Key Question 5: Comparative Effectiveness and Harms of Prescription Drug Treatment Versus Other Active Treatments for Cognition, Function, and Quality of Life

Howard A. Fink; Laura S. Hemmy; Eric J. Linskens; Pombie C. Silverman; Roderick MacDonald; J. Riley McCarten; Kristine M.C. Talley; Priyanka J. Desai; Mary L. Forte; Margaret A. Miller; Michelle Brasure; Victoria A. Nelson; Brent C. Taylor; Weiwen Ng; Jeannine M. Ouellette; Nancy L. Greer; Kerry M. Sheets; Timothy J. Wilt; Mary Butler

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Fink HA, Hemmy LS, Linskens EJ, et al. Diagnosis and Treatment of Clinical Alzheimer’s-Type Dementia: A Systematic Review [Internet]. Rockville (MD): Agency for Healthcare Research and Quality (US); 2020 Apr. (Comparative Effectiveness Review, No. 223.)

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Diagnosis and Treatment of Clinical Alzheimer’s-Type Dementia: A Systematic Review [Internet].

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Appendix GKey Question 5: Comparative Effectiveness and Harms of Prescription Drug Treatment Versus Other Active Treatments for Cognition, Function, and Quality of Life

Galantamine Versus Donepezil

Appendix Table G.1Characteristics of eligible studies: galantamine versus donepezil

Study Characteristics:

Author/Year

Design

Country

Risk of Bias

Population:

AD Severity

Mean Age

% Female

% White

Education (mean yrs.)

Baseline Cognition

Intervention: Intervention mode Components Frequency Duration

Comparison: Comparison mode Components Frequency Duration

Outcome Timing

Outcom

Domain [Instrument]

Wilcock 2003²⁴³

RCT UK

Medium

188

AD not defined (most had MMSE scores <18, mean 15) Mean Age 73

62% Female

Race: White 99%

Education NR

Baseline Cognition: MMSE 15

Galantamine, up to 24 mg/day

Donepezil, up to 10 mg/day based on subject tolerance

52 weeks

Cognitive Tests

MMSE

ADAS-cog/11

Function

Bristol Activities of Daily Living Scale

Harms

SAEs

Withdrawal due to AE

All-cause mortality

Shimizu 2015²⁴⁴

RCT

Japan High

Mild to Moderate AD

Mean Age 77

55% Female

Race: NR

Education: mean 7 years

Baseline Cognition: MMSE 21

Galantamine, 24 mg/day

Cognitive Tests

MMSE

ADAS-cog

Function

Functional Activities Questionnaire

Harms

Withdrawal due to AE

Aguglia 2004²⁴⁵

CCT

Italy

High

121

Mild to Moderate AD

Mean Age 78

66% Female

Race: NR

Education: mean 7 years

Baseline Cognition: MMSE 21

Galantamine, 16 mg/day

Donepezil, up to 10 mg/day

26 weeks

Cognitive Tests

MMSE

ADAS-cog

Function

ADL

IADL

Harms

All-cause mortality

: Abbreviations: AD=Alzheimer’s Disease; ADAS-Cog= Alzheimer’s Disease Assessment Scale-Cog; ADCS-ADL=Alzheimer’s Disease Cooperative Study-Activities of Daily Living; AEs=Adverse Events; CIBIC-plus= Clinician’s Interview-Based Impression of Change-Plus Caregiver Input; DAD= Disability Assessment for Dementia; ER=Extended Release; GDS=Global Deterioration Scale; MDS ADL=Minimum Data Set Activities of Daily Living; MMSE=Mini-Mental State Examination; RCT=Randomized Controlled Trial; RoB=Risk of Bias; SAEs=Serious Adverse Events; SIB=Severe Impairment Battery

Appendix Table G.2Risk of bias ratings: galantamine versus donepezil

Study	Time	Selection Bias	Attrition Bias	Performance Bias	Detection Bias	Reporting Bias	Overall Rating
Wilcock 2003²⁴³	52 weeks	Low	Medium	Medium	Low	Low	Medium
Shimizu 2015²⁴⁴	52 weeks	Medium	High	High	Low	Low	High
Aguglia 2004²⁴⁵	26 weeks	Medium	High	High	High	Medium (withdrawals)	High

Appendix Table G.3Primary outcomes summary low and medium risk of bias studies: galantamine versus donepezil

Drug Comparison

AD Severity

Study

Followup

RoB

Cognitive

Function

QoL

Global Change

Harms

Galantamine (G) vs. Donepezil (D)

Mild to Moderate AD

Wilcock 2003²⁴³

52 weeks

N=182

Medium

MMSE

Mean Change from Baseline (SD)

G: -0.52 (SE 0.39)

D: -1.58 (SE 0.42)

P NS between groups

ADAS-Cog/11

Mean Change from Baseline (SD)

G: -2.22 (SE 0.77)

D: -3.43 (SE 0.80)

P NS between groups

Bristol Activities of Daily Living Scale (increase denotes decline)

Mean Change from Baseline (SD)

G: 2.46 (SE 0.71)

D: 2.67 (SE 0.74)

P NS between groups

SAEs

G: 18.6% (18/97)

