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Journal of Alzheimer’s Disease xx (20xx) x–xx 1

DOI 10.3233/JAD-190546
IOS Press

1 Efficacy and Safety of Cholinesterase


2 Inhibitors for Mild Cognitive Impairment:
A Systematic Review and Meta-Analysis

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3

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4 Shinji Matsunagaa,∗ , Hiroshige Fujishirob and Hajime Takechia
5
a Department of Geriatrics and Cognitive Disorders, Fujita Health University School of Medicine, Kutsukake,
Toyoake, Aichi, Japan

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6

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b Department of Psychiatry, Kawasaki Memorial Hospital, Miyamae, Kawasaki, Kanagawa, Japan

Accepted 9 July 2019

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8 Abstract.
9 Background: The clinical benefit of cholinesterase inhibitors (ChEIs) for mild cognitive impairment (MCI) remains incon-
10 clusive.
Objective: We performed a systematic review and meta-analysis of the efficacy/safety of ChEIs on subjects with MCI.
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12 Methods: We included randomized controlled trials (RCTs) of ChEIs in subjects with MCI, using cognitive function scores
13 as a primary outcome measure.
14 Results: Fourteen RCTs (six using donepezil, four using galantamine, and four using rivastigmine) with 5,278 subjects were
15 included. We found no significant difference in cognitive function scores between the ChEIs and placebo groups [standardized
16 mean difference (SMD) = –0.06, p = 0.38, I2 = 76%]. However, in the secondary outcomes, ChEIs were associated with a lower
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17 incidence of progression to dementia compared with placebo (risk ratio = 0.76, the number needed to treat = 20). For safety
18 outcomes, ChEIs were associated with a lower prevalence of fall than placebo. On the other hand, compared with placebo,
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19 ChEIs were associated with a higher incidence of discontinuation due to all causes, discontinuation due to adverse events,
20 at least one adverse event, abnormal dreams, diarrhea, dizziness, headache, insomnia, loose stools, muscle cramps, nausea,
21 vomiting, and weight loss.
22 Conclusions: Although ChEIs have a slight efficacy in the treatment of MCI, there are many safety issues. Therefore, ChEIs
23 are difficult to recommend for MCI. However, the efficacy and safety of ChEIs on MCI with a biomarker-based diagnosis is
unclear. Further RCTs are needed to confirm the efficacy and safety of ChEIs when used for individual neuropathological
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24

25 classifications of MCI.

26 Keywords: Cholinesterase inhibitors, donepezil, galantamine, meta-analysis, mild cognitive impairment, rivastigmine
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27 INTRODUCTION incidence per 1,000 person-years were 22.5 for ages 32

75–79 years, 40.9 for ages 80–84 years, and 60.1 33


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28 Mild cognitive impairment (MCI) describes older for ages 85+ years [2]. Individuals with MCI have 34

29 subjects with a small demonstrable loss of cognitive an increased risk of developing Alzheimer’s disease 35

30 ability who have not yet crossed the threshold for (AD) or other dementia, which has long made the 36

31 dementia [1]. Recent meta-analysis estimates of MCI development of effective treatments for MCI a critical 37

issue [1, 2]. 38


∗ Correspondence to: Shinji Matsunaga, Department of Geri- Cholinesterase inhibitors (ChEIs), including 39
atrics and Cognitive Disorders, Fujita Health University School of
Medicine, 1-98 Dengakugakubo, Kutsukake-cho, Toyoake, Aichi
donepezil, galantamine, and rivastigmine, are cur- 40

470-1192, Japan. Tel.: +81 562 93 9083; Fax: +81 562 93 9021; rently approved treatments for AD, and indeed, the 41

E-mail: shinji@fujita-hu.ac.jp. efficacy of these medications on the progression of 42

ISSN 1387-2877/19/$35.00 © 2019 – IOS Press and the authors. All rights reserved
2 S. Matsunaga / Cholinesterase Inhibitors for MCI

43 mild and moderate AD has been well established [3]. the International Clinical Trials Registry Platform 91

44 Furthermore, recent meta-analyses have suggested (http://www.who.int/ictrp/en/) websites to ensure 92

45 that ChEIs also alleviate cognitive impairment comprehensive inclusion of RCTs and to minimize 93

46 against Lewy body disease and vascular cognitive the possibility of publication bias. They indepen- 94

47 impairment [4, 5]. On the other hand, the efficacy dently assessed the inclusion/exclusion criteria and 95

48 of ChEIs for MCI has not been shown. Previous selected the relevant studies. References to included 96

49 meta-analyses suggested that ChEIs had minimal articles and reviews were also searched for citations 97

50 impact on the progression to dementia and no impact of additional relevant published and unpublished 98

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51 on cognitive function scores for MCI, even while studies, including conference abstracts. 99

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52 producing a higher frequency of adverse events [6,
53 7]. However, the results of previous meta-analyses Data synthesis and outcome measures 100

54 regarding MCI may have been affected by small


55 sample sizes. The rate of conversion from MCI to The primary outcome was the change in cog- 101

56 dementia is about 10% each year, and the pace of nitive function scores from baseline to the last 102

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57 cognitive decline for individuals with MCI is slow available follow-up. Cognitive function scores were 103

58 [8], so larger sample sizes are needed to determine derived from the Alzheimer’s Disease Assessment 104

