Comparative safety and efficacy of cognitive enhancers for Alzheimer's dementia: a systematic review with individual patient data network meta-analysis

Areti Angeliki Veroniki; Huda M Ashoor; Patricia Rios; Georgios Seitidis; Lesley Stewart; Mike Clarke; Catrin Tudur-Smith; Dimitris Mavridis; Brenda R Hemmelgarn; Jayna Holroyd-Leduc; Sharon E Straus; Andrea C Tricco

doi:10.1136/bmjopen-2021-053012

Comparative safety and efficacy of cognitive enhancers for Alzheimer's dementia: a systematic review with individual patient data network meta-analysis

Areti Angeliki Veroniki, Huda M Ashoor, Patricia Rios, Georgios Seitidis, Lesley Stewart, Mike Clarke, Catrin Tudur-Smith, Dimitris Mavridis, Brenda R Hemmelgarn, Jayna Holroyd-Leduc, Sharon E Straus, Andrea C Tricco

Centre for Reviews and Dissemination

Research output: Contribution to journal › Article › peer-review

Abstract

OBJECTIVE: To examine the comparative efficacy and safety of cognitive enhancers by patient characteristics for managing Alzheimer's dementia (AD).

DESIGN: Systematic review and individual patient data (IPD) network meta-analysis (NMA) based on our previously published systematic review and aggregate data NMA.

DATA SOURCES: MEDLINE, Embase, Cochrane Methodology Register, CINAHL, AgeLine and Cochrane Central Register of Controlled Trials up to March 2016.

PARTICIPANTS: 80 randomised controlled trials (RCTs) including 21 138 adults with AD, and 12 RCTs with IPD including 6906 patients.

INTERVENTIONS: Cognitive enhancers (donepezil, rivastigmine, galantamine and memantine) alone or in any combination against other cognitive enhancers or placebo.

DATA EXTRACTION AND SYNTHESIS: We requested IPD from authors, sponsors and data sharing platforms. When IPD were not available, we used aggregate data. We appraised study quality with the Cochrane risk-of-bias. We conducted a two-stage random-effects IPD-NMA, and assessed their findings using CINeMA (Confidence in Network Meta-Analysis).

PRIMARY AND SECONDARY OUTCOMES: We included trials assessing cognition with the Mini-Mental State Examination (MMSE), and adverse events.

RESULTS: Our IPD-NMA compared nine treatments (including placebo). Donepezil (mean difference (MD)=1.41, 95% CI: 0.51 to 2.32) and donepezil +memantine (MD=2.57, 95% CI: 0.07 to 5.07) improved MMSE score (56 RCTs, 11 619 participants; CINeMA score: moderate) compared with placebo. According to P-score, oral rivastigmine (OR=1.26, 95% CI: 0.82 to 1.94, P-score=16%) and donepezil (OR=1.08, 95% CI: 0.87 to 1.35, P-score=30%) had the least favourable safety profile, but none of the estimated treatment effects were sufficiently precise when compared with placebo (45 RCTs, 15 649 patients; CINeMA score: moderate to high). For moderate-to-severe impairment, donepezil, memantine and their combination performed best, but for mild-to-moderate impairment donepezil and transdermal rivastigmine ranked best. Adjusting for MMSE baseline differences, oral rivastigmine and galantamine improved MMSE score, whereas when adjusting for comorbidities only oral rivastigmine was effective.

CONCLUSIONS: The choice among the different cognitive enhancers may depend on patient's characteristics. The MDs of all cognitive enhancer regimens except for single-agent oral rivastigmine, galantamine and memantine, against placebo were clinically important for cognition (MD larger than 1.40 MMSE points), but results were quite imprecise. However, two-thirds of the published RCTs were associated with high risk of bias for incomplete outcome data, and IPD were only available for 15% of the included RCTs.

PROSPERO REGISTRATION NUMBER: CRD42015023507.

Original language	English
Article number	e053012
Number of pages	10
Journal	BMJ Open
Volume	12
Issue number	4
DOIs	https://doi.org/10.1136/bmjopen-2021-053012
Publication status	Published - 26 Apr 2022

Bibliographical note

Keywords

Adult
Alzheimer Disease/drug therapy
Donepezil/therapeutic use
Galantamine/therapeutic use
Humans
Memantine/therapeutic use
Network Meta-Analysis
Nootropic Agents/adverse effects
Rivastigmine/therapeutic use

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Comparative safety and efficacy of cognitive enhancers for Alzheimer’s dementia: a systematic review with individual patient data network metaanalysis
© Author(s) (or their employer(s)) 2022
Final published version, 973 KBLicence: CC BY

Cite this

Veroniki, A. A., Ashoor, H. M., Rios, P., Seitidis, G., Stewart, L., Clarke, M., Tudur-Smith, C., Mavridis, D., Hemmelgarn, B. R., Holroyd-Leduc, J., Straus, S. E., & Tricco, A. C. (2022). Comparative safety and efficacy of cognitive enhancers for Alzheimer's dementia: a systematic review with individual patient data network meta-analysis. BMJ Open, 12(4), Article e053012. https://doi.org/10.1136/bmjopen-2021-053012