D: 19.8% (18/91)

Withdrawal due to AE

G: 13.4% (13/97)

D: 13.2% (12/91)

Falls

G: 16.5% (16/97)

D: 8.8%% (8/91)

All-cause mortality

G: 2.1% (2/97)

D: 3.3% (3/91)

: Abbreviations: AD=Alzheimer’s Disease; ADAS-Cog=Alzheimer’s Disease Assessment Scale-Cog; AEs=Adverse Events; CI=Confidence Interval; CIBIC-plus= Clinician’s Interview-Based Impression of Change-Plus Caregiver Input; DAD= Disability Assessment for Dementia; LS=Least Squares; MDS ADL=Minimum Data Set Activities of Daily Living; MMSE=Mini-Mental State Examination; NR=Not Reported; RoB=Risk of Bias; SAEs=Serious Adverse Events; SD=Standard Deviation; SIB=Severe Impairment Battery

Appendix Table G.4Summary of strength of evidence: galantamine versus donepezil

Outcome	AD Severity	Timing	# Studies/ Design (n analyzed)	Finding or Summary Statistic	Study Limitations	Consistency	Directness	Precision	Overall Grade/Conclusion
Cognition (Global Brief Stand-Alone Tests-MMSE)	Moderate to severe AD	52 weeks	1 RCT (n=182)	Improvement in MMSE was similar with galantamine compared with donepezil, SMD 0.28 [95%CI -0.02 to 0.57].	Medium	Unknown	Direct	Imprecise	Insufficient (medium ROB, large imprecision, and unknown consistency)
Cognition (Multiple Measures – ADAS-cog)	Moderate to severe AD	52 weeks	1 RCT (n=182)	Improvement in ADAS-cog was similar with memantine compared with donepezil, SMD -0.16 [95%CI -0.45 to 0.13]	Medium	Unknown	Direct	Imprecise	Insufficient (medium ROB, imprecision, and unknown consistency)
Serious Adverse Events	Moderate to severe AD	52 weeks	1 RCT (n=188)	Participants treated with galantamine were not more likely to experience a serious adverse event than those treated with donepezil, 18.6% vs. 19.8%; ARD -1.2% [95% CI -12.5 to 10.0]; RR 0.94 [95% CI 0.52 to 1.69]	Medium	Unknown	Direct	Imprecise	Insufficient (medium RoB, imprecision, and unknown consistency)
Withdrawals due to Adverse Events	Moderate to severe AD	52 weeks	1 RCT (n=188)	Participants treated with galantamine were not more likely to experience a serious adverse event than those treated with donepezil, 13.4% vs. 13.2%; ARD 0.2% [95% CI -9.5 to 9.9]; RR 1.02 [95% CI 0.49, 2.11]	Medium	Unknown	Direct	Imprecise (large)	Insufficient (medium RoB, large imprecision, and unknown consistency)

: Abbreviations: AD=Alzheimer’s Disease; ADAS-Cog=Alzheimer’s Disease Assessment Scale-Cog; RCT=Randomized Controlled Trial; SIB=Severe Impairment Battery

Memantine Versus Donepezil

Appendix Table G.5Characteristics of eligible studies: memantine versus donepezil

Study Characteristics:

Author/Year

Design

Country

Risk of Bias

Population:

AD Severity

Mean Age

% Female

% White

Education (mean yrs.)

Baseline Cognition

Intervention: Intervention mode Components Frequency Duration

Comparison: Comparison mode Components Frequency Duration

Outcome Timing

Outcome

Domain [Instrument]

Modrego 2010²⁴⁶

RCT

Spain

Medium

Mild to Moderate AD

Mean Age 77

70% Female

Race NR

Education NR

Baseline Cognition: MMSE 23

Memantine, 20 mg/day

Donepezil, 10 mg/day

24 weeks

Cognitive Tests

ADAS-cog

Function

DAD

Harms

Harm outcomes of interest NR

: Abbreviations: AD=Alzheimer’s Disease; ADAS-Cog= Alzheimer’s Disease Assessment Scale-Cog; ADCS-ADL=Alzheimer’s Disease Cooperative Study-Activities of Daily Living; AEs=Adverse Events; CIBIC-plus= Clinician’s Interview-Based Impression of Change-Plus Caregiver Input; DAD= Disability Assessment for Dementia; ER=Extended Release; GDS=Global Deterioration Scale; MDS ADL=Minimum Data Set Activities of Daily Living; MMSE=Mini-Mental State Examination; RCT=Randomized Controlled Trial; RoB=Risk of Bias; SAEs=Serious Adverse Events; SIB=Severe Impairment Battery

Appendix Table G.6Risk of bias ratings: memantine versus donepezil

Study	Time	Selection Bias	Attrition Bias	Performance Bias	Detection Bias	Reporting Bias	Overall Rating
Modrego 2010²⁴⁶	24 weeks	Low	Low	Medium	Low	Low	Low

Appendix Table G.7Primary outcomes summary low and medium risk of bias studies: memantine versus donepezil