59 the overall net benefits of ChEIs. Therefore, we Scale-cognitive subscale (ADAS-cog) [10], the Mini- 105

60 conducted an updated systematic review and meta- Mental State Examination (MMSE) [11], and the 106

Montreal Cognitive Assessment (MoCA) [12]. The

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61 analysis to achieve more robust evidence regarding 107

62 the consequences of using ChEIs to treat MCI. following secondary outcomes were also assessed: 108

progression to dementia, Clinical Dementia Rating 109

63 MATERIALS AND METHODS Sum of Boxes (CDR-SB) [13], global scores [Clin- 110

ical Dementia Rating (CDR) [13], clinical global 111


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64 This systematic review and meta-analysis was impression change (CGI-C) and CGI-C MCI version 112

65 performed according to the Preferred Report- [14, 15], activities of daily living [the Alzheimer’s 113

66 ing Items for Systematic Reviews and Meta- Disease Cooperative Study-Activities of Daily Liv- 114

67 Analyses guidelines (PRISMA checklist, Supple- ing (ADCS-ADL) and ADCS-ADL MCI version 115

68 mentary Material) [9] and was registered with [16], the Neuropsychiatric Inventory 12 (NPI12) [17], 116

the Symbol Digit Modalities Test (SDMT) [18],


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69 the International Prospective Register of System- 117

70 atic Reviews (PROSPERO, available in the public the Digit Span Backwards Test (DSBT) [19], and 118

the Global Deterioration Scale (GDS) [20]. Also


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71 domain at http://www.crd.york.ac.uk/PROSPERO/. 119

72 CRD42019126818). included were data on the discontinuation due to 120

all causes, discontinuation due to adverse events, 121

73 Search strategy and inclusion criteria and the incidence of individual adverse events. The 122

methodologic quality of each trial we selected for 123


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74 We included only RCTs on the ChEIs treatment inclusion was assessed according to the risk-of-bias 124

75 of subjects with MCI. To identify the relevant criteria in the Cochrane Handbook for Systematic 125

76 studies, two authors (S.M. and H.T.) independently Reviews of Interventions (version 5.2.0; Cochrane 126

77 searched the MEDLINE, Cochrane Library, and Collaboration, available in the public domain at 127
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78 Scopus databases, without language restrictions, http://training.cochrane.org/handbook). 128

79 from the date of these databases’ inception to


80 April 16, 2019, using the following search strategy: Data extraction 129

81 (“cognitive dysfunction” [Mesh] OR “mild cognitive


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82 impairment” OR “MCI”) AND (“cholinesterase Two authors (S.M. and H.T.) independently 130

83 Inhibitors” [Mesh] OR “cholinesterase Inhibitors” extracted data from the included studies. Where 131

84 OR “donepezil” [Mesh] OR “donepezil” OR possible, an intention-to-treat or a full analysis set 132

85 “E2020” OR “Rivastigmine” [Mesh] OR “Rivastig- population was used. When such data were unavail- 133

86 mine” OR “ENA713” OR “Galantamine” [Mesh] able, the per-protocol analysis results were extracted 134

87 OR “Galantamine”) AND (“randomized” OR from each study. When data required for the meta- 135

88 “randomly” OR “random”). They also searched analysis were missing, investigators or the pharma 136

89 ClinicalTrials.gov (http://clinicaltrials.gov/), the sponsors of the relevant research were contacted and 137

90 ISRCTN registry (https://www.isrctn.com/), and asked to provide unpublished data. 138


S. Matsunaga / Cholinesterase Inhibitors for MCI 3

139 Meta-analysis methods cates, 365 were excluded after a review of the abstract 187

or title, and 15 were excluded after a review of the 188

140 The meta-analysis was conducted using the full text (one non-RCT, ten review articles, and four 189

141 Review Manager software (version 5.3 for Win- same studies that were included in our meta-analysis). 190

142 dows; Cochrane Collaboration, available in the public In the hand search, we added one RCT [22] from 191

143 domain at http://tech.cochrane.org/revman). A ran- the review article [6]. No further studies were added 192

144 dom effects model was selected for this meta-analysis from the clinical trials registration. In the end, thirteen 193

145 because of its potential heterogeneity across studies. studies, which included 14 RCTs that tested ChEIs 194

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146 Dichotomous outcomes were presented as risk ratios for MCI, were accepted for the current meta-analysis 195

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147 (RRs) with 95% confidence intervals (CIs). When the [15, 22–33] (Supplementary Figure 1). 196

148 random effects model showed significant differences The characteristics of the included trials are shown 197

149 between groups, the number needed to treat (or harm) in Table 1. Six studies assessed the effects of 198

150 (NNT or NNH) was calculated. The NNT (or NNH) donepezil on MCI [15, 23–27]), four studies assessed 199

151 values were derived from the risk difference (RD) the effect of galantamine on MCI [28–30], and four 200

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152 using the following formula: NNT (or NNH) = 1/RD. studies assessed the effect of rivastigmine on MCI 201

153 For continuous data, we used the mean differences [22, 31–33]. All studies were double-blind RCTs. 202

154 (MD) and 95% CIs when data that were measured The mean duration of the included studies was 67.9 203

155 using the same scale were being combined. To com- weeks, and the mean patient age was 70.3 years. Two 204

bine the data measured using different scales, we used

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156 studies were supported by funding from Eisai and 205

