction of low bias trials, and the cumulative Z curve crossed ␣-spending monitoring boundary (trial sequential analysis adjusted 95% CI 1.11 to 1.55) (Supplementary Fig. 6). However, trial sequential analysis

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Fig. 6. Safety outcomes comparison on any reason caused dropouts in cholinesterase inhibitors and memantine trials by drug and dose.

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Fig. 7. Safety outcomes comparison on adverse events caused dropouts in cholinesterase inhibitors and memantine trials by drug and dose.

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The use of cholinesterase inhibitors for AD is based on the cholinergic hypothesis of memory impairment [35], which implies that cholinergic deficits are responsible for cognitive and behavioral changes in patients with dementia and age-related memory impairment and, further, that pharmacologic augmentation of central cholinergic function will improve cognitive function [36]. On the other hand, memantine was approved by the FDA in late 2003 for moderate to severe AD. As a moderate-affinity, uncompetitive NMDA receptor antagonist, it may protect against overstimulation of NMDA receptors that may occur in AD as well as consequent glutamate- and calciummediated neurotoxicity. We have obtained the treatment effects of 11,024 patients with AD from 23 trials. Meta-analyses of these placebo-controlled trials show the drugs’ benefits for stabilizing or slowing decline in cognition, function, behavior, and clinical global change of patients with AD. The trials included patients with AD in progressive different stages of severity failed to address whether particular subgroups of patients might have benefited. Cognitive effects were significant for all drugs with mild heterogeneity. And the worsening in the placebo group rather than improvement in the drug groups contributes largely to the significant differences between drug and placebo on ADAS-cog. All drugs were associated with a significant likelihood for improved versus no change or worsened with the CIBIC-plus except the pool analysis of memantine and 32 mg daily galantamine trials. We may notice the apparent disconnection between the relatively marked positive effects of galantamine 32 mg on ADAS-Cog and the lack of efficacy on CIBIC-Plus. The pooled analysis is based on the same study [25]. The clinical benefits of galantamine were seen with measures of cognitive function on the ADAS-Cog, which was an exploratory analysis. However, the global assessment provided by the CIBIC-Plus is one way of measuring the clinical relevance of any improvements in cognitive function. Moreover, the significant effects on donepezil 5 mg, donepezil 10 mg, and rivastigmine 12 mg were confirmed in trial sequential analysis. However, the significant heterogeneity among the 5 mg daily donepezil groups may derived from the different stages of severity in each study. No behavioral benefits were observed, except for the 10 mg daily donepezil group and 24 mg daily galantamine trial. We got some surprising results on NPI. Three studies [12, 29, 30] found that the placebo improvement

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showed that only 994 of the heterogeneity adjusted required information size of 1,560 patients was accrued in 24 mg daily galantamine trials and the cumulative Z curve did not cross ␣-spending monitoring boundary (trial sequential analysis adjusted 95% CI 0.98 to 1.59), suggesting that a relative risk reduction of 30% or greater could not be detected here (Supplementary Fig. 7). The pooled RRs of withdrawals because of adverse events were significantly greater in patients treated with 10 mg daily donepezil group (1.83 [95% CI 1.44 to 2.33]), 12 mg daily rivastigmine (2.00 [95% CI 1.46 to 2.76]), and 32 mg daily galantamine (3.49 [95% CI 2.25 to 5.42]) than with placebo (Fig. 7). Pooled proportions of patients withdrawing were 15.3% versus 8.4% for 10 mg daily donepezil, 13.4% versus 6.7% for 12 mg daily rivastigmine, and 23.8% versus 7.1% for 32 mg daily galantamine. Similarly, there was no significant difference on adverse events caused dropouts between subjects with donepezil 5 mg (0.86 [95% CI 0.58 to 1.28]), 24 mg daily galantamine (1.31 [95% CI 1.00 to 1.70]), and memantine (1.24 [95% CI 0.95 to 1.62]). Pooled dropouts were 10.9% versus 8.3% for 24 mg daily galantamine, 10.0% versus 8.4% for memantine, and 7.8% versus 9.1% for 5 mg daily donepezil. Heterogeneity was low (I2 = 0%) for analysis of 24 mg daily galantamine and donepezil, but significant (I2 = 55%–77%) for analysis of 12 mg daily rivastigmine and 32 mg daily galantamine and memantine trials. Trial sequential analysis showed that the heterogeneity adjusted required information size was 3,290 patients in donepezil 10 mg trials at a relative risk reduction of low bias trials, and the cumulative Z curve crossed ␣-spending monitoring boundary (trial sequential analysis adjusted 95% CI 1.33 to 2.51) (Supplementary Fig. 8). However, trial sequential analysis showed that the information fraction of 12 mg daily rivastigmine and 32 mg daily galantamine trials was too small to produce inner wedge futility area. Across all included studies, the most frequently reported adverse events were gastrointestinal adverse events, including nausea, vomiting, diarrhea, and anorexia. Significant risks were reported for the following adverse events: dizziness and headache on 5 mg daily donepezil; nausea, vomiting, diarrhea, and anorexia on 10 mg daily donepezil; nausea, vomiting, diarrhea, anorexia, and dizziness on galantamine; and nausea, vomiting, diarrhea, anorexia, dizziness, and headache on rivastigmine. Memantine was not associated with increased risks for the adverse events reported (Table 2).