Drug Comparison

AD Severity

Study

Followup

RoB

Cognitive

Function

QoL

Global Change

Harms

Memantine vs. Donepezil

Mild to Moderate AD

Modrego 2010²⁴⁶

24 weeks

N=67

Medium

ADAS-Cog

Mean Change from Baseline (SD)

M: -1.37 (NR)

D: -0.12 (NR)

Between-group difference (95% CI) -1.25 (NR); PNS

DAD

Mean Change from Baseline (SD)

M: 4.5 (NR)

D: 6.7 (NR)

Between-group difference (95% CI) -2.2 (NR); P NS

Three patients on memantine were changed to donepezil because of headache and irritability, and one on donepezil to memantine because of gastric disturbances

: Abbreviations: AD=Alzheimer’s Disease; ADAS-Cog=Alzheimer’s Disease Assessment Scale-Cog; AEs=Adverse Events; CI=Confidence Interval; CIBIC-plus= Clinician’s Interview-Based Impression of Change-Plus Caregiver Input; DAD= Disability Assessment for Dementia; LS=Least Squares; MDS ADL=Minimum Data Set Activities of Daily Living; MMSE=Mini-Mental State Examination; NR=Not Reported; RoB=Risk of Bias; SAEs=Serious Adverse Events; SD=Standard Deviation; SIB=Severe Impairment Battery

Appendix Table G.8Summary of strength of evidence: memantine versus donepezil

Outcome	AD Severity	Timing	# Studies/ Design (n analyzed)	Finding or Summary Statistic	Study Limitations	Consistency	Directness	Precision	Overall Grade/Conclusion
Cognition (Multiple Measures)	Mild to Moderate AD	24 weeks	1 RCTs (n=67)	Improvement in global cognitive function as measured by brief multidomain batteries (ADAS-cog) was similar with memantine compared with donepezil, SMD -0.14 [95%CI -0.65 to 0.35]	Medium	Unknown	Direct	Imprecise (large)	Insufficient (large imprecision, and unknown consistency)

: Abbreviations: AD=Alzheimer’s Disease; ADAS-Cog=Alzheimer’s Disease Assessment Scale-Cog; RCT=Randomized Controlled Trial; SIB=Severe Impairment Battery

Memantine Versus Antipsychotics

Appendix Table G.9Characteristics of eligible studies: memantine versus antipsychotic

Study Characteristics:

Author/Year

Design

Country

Risk of Bias

Population:

AD Severity

Mean Age

% Female

% White

Education (mean yrs.)

Baseline Cognition

Intervention: Intervention mode Components Frequency Duration

Comparison: Comparison mode Components Frequency Duration

Outcome Timing

Outcome

Domain [Instrument]

Ballard 2015²⁴⁷

UK, Norway

Medium

199

NR (Severe by MMSE)

83 yrs.

69% female

% white NR

Education: NR

MMSE: 8

(based on 130 of 199 patients at baseline)

All residing in care homes, and all taking antipsychotic for ≥ 3 months at baseline

(Memantine + placebo antipsychotic) [=discontinue antipsychotic], with or without AChEI n=99 20 mg/day (= 10 mg twice/day) 24 weeks

Concurrent neuroleptic: 26%

(Placebo memantine + continue antipsychotic: [haloperidol, risperidone, olanzapine, or quetiapine]), with or without AChEI n=100 1 to 2 times/day 24 weeks

Concurrent neuroleptic: 27%

24 weeks

Cognitive: MMSE

Function: BADLS

Staging: FAST (baseline only)

Global Change: CGIC

Harms: AE, SAE, CVA, mortality

Other: CMAI, NPI

: Abbreviations: AChEI= acetylcholinesterase inhibitor; AE=Adverse Events; BADLS= Bristol Activities of Daily Living Scale; CGIC=Clinical Global Impression of Change; CMAI=Cohen-Mansfield Agitation Inventory; CVA=cerebrovascular accident; FAST=Functional Assessment Staging Tool; mg=milligrams; MMSE=Mini-Mental State Examination; n=number; NPI=Neuropsychiatric Inventory; NR=not reported; SAE=Serious Adverse Events; UK=United Kingdom

Appendix Table G.10Primary outcomes summary of low and medium risk of bias studies: memantine versus antipsychotic

Drug Comparison

AD Severity

Study Characteristics:

Author/Year

Followup

Risk of Bias

Cognitive

Function

Quality of Life

Global Change

Harms**

Memantine vs. continued antipsychotic

NR (Table 1 shows Severe AD by MMSE)

Ballard 2015²⁴⁷

24 weeks

Medium

NR^*

BADLS: Mean score (SD) at 24 weeks [out of 199 randomized]:

I: 34.9 (10.8); n=81

C: 32.3 (10.3); n=83

Difference^* [95% CI] = 0.23 [-1.8, 2.3], p=0.8204

SMD 0.03 [-0.27 to 0.34]

*adjusted for baseline score

NR^*

SAE:

I: 18/NR (% NR)

C: 25/NR (% NR) p=NR

CVA:

I: 0/NR

C: “> 1”/NR (% NR) p=NR

Mortality

I: 9/NR (% NR)