157 the standardized mean difference (SMD), combining Pfizer [15, 24], one study was supported by fund- 206

158 effect size (Hedges’ g) data, and 95% CIs. Lower ing from Eisai, Teaneck NJ, and Pfizer [27], one 207

159 MMSE, MoCA, ADCS-ADL, SDMT, and DSBT study was supported by funding from Eisai [25], one 208

160 scores indicated more impairment or more severe study was supported by funding from Pfizer [26], one 209
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161 symptoms, and therefore, the algebraic sign of the study was supported by funding from Janssen [28], 210

162 numerical scores was reversed for these scales. Study two studies were supported by funding from Janssen 211

163 heterogeneity was assessed using the I2 statistic, with and Johnson & Johnson [30], and four studies were 212

164 I2 ≥ 50% reflecting considerable heterogeneity [21]. supported by funding from Novartis [22, 31–33]. 213

165 In cases with I2 ≥ 50% for the primary outcome The methodologic quality of the included studies 214

measure, we conducted sensitivity analyses to deter- was evaluated according to the Cochrane risk-of-bias
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166 215

167 mine the reasons for heterogeneity. We examined criteria (Supplementary Figure 2). Six studies did not 216

the following confounding factors: neuropathologi-


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168 mention the randomization method [23, 25, 27–29, 217

169 cal classification, sponsorship, study duration (102 31]. Six studies did not mention the method of allo- 218

170 weeks ≤ or 102 weeks>), and type of drug. A meta- cation concealment [23, 25, 27–29, 31]. Six studies 219

171 regression analysis was performed to evaluate the did not mention the method of blinding [15, 27, 28, 220

172 association between the results of the meta-analysis 30, 31]. Two studies did not mention how to address 221
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173 on cognitive function scores and specific modulators incomplete outcome data [28, 31]. One study did not 222

174 (patient age and study duration) using the Compre- report some of the preplanned outcomes [23]. 223

175 hensive Meta-Analysis software, version 3 (Biostat,


176 Inc., Englewood, NJ, USA). We also performed sub- Results of the meta-analysis 224
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177 group analyses to examine the efficacy and safety of


178 individual ChEIs. Funnel plots were examined visu- Efficacy outcomes 225

179 ally to assess publication bias in primary outcomes No significant difference between the ChEIs and 226

180 when ≥ 10 studies were included [21]. In addition, placebo groups were found regarding cognitive func- 227
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181 Egger’s regression test was used to detect publication tion scores (SMD = –0.06, 95% CI = –0.20–0.08, 228

182 bias in meta-analyses. p = 0.38, I2 = 76%; N = 10, n = 4,632; Fig. 1). Regard- 229

ing the individual ChEIs, donepezil significantly 230

183 RESULTS improved cognitive function scores compared with 231

placebo (SMD, –0.16; 95% CI, –0.28 to –0.04; 232

184 Study characteristics p = 0.009, I2 = 21%; N = 5, n = 1,637). In contrast, 233

galantamine and rivastigmine produced no significant 234

185 Of the 576 articles obtained from our literature differences in the cognitive function scores compared 235

186 search, 184 were excluded because they were dupli- with placebo. The data for cognitive function scores 236
Table 1

4
Characteristics of included randomized controlled trials
Study, country, Total Methods Patients Intervention, n Age Male Baseline MMSE Main outcomes
sponsorship n (1) Study design (1) Diagnosis dose (mg/day) (mean ± SD), y (%) (mean ± SD)
(2) Duration (2) Inclusion
(3) Analyzed criteria
population
Devanand 2018 61 (1) DBRCT (1) MCI, ADNI DON, 5–10 mg 30 67.1 ± 7.7 46.7 27.5 ± 2.2 ADAS-cog, BDI-II,
[23], USA, (2) 62 weeks criteria BNT-15, FAQ, HAM-D,
non-industry (3) ITT (2) age 55–95, LAN, SCWT, SRT,
PLA 31 72.4 ± 8.9 51.6 28.1 ± 1.7
CDR = 0.5, TMT-A, TMT-B,
MMSE ≥ 21, WAIS-III (BD),

Un HAM-D ≥ 14,
major depression
or dysthymic
WAIS-III (DS),
WMS-III (VR), AEs

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S. Matsunaga / Cholinesterase Inhibitors for MCI


disorder
(DSM-IV)

Doody 2009 [24],


USA, industry
821 (1) DBRCT
(2) 48 weeks
(3) ITT rre (1) MCI, Petersen
criteria
(2) age 45–90,
DON, 10 mg
PLA
409
412
70.2 ± 9.7
69.8 ± 10.3
51.7
57.4
27.5 ± 1.9
27.4 ± 1.9
ADAS-cog, CDR-SB,
CGIC-MCI, DSB,
MMSE, NPI, PDQ,

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CDR = 0.5,
MMSE 24–28
PDQ-R, PGA, SDMT,
AEs

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Dubois 2015 [25], 216 (1) DBRCT (1) MCI, NR DON, 10 mg 113 74.1 ± 6.4 47.8 26.1 ± 2.2 ADAS-cog-MCI, BT,
France, industry (2) 52 weeks (2) age ≥ 50, CVLT IVLFT, MMSE,
PLA 103 73.7 ± 6.6 47.6 25.8 ± 2.6

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(3) ITT CDR = 0.5 MRI, TMT-A, TMT-B,
AEs