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Table 2 Risk ratios (RR) by meta-analysis and pooled occurrence of adverse effects in cholinesterase inhibitor or memantine trials compared with placebo Nausea

Donepezil 5 mg Donepezil 10 mg Galantamine 24 mg Galantamine 32 mg Rivastigmine 12 mg Memantine 20 mg

RR (95%CI) Pooled frequency (%) versus placebo RR (95%CI) Pooled frequency (%) versus placebo RR (95%CI) Pooled frequency (%) versus placebo RR (95%CI) Pooled frequency (%) versus placebo RR (95%CI) Pooled frequency (%) versus placebo RR (95%CI) Pooled frequency (%) versus placebo

RR, Risk ratios;. . . Not available.

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1.21 [0.73, 2.01] 5.5% versus 4.6% 3.02 [2.19, 4.15] 12.5% versus 4.2% 2.95 [2.23, 3.92] 18.2% versus 6.0% 3.30 [2.22, 4.90] 39.9% versus 12.1% 4.29 [3.37, 5.44] 39.1% versus 9.0% 0.37 [0.12, 1.15] 2.2% versus 5.9%

Vomiting

Diarrhea

Anorexia

Dizziness

Headache

1.11 [0.64, 1.93] 3.8% versus 3.4% 2.55 [1.82,3.56] 11.6% versus 4.6% 2.60 [1.88, 3.60] 13.0% versus 4.8% 4.05 [2.01, 8.19] 17.0% versus 4.2% 5.23 [3.76, 7.28] 26.2% versus 5.0% ... ...

1.77 [1.15, 2.74] 7.9% versus 4.5% 2.65 [1.99, 3.54] 13.7% versus 5.1% 0.83 [0.61, 1.13] 7.3% versus 8.6% 1.79 [1.00, 3.19] 13.3% versus 7.4% 1.83 [1.32, 2.52] 12.3% versus 6.7% 0.88 [0.55, 1.40] 6.1% versus 7.0%

1.72 [0.79, 3.74] 2.6% versus 1.5% 2.91 [1.77, 4.79] 7.2% versus 2.5% 3.45 [2.09, 5.68] 7.2% versus 2.0% 46.36 [2.83, 758.38] 10.6% versus 0.0% 6.70 [3.78, 11.88] 11.5% versus 1.7% ... ...

1.42 [0.82, 2.45] 6.8% versus 4.8% 1.66 [1.11, 2.47] 8.2% versus 5.0% 2.17 [1.17, 4.02] 14.1% versus 3.1% 2.56 [1.27, 5.19] 11.9% versus 4.7% 2.70 [1.91, 3.82] 14.3% versus 5.2% 1.06 [0.71, 1.58] 5.9% versus 5.8%

3.85 [0.44, 34.02] 2.9% versus 0.8% 1.43 [0.88, 2.35] 10.8% versus 7.7% 1.29 [0.80, 2.10] 5.7% versus 4.3% 3.52 [1.56, 7.97] 11.5% versus 3.3% 2.13 [1.53, 2.96] 13.0% versus 6.0% 1.39 [0.86, 2.23] 5.0% versus 4.3%

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Bakchine [29], we still failed to get access to detailed information of other trials [16, 20, 21, 37]. These insufficient data may limit the conclusion of our analysis. In addition, we should consider other factors which may bias our results. Firstly, AD is progressive, and patients declined at progressive different stages of severity. This may influence the results when pooling data. In our analysis, we pooled data from all studies regardless of dementia severity, which may limit our conclusion. Secondly, whether accepted previous drugs treatment may also influence results. For example, some trials excluded the patients receiving a cholinesterase inhibitor before the studies [34], while another study required the patients accepting ongoing cholinesterase inhibitor therapy [33]. Meanwhile, some studies permitted but not required concurrent treatment. We conducted the analysis without considering this factor, potentially biasing our results. Other population inclusion and exclusion criteria such as doses of the drugs, whether have concomitant disease might also limit our conclusion. The implication of these distinctions may be significant, which can be likely reflected by the moderate to high heterogeneity we detected in some meta-analysis. In addition, as all the trials were sponsored by the drugs’ manufacturers, some trials may have been missed. Other trials may have been done but not reported, possibly because they had negative results. These limitations also affect the interpretations. The strengths of this study include the inclusion of primary outcomes which were analyzed by ITT, and the exclusion of biased studies. An Interventionto-treat analysis is often recommended as the least biased way to estimate intervention effects in randomized trial when some outcome data are missing [38]. Moreover, we derive the standard deviation from certain standard errors, confidence intervals, t values, or p values, thus minimizing missing data. In addition, we also conducted trial sequential analyses in which monitoring boundaries are used to determine whether clinical trials could be terminated early when a p value is small enough to detect the expected effect, ultimately defining strength of evidence and information size. Similarly, we assessed quality of the included trials according to the GRADE criteria, and applied GRADE Profiler 3.6 to produce a summary table of outcomes. This study presents some of the challenges in designing clinical trials for AD. To detect clinically meaningful results, therapeutic trials for AD must better account for both clinical presentation and brain lesions. The relatively good safety profile of these medications, along with their efficacy in alleviating