C:4/NR (% NR) p=NR

: Abbreviations: AD=Alzheimer’s Disease; BADLS= Bristol Activities of Daily Living Scale; C=Control group; CVA=cerebrovascular accident; I=Intervention group; n=number; NR=not reported; SAE=Serious Adverse Events; SD=Standard Deviation; SMD=standardized mean difference
*: High risk of bias outcomes were not extracted

Appendix Table G.11Risk of bias ratings: memantine versus antipsychotic

Study

Time

Selection Bias

Attrition Bias

Performance Bias

Detection Bias

Reporting Bias

Overall Risk of Bias Rating

Ballard 2015²⁴⁷

UK, Norway

24 weeks

Low

Medium 16.6%

MMSE: 43.2%

BADLS: 17.6%

CGIC: 25.6%

Low

MEDIUM for BADLS

HIGH for MMSE

HIGH for CGIC

: Abbreviations: BADLS= Bristol Activities of Daily Living Scale; CGIC=Clinical Global Impression of Change; MMSE=Mini-Mental State Examination; UK=United Kingdom

Appendix Table G.12Summary of strength of evidence: memantine versus antipsychotic

Drug Comparison	Outcome	AD Severity	Timing	# Studies/ Design (n analyzed)	Finding or Summary Statistic	Study Limitations	Consistency	Directness	Precision	Overall Grade/Conclusion
Memantine vs. continued antipsychotic with or without AChEI	BADLS	Severe AD	24 weeks	1 RCT (n=164^*)	No difference	Medium	Unknown	Direct	Imprecise	Insufficient

: Abbreviations: AChEI= acetylcholinesterase inhibitor; AD=Alzheimer’s Disease; BADLS= Bristol Activities of Daily Living Scale; n=number; RCT=Randomized Controlled Trial
*: Outcomes reported for 164 of 199 randomized

Supplements Versus Drugs

Appendix Table G.13Characteristics of eligible studies: supplement versus drug

Supplement Drug	Study Characteristics: Author/Year Design Country Risk of Bias	N=	Population: AD Severity Mean Age % Female % White Education (mean yrs.) Baseline Cognition	Intervention: Intervention mode Components Frequency Duration	Comparison: Comparison mode Components Frequency Duration	Outcome Timing	Outcome Domain [Instrument]
Ginkgo Biloba Rivastigmine	Nasab 2012²⁴⁸ RCT Iran High	56	Mild to Moderate AD Mean Age 66 55% Female Baseline Cognition: MMSE 16.6	Ginkgo Biloba, 120 mg/day	Rivastigmine, 4.5 mg/day	24 weeks	Cognitive Tests MMSE 7MS
Ginkgo Biloba Donepezil	Mazza 2006¹³⁵ RCT Italy Medium	50	Mild to Moderate AD Mean Age 68.5 54% Female Baseline Cognition: MMSE 18.7	Ginkgo Biloba, 160 mg/day	Donepezil, 5 mg/day	24 weeks	Cognitive Tests MMSE SKT Global Change CGI item 2 Harms Withdrawal due to AEs
Saffron Extract Memantine	Farokhnia 2014²⁴⁹ RCT Iran Medium	68	Moderate to Severe AD Mean Age 77.6 43% Female Baseline Cognition: MMSE 11.2	Saffron Extract, 30 mg/day	Memantine, 20 mg/day	12 months	Cognitive Tests MMSE SCIRS Global Change FAST Harms CVD mortality Sedation Confusion
Vitamin E Donepezil	Onofrj 2002 ²⁵⁰ RCT Italy High	67	Mild to Severe AD Mean Age 66 55% Female Mean Years Education 6.5 Baseline Cognition: MMSE 16.6	Vitamin E, 2000 IU/day, postprandial	Donepezil, 10 mg/day, postprandial	6 months	Cognitive Tests MMSE ADAS-Cog Verbal and Performance WAIS subscales Harms Withdrawal due to AEs
Vitamin E Donepezil	Thomas 2001²⁵¹ RCT Italy Medium	40	Mild to Severe AD Mean Age 66.0 53% Female Baseline Cognition: MMSE 16	Vitamin E, 2000 IU/day, postprandial	Donepezil, 10 mg/day, postprandial	26 weeks	Cognitive Tests MMSE ADAS-Cog WAIS, Verbal and Performance subscales Harms Withdrawal due to AEs
Vitamin E Rivastigmine	Thomas 2001²⁵¹ RCT Italy Medium	40	Mild to Severe AD Mean Age 65.3 53% Female Baseline Cognition: MMSE 16x	Vitamin E, 2000 IU/day, postprandial	Rivastigmine, 6 mg twice a day, postprandial	26 weeks	Cognitive Tests MMSE ADAS-Cog WAIS, Verbal and Performance Subscales Harms Withdrawal due to AEs
Vitamin E Memantine	Dysken 2014¹⁹⁵ RCT United States High	307	Mild to Moderate AD Mean Age 78.8 3% Female 86% White 78% high school graduate or higher Baseline Cognition: MMSE 21	Vitamin E, 1000 IU twice a day	Memantine, 10 mg twice a day	Mean follow-up 2.27 years	Cognitive Tests MMSE ADAS-Cog Function ADCS-ADL CAS Dependence Scale Behavior NPI Harms SAEs Withdrawal due to AEs Falls All-cause mortality CVD mortality Non-CVD mortality
Yishen Huazhuo decoction (YHD) Donepezil	Zhang 2015²⁵²^, ²⁵³ RCT China High	144	Mild AD Mean Age 72.9 62% Female 11% College-educated Baseline cognition: MMSE 20.2	YDH 100 mL daily 30 min before breakfast	Donepezil, 5mg nightly	24 weeks	Cognitive Tests MMSE ADAS-Cog Function ADL scale Behavior NPI Harms SAEs Withdrawal due to AEs Stroke
Huannao Yicong Formula (HYF) Donepezil	Yang 2018²⁵⁴ RCT China Medium	60	Mild to Moderate AD Mean Age 62.3 75% Female Mean Years Education 5.5 Baseline Cognition: MMSE 21.8	HYF 5 gm twice a day and placebo daily	Donepezil 5mg once daily and placebo twice a day	6 months	Cognitive Tests ADAS-Cog MMSE MoCA Harms SAEs Mortality