73.5 ± 5.7 27.4 ± 2.2

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Montero-Odasso 60 (1) DBRCT (1) MCI, Petersen DON, 10 mg 31 52 BNT, DSB, DSF, DTC,
2018 [26], (2) 26 weeks criteria PLA 29 77.2 ± 8.1 59 27.5 ± 1.7 GS, GV, LNS, MMSE,
Canada, industry (3) ITT (2) age ≥ 65, MoCA, RAVLT,
CDR = 0.5 TMT-A, TMT-B, AEs

Petersen 2005
[15], USA and
512 (1) DBRCT
(2) 156 weeks
(1) MCI, Petersen
criteria
DON, 10 mg
PLA
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259
73.1 ± 7.1
72.9 ± 7.6
56
53
27.3 ± 1.8
27.4 ± 1.8
ADAS-cog, ADCS-
ADL-MCI, BNT, CDR,

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Canada, industry (3) ITT (2) age 55–90, CDR-SB, CDT, CFT,
CDR = 0.5, DSB, GDS, MMSE,
MMSE 24–30 MTT, NC, NYUPR,
SDMT, AEs

Salloway 2004
[27], USA,
industry
270 (1) DBRCT
(2) 24 weeks
(3) ITT
(1) MCI, NR
(2) age 55–90,
CDR = 0.5,
MMSE ≥ 24
DON, 10 mg
PLA
133
137
72.1 ± 8.0
72.7 ± 8.0
57.6
57.7
27.5 ± 2.2
27.4 ± 2.0 f ADAS-cog, BNT,
CGIC-MCI, DSB, MT,
NC, NYUPDR,
NYUPIR, PGA, SDMT,
VF, AEs
Koontz 2005 [28], 19 (1) DBRCT (1) MCI, Petersen GAL, 24 mg 8 71 ± 9.3 100 NR CANTAB, CVLT, FAQ,
USA, industry (2) 16 weeks criteria PLA 11 AEs
(3) NR (2) MMSE ≥ 26

Peters 2012 [29], 154 (1) DBRCT (1) MCI, NR GAL, 16 mg 75 67.9 ± 8.3 NR 27.4 ± 2.2 ADAS-cog, CDT,

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Germany, (2) 104 weeks (2) CDR = 0.5 PLA 79 67.2 ± 7.6 26.9 ± 2.1 CERAD, TMT-A,
non-industry (3) ITT TMT-B, AEs

69.2 ± 9.1

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Winblad 2008 995 (1) DBRCT (1) MCI, NR GAL, 16–24 mg 497 48 NR ADAS-cog-MCI, ADCS-

S. Matsunaga / Cholinesterase Inhibitors for MCI


study 1 [30], (2) 104 weeks (2) age ≥ 50, PLA 498 70.1 ± 9.1 45 NR ADL-MCI, CDR,
USA and (3) ITT CDR = 0.5 CDR-SB, DSST, AEs

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Canada, industry

Winblad 2008 1062 (1) DBRCT (1) MCI, NR GAL, 16–24 mg 532 70.6 ± 8.7 45 NR ADAS-cog-MCI, ADCS-

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study 2 [30], (2) 104 weeks (2) age ≥ 50, PLA 530 70.9 ± 8.7 41 NR ADL-MCI, CDR,
USA and (3) ITT CDR = 0.5 CDR-SB, DSST, AEs
Canada, industry

Bokde 2016 [31],


Germany,
industry

Feldman 2007
12

1018
(1) DBRCT
(2) 12 weeks
(3) NR

(1) DBRCT
(2) NR d
(1) MCI, Petersen
criteria

(1) MCI, NR
RIV, 9 mg
PLA

RIV, 3–12 mgAu


8
4

508
68 ± 8.5
50 ± 2.6

70.3 ± 7.4
60
100

46.9
25.2 ± 3.6

27.0 ± 2.6
CERAD, MRI

ADAS-cog, ADCS-ADL,
[32], multiple
countries,
industry
(2) 208 weeks
(3) ITT
(2) age 55–85,
CDR = 0.5
PLA

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510 70.6 ± 7.6 48.6 26.9 ± 2.8
BDI, BFCSR, CDR,
CDT, DCT, DWLR,
GDS, LNS, MMSE,

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MRI, MT, NPI,
NYUPR, QOL, SDMT,
VF, AEs

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Table 1
(Continued)
Study, country, Total Methods Patients Intervention, n Age Male Baseline MMSE Main outcomes
sponsorship n (1) Study design (1) Diagnosis dose (mg/day) (mean ± SD), y (%) (mean ± SD)
(2) Duration (2) Inclusion criteria
(3) Analyzed
population
62.6 ± 10.1

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Mamikonyan 28 DBRCT (cross over) (1) MCI, Winblad RIV-P, 4.6–9.5 mg 14 71.4 NR CGIC, ECB, DRS-2,
2015 [33], USA, (2) 10 weeks (3) ITT criteria PLA 14 66.1 ± 5.5 85.7 GDSy, GDS-15,
industry (2) age 40–85, MoCA, NCTS, PDAQ,
CDR = 0.5, PD for PDQ-8, PPS, STAI