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was greater than drugs. Confounding factors such as concomitant psychotropic medications may provide a plausible explanation to these somewhat unusual results. Only 5 mg daily donepezil had no effect on the function outcome. The pooled mean change from baseline on the ADCS/ADL showed that functional abilities were maintained to a greater extent in patients receiving drugs than in the placebo group. Safety is as important as the efficacy of the interventions in clinical studies. Donepezil 10 mg daily, rivastigmine 12 mg daily, and galantamine 32 mg daily treated patients showed significantly higher risk on dropouts due to any reason or adverse events, compared to the placebo treated patients in meta-analyses; correspondingly, trial sequential analysis also confirmed these effects. Likewise, it prevented the full evaluation on the safety and tolerability that the very few available trials and the limited duration in the trials. Across all included studies, the most frequently reported adverse events were gastrointestinal adverse events, including nausea, vomiting, diarrhea, and anorexia. According to the analysis, the frequency in which these events were reported was generally lowest for donepezil and highest for rivastigmine. So were the overall withdrawal rates and discontinuations for adverse events. Although these data provide a compelling argument in favor of donepezil from the respect of tolerability, the significant heterogeneity must be considered. Mixed factors including different assessment of the adverse events and varied given drugs have great impact on heterogeneity. Many different measurement scales are adopted in assessing outcomes of AD treatment. We focus on four representative measurement scales as the primary measure of cognition, function, behavior, and global assessment of change, respectively. For example, we chose the ADAS-cog as the primary measure of cognition. However, this relatively common scale only used to assess cognition in trials of mild to moderate dementia. The patients with more severe dementia are subject to be assessed by other measurement scales (the SIB). As the number of trials conducted in patients with severe dementia and using this scale were too few, we could not analysis these data. Hence, we limited our analysis to population with mild to moderate dementia by excluding studies that did not adopt predefined outcome measures. In addition, some detailed data (e.g., SD) were not reported in some publications, which were also very crucial for our analysis. We tried to contact with the corresponding authors of the trials to seek potential collaboration with their research group. Although we got valuable data from the Prof. S.

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ACKNOWLEDGMENTS

We thank Prof. S. Bakchine for providing their memantine trial data. This work was supported by grants from the National Natural Science Foundation of China (81000544, 81171209, 81371406) and Shandong Provincial Natural Science Foundation, China (ZR2010HQ004, ZR2011HZ001). Authors’ disclosures available online (http://www.jalz.com/disclosures/view.php?id=2152).

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Supplementary figures are available in the electronic version of this article: http://dx.doi.org/10.3233/JAD132690. [15]

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symptoms, is supported by these short-term, randomized, placebo-controlled trials. However, the 6-month duration of the trials are of limited value in assessing the real-world clinical and economic impact of AD therapies, and long-term trials would be more likely to provide complementary information to results from short-term clinical trials and more accurately assess practical long-term benefits, risks, costs, and effects on clinically meaningful end points. Furthermore, trials need to be designed to assess individual patients’ responses as primary clinical outcomes and not to rely on mean differences in scores between groups. Results of clinical trials on marketed drugs should be rapidly disseminated irrespective of outcome to support fully informed and evidence-based practice. Available evidence indicates that cholinesterase inhibitors and memantine are able to stabilize or slow decline in cognition and function. Cholinesterase inhibitors show the modest overall benefits for slowing decline in behavior and clinical global change of patients with AD. Compared with placebo, more dropouts and adverse events occurred with the cholinesterase inhibitors, but not with memantine, which may represent good safety profile of memantine with greater tolerability.

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Efficacy and safety of donepezil, galantamine, rivastigmine, and memantine for the treatment of Alzheimer's disease: a systematic review and meta-analysis.

The role of currently available drugs for Alzheimer's disease (AD) has been controversial, with some national formularies restricting their use, and h...
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