: Abbreviations: ADL=Activities of Daily Living; AEs=Adverse Events; AD=Alzheimer’s Disease; ADAS-Cog=Alzheimer’s Disease Assessment Scale-Cognition; ADCS-ADL=Alzheimer’s Disease Cooperative Study/Activities of Daily Living; CVD=Cardiovascular; CAS=Caregiver Activity Survey; CGI=Clinical Global Impression; FAST=Functional Assessment Staging Tool; GBS-scale=Geriatric Behavioral Syndrome scale; GDS=Global Deterioration Scale; MMSE=Mini-Mental State Examination; MoCA=Montreal Cognitive Assessment; NPI=Neuropsychiatric Inventory; RoB=Risk of Bias; 7MS=Seven Minute Test; SKT=Syndrom Kurz Test; SCIRS=Severe Cognitive Impairment Rating Scale; WAIS=Wechsler Adult Intelligence Scale; YHD=Yishen Huazhuo Decoction (Composed of Yinyanghuo [Epimedium], Nvzhenzi [Fructus Ligustri Lucidi], Buguzhi [Psoralea fruit], Heshouwu [Radix Polygoni Multiflori], Huangqi [Radix Astragali], Chuanxiong [Ligusticum wallichi Franchat], Shichangpu [Acorus gramineus])

Appendix Table G.14Risk of bias ratings: supplement versus drug

Supplement Drug	Study	Time	Selection Bias	Attrition Bias	Performance Bias	Detection Bias	Reporting Bias	Overall Rating
Gingko Biloba Rivastigmine	Nasab 2012²⁴⁸	24 weeks	Medium	Low	High	Low	High	High
Ginkgo Biloba Donepezil	Mazza 2006¹³⁵	24 weeks	Low	Medium	Low	Low	Low	Medium
Saffron Extract Memantine	Farokhnia 2014²⁴⁹	12 months	Low	Medium	Low	Low	Low	Medium
Vitamin E Donepezil	Onofrj 2002²⁵⁰	6 months	Medium	Medium	High	Low	High	High
Vitamin E Donepezil Rivastigmine	Thomas 2001²⁵¹	26 weeks	Low	Medium	Medium	Low	High	Medium
Vitamin E Memantine Placebo	Dysken 2014¹⁹⁵	Mean follow-up 2.27 years	Low	High	Low	Low	Low	High
YHD Donepezil	Zhang 2015²⁵²^, ²⁵³[	24 weeks	Low	High	Low	Low	Low	High
HYF Donepezil	Yang 2018²⁵⁴[	6 months	Low	Medium	High	Low	Low	Medium

: Abbreviations: YHD=Yishen Huazhuo Decoction (Composed of Yinyanghuo [Epimedium], Nvzhenzi [Fructus Ligustri Lucidi], Buguzhi [Psoralea fruit], Heshouwu [Radix Polygoni Multiflori], Huangqi [Radix Astragali], Chuanxiong [Ligusticum wallichi Franchat], Shichangpu [Acorus gramineus])

Appendix Table G.15Outcome instruments used in low/medium risk of bias studies: supplement versus drug

Supplement Drug	Study	RoB	AD Severity	Global Brief Stand-Alone Tests	Global Multidomain Tests	Domain Level Tests Typically Part of a Larger Battery^*	Function	Quality of Life	Clinical Impression of Change
Ginkgo Biloba Donepezil	Mazza 2006¹³⁵	Medium	Mild to Moderate AD	MMSE SKT	NR	NR	NR	NR	CGI item 2
Saffron Extract Memantine	Farokhnia 2014²⁴⁹	Medium	Moderate to Severe AD	MMSE SCIRS	NR	NR	NR	NR	FAST
Vitamin E Rivastigmine	Thomas 2001{Thom as, 2001 #201]	Medium	Mild to Severe AD	MMSE	WAIS, Verbal and Performance subscales ADAS-Cog	NR	NR	NR	NR
Vitamin E Rivastigmine	Thomas 2001²⁵¹	Medium	Mild to Severe AD	MMSE	WAIS, Verbal and Performance subscales ADAS-Cog	NR	NR	NR	NR
HYF Donepezil	Yang 2018²⁵⁴	Medium	Mild to Moderate AD	MMSE MoCA	ADAS-Cog	NR	NR	NR	NR
	TOTAL			8	5	0	0	0	1