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S. Matsunaga / Cholinesterase Inhibitors for MCI


more than 2 years (anxiety subscale),
UPDRS-III, AEs

Narasimhalu 2010 50
[22], Singapore,
industry
(1) DBRCT
(2) 24 weeks
(3) ITT rre (1) MCI, NR
(2) age 55–85
RIV, 3-9mg
PLA
25
25
68.1 ± 6.8
69.4 ± 9.1
20
48
23.7 ± 3.4
23.9 ± 3.2
ADAS-cog, ADCS-
ADL-MCI, CB, CDT,
CTT, FAB, GD,

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ADAS-cog, Alzheimer’s Disease Assessment Scale-cognitive subscale; ADAS-cog-MCI, Alzheimer’s Disease Assessment Scale-cognitive subscale, Mild Cognitive Impairment version; ADCS-

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ADL-MCI, Alzheimer’s Disease Cooperative Study Activities of Daily Living scale Mild Cognitive Impairment version; ADNI, Alzheimer’s Disease Neuroimaging Initiative; AEs, adverse
events; BDI, Beck depression inventory; BFCSR, Buschke free and cued selective reminding test; BNT(-15), Boston Naming Test (15-item); BT, Benton Test; CANTAB, Cambridge Automated

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Neuropsychiatric Test Assessment Battery; CB, Cognitive Battery; CDR, Clinical Dementia Rating; CDR-SB, Clinical Dementia Rating Sum of Boxes; CDT, clock-drawing test; CERAD,
Consortium to Establish a Registry for Alzheimer’s Disease test; CFT, category-fluency test; CGIC(-MCI), Clinical Global Impression of Change(-Mild Cognitive Impairment); CVLT, California
Verbal Learning Test; DBRCT, double-blind randomized controlled trial; DCT, digit cancellation task; DON, donepezil; DRS-2, Dementia Rating Scale-2; DSB, Digit Span Backwards test; DSF,

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Digit Span Forward test; DSM-IV, Diagnostic and Statistical Manual of Mental Disorders Fourth Edition; DSST, Digit Symbol Substitution Test; DTC, dual-task gait cost; DWLR, delayed word
list recall; ECB, Everyday Cognition Battery; FAB, Frontal Assessment Battery; FAQ, Pfeffer Functional Activities Questionnaire; GAL, galantamine; GD, Geriatric Depression Scale; GDS,
Global Deterioration Scale; GDSy, Gordon Diagnostics System; GDS-15, 15-item Geriatric Depression Scale; GS, gait speed; CTT, Color Trails Test; GV, gait variability; HAM-D, Hamilton

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Rating Scale for Depression; ITT, intention to treat; IVLFT, Isaacs verbal fluency and lexical fluency test; LAN, letter and animal naming; LNS, letter–number sequence; MCI, mild cognitive
impairment; MMSE, Mini-Mental State Examination; MoCA, Montreal Cognitive Assessment; MRI, magnetic resonance imaging; MT, Maze test; MTT, maze-tracing task; n, number of patients;
NC, number-cancellation test; NCTS, Neurotrax Comprehensive Testing Suite; NPI, Neuropsychiatric Inventory; NR, not reported; NYUPDR, New York University paragraph test delayed recall;

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NYUPIR, New York University paragraph test immediate recall; NYUPR, New York University paragraph-recall test; PD, Parkinson’s disease; PDAQ, Penn Daily Activities Questionnaire; PDQ,
Perceived Deficits Questionnaire; PDQ-R, Perceived Deficits Questionnaire for Relatives; PDQ-8, Parkinson’s Disease Questionnaire-8; PGA, Patient Global Assessment; PLA, placebo; PPS,
Parkinson Psychosis Scale; QOL, quality of life; RAVLT, Rey Auditory Verbal Learning Test; RIV, rivastigmine; RIV-P, rivastigmine patch; SCWT, Stroop Color and Word Test; SD, standard

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deviation; SDMT, Symbol Digit Modalities Test; SRT, Selective Reminding Test; STAI, State Trait Anxiety Inventory; TMT, Trail Making Test; UPDRS, Unified Parkinson’s Disease Rating Scale;
VF, Verbal Fluency test; WAIS-III (BD), Wechsler Adult Intelligence Scale-Third Edition Block Design Subtest; WAIS-III (DS), Wechsler Adult Intelligence Scale-Third Edition Digit Symbol
Subtest; WMS-R, Wechsler Memory Scale Revised; WMS-III (VR), Wechsler Memory Scale-Third Edition Visual Reproduction Subtest.
S. Matsunaga / Cholinesterase Inhibitors for MCI 7

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Fig. 1. Forest plot of cognitive function scores.

Table 2
Sensitivity analysis (cholinesterase inhibitors for cognitive function scores)
I2
Subgroup N n
Au SMD [95% CIs] p Test for subgroup
differences
Neuropathological Parkinson disease 1 27 na –0.66 [–1.44, 0.12] 0.10 p = 0.13, I2 = 56.3%
classification No classification 9 4605 77 –0.05 [–0.19, 0.09] 0.51
Sponsorship Industry 9 4571 78% –0.06 [–0.21, 0.09] 0.42 p = 0.89, I2 = 0%
Non-industry 1 61 na –0.10 [–0.60, 0.40] 0.70
Study duration Long study duration (102 weeks≤) 4 3431 0 –0.03 [–0.09, 0.04] 0.41 p = 0.90, I2 = 0%
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Short study duration (102 weeks>) 6 1207 85 –0.05 [–0.45, 0.34] 0.79
Type of drug Donepezil 5 1637 21% –0.16 [–0.28, –0.04] 0.009 p = 0.20, I2 = 38.4%
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Galantamine 2 1901 9% –0.03 [–0.12, 0.06] 0.53


Rivastigmine 3 1094 92% 0.31 [–0.74, 1.36] 0.57
CIs, confidence intervals: N, number of studies: n, number of patients: na, not applicable: SMD, standardized mean difference.