*: Domain level tests typically part of a larger battery are tests of memory, executive function, language and/or attention:
a: Memory;
b: Executive Function;
c: Language;
d: Attention
: Abbreviations: AD=Alzheimer’s Disease; CGI=Clinical Global Impression; FAST=Functional Assessment Staging Tool; MMSE=Mini-Mental State Examination; NR=Not Rated; RoB=Risk of Bias; SCIRS=Severe Cognitive Impairment Rating Scale; SKT=Syndrom Kurz Test

Appendix Table G.16Primary outcomes summary low and medium risk of bias studies: supplement versus drug

Supplement Drug	AD Severity	Study Characteristics: Author/Year Followup Risk of Bias	Cognitive	Function	QoL	Clinical Impression of Change	Harms
Ginkgo Biloba Donepezil	Mild to Moderate AD	Mazza 2006¹³⁵^* 24 weeks Medium	MMSE Mean Change from Baseline (95% CI) Ginkgo Biloba: 0.6 (-1.8 to 3) Donepezil: 1.2 (-1.2 to 3.6) No difference between groups SMD -0.18 (95% CI -0.80, 0.43) SKT Mean Change from Baseline (95% CI) Ginkgo Biloba: -3.3 (-2.3 to -4.27) Donepezil: -3.3 (-2.3 to -4.29) No difference between groups SMD, 0.0 (95% CI -0.61, 0.61)	NR	NR	CGI item 2 Mean Change from Baseline (95% CI) Ginkgo Biloba: -0.9 (-0.5 to -1.2) Donepezil: -0.9 (-0.5 to -1.2) No difference between groups SMD, 0.0 (95% CI -0.61, 0.61)	Withdrawal due to AEs Gingko Biloba: 0/25 (0%) Donepezil: 4/25 (16%) RR, 0.11 (95% CI 0.01, 2.0)
Saffron Extract Memantine	Moderate to Severe AD	Farokhnia 2014²⁴⁹ 12 months Medium	MMSE Mean Change from Baseline (SD) Saffron Extract: -1.29 (1.36) Memantine: -1.67 (1.57) p=0.28 SMD 0.28 (95% CI -0.79, 0.23) SCIRS Mean Change from Baseline (SD) Saffron Extract: -1.88 (1.14) Memantine: -1.61 (1.34) p=0.38 SMD 0.22 (95% CI -0.29, 0.73)	NR	NR	FAST Mean Change from Baseline (SD) Saffron Extract: -0.94 (0.73) Memantine: -0.97 (0.83) p=0.87 SMD -0.03 (95% CI -0.53 to 0.48)	CVD mortality Saffron Extract: 1/34 (2.9%) Memantine: 1/34 (2.9%) RR, 1.0 (95% CI 0.7, 15.3) Sedation Saffron Extract: 1/34 (2.9%) Memantine: 3/34 (8.8%) RR, 0.33 (95% CI 0.04, 3.0) Confusion Saffron Extract: 1/34 (2.9%) Memantine: 1/34 (2.9%) RR, 1.0 (95% CI 0.7, 15.3)
Vitamin E Donepezil	Mild to Severe AD	Thomas²⁵¹ 2001 26 weeks Medium	MMSE Vitamin E Baseline (SE): 16 (0.5) 26 weeks (SE): 15 (0.6) p=0.07 Donepezil Baseline (SE): 16 (0.5) 26 weeks (SE): 16 (0.5) p=0.06 Post-treatment SMD -0.42 (95% -1.06, 0.23) WAIS, Verbal and Performance subscales Vitamin E Baseline (SE): 72 (2.0) 26 weeks (SE): 71 (2.1) p=0.43 Donepezil Baseline (SE): 72 (2.0) 26 weeks (SE): 75 (2.0) p=0.15 Post-treatment SMD -0.45 (95% CI -1.09, 0.20) ADAS-Cog Vitamin E Baseline (SE): 33.45 (2.6) 26 weeks (SE): 39.07 (2.7) p<0.01 Donepezil Baseline (SE): 33.34 (2.7) 26 weeks (SE): 31.84 (2.7) p<0.001Post-treatment SMD -0.61 (95% CI -1.26, 0.04)	NR	NR	NR	Withdrawal due to AEs: Vitamin E: 0/20 (0%) Donepezil: 0/20 (0%)
Vitamin E Rivastigmine	Mild to Severe AD	Thomas²⁵¹ 2001 26 weeks Medium	MMSE Vitamin E Baseline (SE): 16 (0.5) 26 weeks (SE): 15 (0.6) p=0.07 Rivastigmine Baseline (SE): 16 (0.5) 26 weeks (SE): 16 (0.5) p=0.06 Post-treatment SMD -0.42 (95% CI -1.09, 0.27) WAIS, Verbal and Performance Subscales Vitamin E Baseline (SE): 72 (2.0) 26 weeks (SE): 71 (2.1) p=0.43 Rivastigmine Baseline (SE): 71 (1.9) 26 weeks (SE): 74 (2.0) P<0.05 Post-treatment SMD -0.34 (95% CI -1.01, 0.34) ADAS-Cog Vitamin E Baseline (SE): 33.45 (2.6) 26 weeks (SE): 39.07 (2.7) p<0.01 Rivastigmine Baseline (SE): 33.39 (2.7) 26 weeks (SE): 31.02 (2.5) p<0.01 Post-treatment SMD -0.71 (-1.40, -0.01)	NR	NR	NR	Withdrawal due to AEs: Vitamin E: 0/20 (0%) Rivastigmine: 3/20 (15%)
HYF Donepezil	Mild to Moderate AD	Yang{Yang, 2018 #468 2018 6 months Medium	MMSE HYF Increase in score, p<0.01 Donepezil Increase in score, p<0.01 No post-treatment difference between groups, p>0.05 MoCA HYF Increase in score, p<0.01 Donepezil Increase in score, p<0.01 Post-treatment difference between groups NR ADAS-Cog HYF Decrease in score, p<0.01 Donepezil Decrease in score, p<0.01 No post-treatment difference between groups, p>0.05	NR	NR	NR	Dreaminess/Confusion HYF: 0/28 (0%) Donepezil: 1/24 (4.2%) RR 0.29 (95% CI 0.01, 6) SAEs No SAEs reported during study period. Mortality No deaths during study period