237 in each treatment group were simulated with no pub- Table 3


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238 lication bias (Funnel plot: Supplementary Figure 3, Meta-regression analysis (cholinesterase inhibitors for cognitive
function scores)
239 Egger’s test p-value = 0.99103).
Covariate Coefficient Standard 95% 95% p
240 We detected considerable heterogeneity in the
error lower upper
241 cognitive function scores (I2 = 76%) and there-
Patient age –0.0465 0.0396 –0.1242 0.0312 0.2407
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242 fore performed four sensitivity analyses to identify Study duration 0.0005 0.0012 –0.0019 0.0029 0.6916
243 the confounding factors that might be affecting
244 these scores (Table 2). When divided according
245 to the type of drug (donepezil, galantamine, or n = 1,094; test for subgroup differences, I2 = 38.4%, 255
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246 rivastigmine subgroups), the significant heterogene- p = 0.2; Table 2). We also performed two meta- 256

247 ity disappeared in the donepezil and galantamine regression analyses to identify the confounding 257

248 subgroups; moreover, there was a significant effect factors affecting these scores (Table 3; Supple- 258

249 of the donepezil subgroup (donepezil subgroup: mentary Figure 4). However, we did not find any 259

250 SMD, –0.16; 95% CI, –0.28 to –0.04; p = 0.009, correlation between the cognitive function scores and 260

251 I2 = 21%; N = 5, n = 1,637; galantamine subgroup: the confounding factors. 261

252 SMD, –0.03.; 95% CI, –0.12–0.06; p = 0.53, I2 = 9%; In the secondary outcomes, ChEIs were associated 262

253 N = 2, n = 1,901; rivastigmine subgroup: SMD, 0.31.; with a lower incidence of progression to dementia 263

254 95% CI, –0.74–1.36; p = 0.57, I2 = 92%; N = 3, compared with placebo (RR = 0.76, NNT = 20, mean 264
8 S. Matsunaga / Cholinesterase Inhibitors for MCI

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Fig. 2. Forest plot of progression to dementia.

265 duration of included studies = 126.8 weeks; Fig. 2). Supplementary Figure 5). For the individual 294
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266 For individual ChEIs, galantamine was associated ChEIs, donepezil, galantamine, and rivastigmine 295

267 with a lower incidence of progression to dementia were associated with a higher rate of dis- 296

268 compared with placebo (RR = 0.68, NNT = 17). In continuation due to adverse events compared 297

269 contrast, donepezil and rivastigmine demonstrated no with placebo (donepezil, RR = 2.48, NNH = 11; 298

270 significant differences in this regard. There were no galantamine, RR = 2.21, NNH = 8; rivastigmine, 299

significant differences in global scores between the RR = 1.28, NNH = 20).


d

271 300

272 ChEIs and placebo groups (Supplementary Figure 5). There was also a significantly higher rate of 301

However, the rivastigmine subgroup significantly at least one adverse event in the ChEIs group
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273 302

274 improved global scores compared with placebo compared with the placebo group (RR = 1.10, 303

275 (SMD, –0.25; 95% CI, –0.37 to –0.13; p = 0.0001, NNH = 13; Supplementary Figure 5). When these 304

276 I2 = 0%; N = 2, n = 1,045). drugs were considered individually, there was a 305

277 No significant differences in other secondary out- significantly higher rate of at least one adverse 306
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278 comes were found between the ChEIs and the placebo event for donepezil and galantamine compared with 307

279 groups (Supplementary Figure 5). placebo (donepezil, RR = 1.19, NNH = 8; galan- 308

tamine, RR = 1.04, NNH = 33). The incidence of 309

280 Safety outcomes serious adverse events was similar between the ChEIs 310
co

281 There was a significantly higher rate of dis- and placebo groups (Supplementary Figure 5). For 311

282 continuation due to all causes in the ChEIs individual ChEIs, the rates of serious adverse events 312

283 compared with the placebo group (RR = 1.25, were also similar between groups. 313

284 NNH = 11; Supplementary Figure 5). Regarding With respect to individual adverse events, ChEIs 314
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285 the individual ChEIs, donepezil, galantamine, and overall were associated with a lower incidence of falls 315

286 rivastigmine were associated with a higher rate than placebo (RR = 0.69, NNH = 33; Supplementary 316

287 of discontinuation due to all causes compared Figure 5). For individual ChEIs, we found a sig- 317

288 with placebo (donepezil, RR = 1.50, NNH = 8; nificantly lower incidence of falls for galantamine 318

289 galantamine, RR = 1.14, NNH = 14; rivastigmine, compared with placebo (RR = 0.71, NNH = 50). 319

290 RR = 1.14, NNH = 14). Moreover, there was also In addition, the ChEIs overall had a higher 320

291 a significantly higher rate of discontinuation incidence of abnormal dreams (RR = 3.98, 321

292 due to adverse events in the ChEIs compared NNH = 13), diarrhea (RR = 2.59, NNH = 10), dizzi- 322