: Abbreviations: AEs=Adverse Events; AD=Alzheimer’s Disease; CVD=Cardiovascular; CGI=Clinical Global Impression; CI=Confidence Interval; FAST=Functional Assessment Staging Tool; MMSE=Mini-Mental State Examination; NR=Not Reported; RR=Relative Risk; RoB=Risk of Bias; SD=Standard Deviation; SCIRS=Severe Cognitive Impairment Rating Scale; SMD=Standardized Mean Difference; SKT=Syndrom Kurz Test
*: Authors reported 95% confidence intervals that appeared consistently incorrect for the MMSE, SKT, and CGI item 2, with the point estimates either far from centered between the upper and lower bounds or outside the confidence intervals. It appeared that authors placed incorrect signs on all the upper and lower confidence interval bounds. The Evidence-based Practice Center has modified the confidence intervals while waiting for clarification from study authors.

Appendix Table G.17Summary of strength of evidence: supplement versus drug

Supplement Drug	Outcome	AD Severity	Timing	# Studies/Design (n analyzed)	Finding or Summary Statistic	Study Limitations	Consistency	Directness	Precision	Overall Grade/Conclusion
Ginkgo Biloba Donepezil	All outcomes	Mild to Moderate AD	24 weeks	1 RCT (n=50)	No preference	Medium	Unknown	Direct	Imprecise	Insufficient
Saffron Extract Memantine	All outcomes	Moderate to Severe AD	12 months	1 RCT (n=68)	No preference	Medium	Unknown	Direct	Imprecise	Insufficient
Vitamin E Donepezil	All outcomes	Mild to Severe AD	26 weeks	1 RCT (n=40)	No preference	Medium	Unknown	Direct	Imprecise	Insufficient
Vitamin E Rivastigmine	All outcomes	Mild to Severe AD	26 weeks	1 RCT (n=40)	No preference	Medium	Unknown	Direct	Imprecise	Insufficient
HYF Donepezil	All outcomes	Mild to Moderate AD	6 months	1 RCT (n=60)	No preference	Medium	Unknown	Direct	Imprecise	Insufficient

: Abbreviations: AD=Alzheimer’s Disease; RCT=Randomized Controlled Trial

Additional Drug Versus Drug Comparisons

Appendix Table G.18Characteristics of eligible studies: rivastigmine versus donepezil

Study Characteristics: Author/Year Design Country Risk of Bias	N=	Population: AD Severity Mean Age % Female % White Education (mean yrs.) Baseline Cognition	Intervention: Intervention mode Components Frequency Duration	Comparison: Comparison mode Components Frequency Duration	Outcome Timing	Outcome Domain [Instrument]
Thomas 2001²⁵¹ RCT Italy High	40	Mild to Moderate CATD Mean Age: 65.8 % Female: 55.0 % White: NR Mean Education: NR Baseline Cognition: MMSE 16	Rivastigmine, 12 mg/day oral	Donepezil, 10 mg/day	26 weeks	Cognition MMSE ADAS-Cog WAIS (subscale composed of verbal and performance scales) Harms Withdrawals due to adverse events Somnolence
Aguglia 2004²⁴⁵ CCT Italy High	191	Mild to Moderate CATD Mean Age: 77.6 % Female: 65.3 % White: NR Mean Education: 8.0 Baseline Cognition: MMSE 20.4	Rivastigmine, 6-12 mg/day oral	Donepezil, 10 mg/day	6 months	Cognition MMSE ADAS-Cog Function ADL IADL Harms Mortality
Bullock 2005²⁵⁵ RCT Australia, Canada, France, Germany, Italy, Spain, UK High	998	Moderate CATD Mean Age: 75.9 % Female: 68.7 % White: 98.8 Mean Education: NR Baseline Cognition: MMSE 15.1	Rivastigmine, 12 mg/day oral	Donepezil, 10 mg/day	104 weeks	Cognition SIB MMSE Function ADCS-ADL Global Change GDS Harms Serious adverse events Withdrawals due to adverse events Mortality
Shimizu 2015²⁴⁴ RCT Japan High	50	Mild to Moderate CATD Mean Age: 77.8 % Female: 55.3 % White: NR Mean Education: 12.7 Baseline Cognition: MMSE 21.0	Rivastigmine, 18 mg/day patch	Donepezil, 5 mg/day	48 weeks	Cognition MMSE ADAS-Cog Cognition (memory) ADAS-Cog memory Cognition (language) ADAS-Cog language Cognition (attention) TMT-A Function FAQ Harms Withdrawals due to adverse events
Abolfazli 2008²⁵⁶ CCT Iran High	70	Mild to Moderate CATD Mean Age: NR % Female: 51.4 % White: NR Mean Education: NR Baseline Cognition: MMSE 20.3	Rivastigmine, 6-12 mg/day oral	Donepezil, 5-10 mg/day	6 months	Cognition MMSE Clock drawing test Cognition (visuospatial and executive) Visual Motor Gestalt test