293 with the placebo group (RR = 2.14, NNH = 11; ness (RR = 1.61, NNH = 17), headache (RR = 1.36, 323
S. Matsunaga / Cholinesterase Inhibitors for MCI 9

324 NNH = 33), insomnia (RR = 1.81, NNH = 20), and rivastigmine had no statistically significant effect 373

325 loose stools (RR = 3.16, NNH = 25), muscle cramps on the progression of MCI to dementia compared 374

326 (RR = 7.78, NNH = 8), nausea (RR = 2.97, NNH = 8), with placebo, these ChEIs did produce a lower rate 375

327 vomiting (RR = 4.35, NNH = not significant), and of transition from MCI to dementia than placebo. 376

328 weight loss (RR = 2.01, NNH = 33), compared with From these results, ChEIs may reduce the progression 377

329 placebo (Supplementary Figure 5). For individual from MCI to dementia. However, the clinical benefit 378

330 ChEIs, compared with placebo, we found that may be limited because the effect size of ChEIs for 379

331 donepezil was associated with a higher incidence the progression from MCI to dementia is very small 380

f
332 of abnormal dreams (RR = 3.98, NNH = 13), diar- (RR = 0.76, NNT = 20). 381

roo
333 rhea (RR = 3.07, NNH = 8), headache (RR = 2.33, Regarding other secondary outcomes, there were 382

334 NNH = 25), insomnia (RR = 2.58, NNH = 17), no significant differences in either the ChEIs or 383

335 loose stools (RR = 3.16, NNH = 25), muscle the placebo groups. For the subgroup analysis of 384

336 cramps (RR = 7.78, NNH = 8), nausea (RR = 2.59, secondary outcomes, only rivastigmine significantly 385

337 NNH = 17), and vomiting (RR = 3.89, NNH = 17. improved global scores compared with placebo; how- 386

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338 Galantamine was associated with a higher inci- ever, again, this effect size was small (SMD = –0.25). 387

339 dence of diarrhea (RR = 1.75, NNH = 14), dizziness Although our results indicated that ChEIs had 388

340 (RR = 1.59, NNH = 20), insomnia (RR = 1.52, slight effects for treating MCI, there were also sig- 389

341 NNH = 25), nausea (RR = 2.76, NNH = 5), and nificantly higher rates of discontinuation due to all 390

tho
342 weight loss (RR = 1.99, NNH = 33) than placebo. causes, discontinuation due to adverse events, and 391

343 Rivastigmine was associated with a higher incidence at least one adverse event in the ChEIs group com- 392

344 of dizziness (RR = 1.62, NNH = 11), headache pared with placebo. Moreover, treatment with ChEIs 393

345 (RR = 1.39, NNH = not significant), insom- was associated with a higher incidence of gastroin- 394

346 nia (RR = 1.45, NNH = 25), nausea (RR = 3.42, testinal adverse events, abnormal dreams, dizziness, 395
Au
347 NNH = not significant), and vomiting (RR = 4.48, headache, insomnia, muscle cramps, and weight loss 396

348 NNH = 5) than placebo. No significant differences compared with placebo. The results of these safety 397

349 were found in the incidences of death between outcomes were similar to the effects of previous meta- 398

350 the ChEIs and the placebo groups (Supplementary analyses for MCI or dementia [6, 34, 35]. On the 399

351 Figure 5). other hand, our meta-analysis showed that ChEIs 400

had a significantly lower incidence of falls compared


d

401

with placebo. A recent meta-analysis suggests that 402


cte

352 DISCUSSION ChEIs may improve gait performance in AD [36], 403

and this implies they might also have similar effects 404

353 Our meta-analysis results showed that ChEIs did on MCI. However, our results regarding the incidence 405

354 not improve cognitive function scores for subjects of falls may include the possibility of statistical errors 406

355 with MCI. However, this overall finding masked because we have included only three studies address- 407
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356 significant underlying heterogeneity. Therefore, we ing this area in our meta-analysis. 408

357 performed the sensitivity analyses to identify the con- Several study limitations should be addressed. 409

358 founding factors affecting these scores. According First, we could not investigate the relationship 410

359 to the sensitivity analysis, one of the reasons for between neuropathological features of MCI and the 411
co

360 heterogeneity may be the type of ChEIs that were efficacy of ChEIs. Although we performed sensi- 412

361 investigated. Our sensitivity analyses detected that tivity analyses for the pathological classification of 413

362 the donepezil subgroup had less deterioration in cog- MCI, there was only one RCT that examined for neu- 414

363 nitive function scores than the placebo groups without ropathological features in the studies included in our 415
Un

364 considerable heterogeneity. However, the clinical meta-analysis (Table 2). Since MCI has neuropatho- 416

365 benefit may be limited because we found that the logical heterogeneity, recent guidelines regarding 417

366 effect size of donepezil for cognitive function scores MCI recommend the inclusion of patient cohorts with 418

367 on subjects with MCI was very small (SMD = –0.16). specific biomarker data in treatment studies targeted 419

368 From the secondary outcomes, our meta-analysis at specific pathologies (e.g., MCI due to AD) [37, 420

369 results suggested that ChEIs reduced the progres- 38]. Therefore, it is necessary to conduct RCTs in 421

370 sion from MCI to dementia. However, looking at the future for neuropathologically classified MCI. 422