: Abbreviations: ADAS-Cog=Alzheimer’s Disease Assessment Scale-Cognitive subscale; ADCS-ADL=Alzheimer’s Disease Cooperative Study—Activities of Daily Living; ADL=Activities of Daily Living; CATD=clinical Alzheimer-type dementia; CCT=controlled clinical trial; FAQ=Functional Activities Questionnaire; GDS=Global Deterioration Scale; IADL=Instrumental Activities of Daily Living; MMSE=Mini-Mental State Examination; NR=Not Reported; RCT=randomized controlled trial; RoB=Risk of Bias; SIB=Severe Impairment Battery; TMT-A=Trail Making Test Part A; WAIS=Wechsler Adult Intelligence Scale

Appendix Table G.19Risk of bias ratings: rivastigmine versus donepezil

Study	Time	Selection Bias	Attrition Bias	Performance Bias	Detection Bias	Reporting Bias	Overall Rating
Thomas 2001²⁵¹	26 weeks	Low	Medium	High	Low	High	High
Aguglia 2004²⁴⁵	6 months	Medium	High	High	High	Medium	High
Bullock 2005²⁵⁵	104 weeks	Low	High	Low	Low	Low	High
Shimizu 2015²⁴⁴	48 weeks	Medium	High	High	Low	Low	High
Abolfazli 2008²⁵⁶	6 months	High	High	High	Low	Low	High

Bookshelf ID: NBK556560

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Fink HA, Hemmy LS, Linskens EJ, et al. Diagnosis and Treatment of Clinical Alzheimer’s-Type Dementia: A Systematic Review [Internet]. Rockville (MD): Agency for Healthcare Research and Quality (US); 2020 Apr. (Comparative Effectiveness Review, No. 223.) Appendix G, Key Question 5: Comparative Effectiveness and Harms of Prescription Drug Treatment Versus Other Active Treatments for Cognition, Function, and Quality of Life.
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Diagnosis and Treatment of Clinical Alzheimer’s-Type Dementia: A Systematic Review [Internet].

Appendix GKey Question 5: Comparative Effectiveness and Harms of Prescription Drug Treatment Versus Other Active Treatments for Cognition, Function, and Quality of Life

Galantamine Versus Donepezil

Appendix Table G.1Characteristics of eligible studies: galantamine versus donepezil

Appendix Table G.2Risk of bias ratings: galantamine versus donepezil

Appendix Table G.3Primary outcomes summary low and medium risk of bias studies: galantamine versus donepezil

Appendix Table G.4Summary of strength of evidence: galantamine versus donepezil

Memantine Versus Donepezil

Appendix Table G.5Characteristics of eligible studies: memantine versus donepezil

Appendix Table G.6Risk of bias ratings: memantine versus donepezil

Appendix Table G.7Primary outcomes summary low and medium risk of bias studies: memantine versus donepezil

Appendix Table G.8Summary of strength of evidence: memantine versus donepezil

Memantine Versus Antipsychotics

Appendix Table G.9Characteristics of eligible studies: memantine versus antipsychotic

Appendix Table G.10Primary outcomes summary of low and medium risk of bias studies: memantine versus antipsychotic

Appendix Table G.11Risk of bias ratings: memantine versus antipsychotic

Appendix Table G.12Summary of strength of evidence: memantine versus antipsychotic

Supplements Versus Drugs

Appendix Table G.13Characteristics of eligible studies: supplement versus drug

Appendix Table G.14Risk of bias ratings: supplement versus drug

Appendix Table G.15Outcome instruments used in low/medium risk of bias studies: supplement versus drug

Appendix Table G.16Primary outcomes summary low and medium risk of bias studies: supplement versus drug

Appendix Table G.17Summary of strength of evidence: supplement versus drug

Additional Drug Versus Drug Comparisons

Appendix Table G.18Characteristics of eligible studies: rivastigmine versus donepezil

Appendix Table G.19Risk of bias ratings: rivastigmine versus donepezil

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