371 the ChEIs individually, we found that only galan- Second, there is the paucity of studies included. For 423

372 tamine achieved this effect. But although donepezil individual ChEIs, there were only six studies for 424
10 S. Matsunaga / Cholinesterase Inhibitors for MCI

425 donepezil, four for galantamine, and four addressing impairment: Systematic review and Bayesian network meta- 472

426 rivastigmine. Because the individual ChEIs have dif- analysis. Neural Regen Res 14, 805-816. 473
[5] Matsunaga S, Kishi T, Yasue I, Iwata N (2015) 474
427 ferent pharmacological mechanisms of action [39], Cholinesterase inhibitors for Lewy body disorders: A meta- 475
428 further studies regarding the effectiveness of indi- analysis. Int J Neuropsychopharmacol 19, pyv086. 476

429 vidual ChEIs for MCI are needed. Third, the RCTs [6] Russ TC, Morling JR (2012) Cholinesterase inhibitors for 477

430 included in our meta-analysis had a short study dura- mild cognitive impairment. Cochrane Database Syst Rev, 478
CD009132. 479
431 tion (mean duration = 67.9 weeks). Our subgroup [7] Tricco AC, Soobiah C, Berliner S, Ho JM, Ng CH, Ashoor 480
432 analysis and meta-regression analysis did not show HM, Chen MH, Hemmelgarn B, Straus SE (2013) Efficacy 481

f
433 a correlation between study duration and cogni- and safety of cognitive enhancers for patients with mild cog- 482

roo
434 tive function scores. However, the pace of cognitive nitive impairment: A systematic review and meta-analysis. 483
CMAJ 185, 1393-1401. 484
435 decline for individuals with MCI is quite slow, and [8] Behrman S, Valkanova V, Allan CL (2017) Diagnosing and 485
436 studies with longer durations may be needed to deter- managing mild cognitive impairment. Practitioner 261, 17- 486

437 mine the overall benefits of ChEIs. Finally, twelve of 20. 487
[9] Moher D, Liberati A, Tetzlaff J, Altman DG, Group P (2009) 488
438 the included studies were industry sponsored, which

rP
Preferred reporting items for systematic reviews and meta- 489
439 tend to show more favorable efficacy results than analyses: The PRISMA statement. BMJ 339, b2535. 490
440 those sponsored by other sources [40]; therefore, a [10] Rosen WG, Mohs RC, Davis KL (1984) A new rating scale 491

441 sponsorship bias may exist in our results. for Alzheimer’s disease. Am J Psychiatry 141, 1356-1364. 492
[11] Folstein MF, Folstein SE, McHugh PR (1975) “Mini-mental 493
442 In conclusions, we found that although ChEIs
state”. A practical method for grading the cognitive state of 494

tho
443 have a slight efficacy in the treatment of MCI, there patients for the clinician. J Psychiatr Res 12, 189-198. 495
444 are many significant safety issues, and this makes [12] Nasreddine ZS, Phillips NA, Bedirian V, Charbonneau 496

445 them difficult to recommend for MCI. However, S, Whitehead V, Collin I, Cummings JL, Chertkow H 497
(2005) The Montreal Cognitive Assessment, MoCA: A brief 498
446 the efficacy and safety of ChEIs on MCI with a screening tool for mild cognitive impairment. J Am Geriatr 499
447 biomarker-based diagnosis remain unclear. There- Soc 53, 695-699. 500
Au
448 fore, further RCTs are needed to confirm the efficacy [13] Morris JC (1993) The Clinical Dementia Rating (CDR): 501

449 and safety of ChEIs when used for individual neu- Current version and scoring rules. Neurology 43, 2412- 502
2414. 503
450 ropathological classifications of MCI. [14] Schneider LS, Olin JT, Doody RS, Clark CM, Morris JC, 504
Reisberg B, Schmitt FA, Grundman M, Thomas RG, Fer- 505

451 DISCLOSURE STATEMENT ris SH (1997) Validity and reliability of the Alzheimer’s 506
Disease Cooperative Study-Clinical Global Impression 507
d

of Change. The Alzheimer’s Disease Cooperative Study. 508


452 Authors’ disclosures available online (https:// Alzheimer Dis Assoc Disord 11(Suppl 2), S22-32. 509
cte

453 www.j-alz.com/manuscript-disclosures/19-0546r1). [15] Petersen RC, Thomas RG, Grundman M, Bennett D, Doody 510
R, Ferris S, Galasko D, Jin S, Kaye J, Levey A, Pfeiffer 511
E, Sano M, van Dyck CH, Thal LJ, Alzheimer’s Disease 512
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454 SUPPLEMENTARY MATERIAL the treatment of mild cognitive impairment. N Engl J Med 514
352, 2379-2388. 515
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455 The supplementary material is available in [16] Galasko D, Bennett D, Sano M, Ernesto C, Thomas R, 516

456 the electronic version of this article: http://dx. Grundman M, Ferris S (1997) An inventory to assess activi- 517
ties of daily living for clinical trials in Alzheimer’s disease. 518
457 doi.org/10.3233/JAD-190546. The Alzheimer’s Disease Cooperative Study. Alzheimer Dis 519
Assoc Disord 11(Suppl 2), S33-39. 520
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[17] Cummings JL, Mega M, Gray K, Rosenberg-Thompson 521


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