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abstract = "OBJECTIVE: To examine the comparative efficacy and safety of cognitive enhancers by patient characteristics for managing Alzheimer's dementia (AD).DESIGN: Systematic review and individual patient data (IPD) network meta-analysis (NMA) based on our previously published systematic review and aggregate data NMA.DATA SOURCES: MEDLINE, Embase, Cochrane Methodology Register, CINAHL, AgeLine and Cochrane Central Register of Controlled Trials up to March 2016.PARTICIPANTS: 80 randomised controlled trials (RCTs) including 21 138 adults with AD, and 12 RCTs with IPD including 6906 patients.INTERVENTIONS: Cognitive enhancers (donepezil, rivastigmine, galantamine and memantine) alone or in any combination against other cognitive enhancers or placebo.DATA EXTRACTION AND SYNTHESIS: We requested IPD from authors, sponsors and data sharing platforms. When IPD were not available, we used aggregate data. We appraised study quality with the Cochrane risk-of-bias. We conducted a two-stage random-effects IPD-NMA, and assessed their findings using CINeMA (Confidence in Network Meta-Analysis).PRIMARY AND SECONDARY OUTCOMES: We included trials assessing cognition with the Mini-Mental State Examination (MMSE), and adverse events.RESULTS: Our IPD-NMA compared nine treatments (including placebo). Donepezil (mean difference (MD)=1.41, 95% CI: 0.51 to 2.32) and donepezil +memantine (MD=2.57, 95% CI: 0.07 to 5.07) improved MMSE score (56 RCTs, 11 619 participants; CINeMA score: moderate) compared with placebo. According to P-score, oral rivastigmine (OR=1.26, 95% CI: 0.82 to 1.94, P-score=16%) and donepezil (OR=1.08, 95% CI: 0.87 to 1.35, P-score=30%) had the least favourable safety profile, but none of the estimated treatment effects were sufficiently precise when compared with placebo (45 RCTs, 15 649 patients; CINeMA score: moderate to high). For moderate-to-severe impairment, donepezil, memantine and their combination performed best, but for mild-to-moderate impairment donepezil and transdermal rivastigmine ranked best. Adjusting for MMSE baseline differences, oral rivastigmine and galantamine improved MMSE score, whereas when adjusting for comorbidities only oral rivastigmine was effective.CONCLUSIONS: The choice among the different cognitive enhancers may depend on patient's characteristics. The MDs of all cognitive enhancer regimens except for single-agent oral rivastigmine, galantamine and memantine, against placebo were clinically important for cognition (MD larger than 1.40 MMSE points), but results were quite imprecise. However, two-thirds of the published RCTs were associated with high risk of bias for incomplete outcome data, and IPD were only available for 15% of the included RCTs.PROSPERO REGISTRATION NUMBER: CRD42015023507.",

keywords = "Adult, Alzheimer Disease/drug therapy, Donepezil/therapeutic use, Galantamine/therapeutic use, Humans, Memantine/therapeutic use, Network Meta-Analysis, Nootropic Agents/adverse effects, Rivastigmine/therapeutic use",

author = "Veroniki, {Areti Angeliki} and Ashoor, {Huda M} and Patricia Rios and Georgios Seitidis and Lesley Stewart and Mike Clarke and Catrin Tudur-Smith and Dimitris Mavridis and Hemmelgarn, {Brenda R} and Jayna Holroyd-Leduc and Straus, {Sharon E} and Tricco, {Andrea C}",

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doi = "10.1136/bmjopen-2021-053012",

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Veroniki, AA, Ashoor, HM, Rios, P, Seitidis, G, Stewart, L, Clarke, M, Tudur-Smith, C, Mavridis, D, Hemmelgarn, BR, Holroyd-Leduc, J, Straus, SE & Tricco, AC 2022, 'Comparative safety and efficacy of cognitive enhancers for Alzheimer's dementia: a systematic review with individual patient data network meta-analysis', BMJ Open, vol. 12, no. 4, e053012. https://doi.org/10.1136/bmjopen-2021-053012

TY - JOUR

T1 - Comparative safety and efficacy of cognitive enhancers for Alzheimer's dementia

T2 - a systematic review with individual patient data network meta-analysis

AU - Veroniki, Areti Angeliki

AU - Ashoor, Huda M

AU - Rios, Patricia

AU - Seitidis, Georgios

AU - Stewart, Lesley

AU - Clarke, Mike

AU - Tudur-Smith, Catrin

AU - Mavridis, Dimitris

AU - Hemmelgarn, Brenda R

AU - Holroyd-Leduc, Jayna

AU - Straus, Sharon E

AU - Tricco, Andrea C

PY - 2022/4/26

Y1 - 2022/4/26

N2 - OBJECTIVE: To examine the comparative efficacy and safety of cognitive enhancers by patient characteristics for managing Alzheimer's dementia (AD).DESIGN: Systematic review and individual patient data (IPD) network meta-analysis (NMA) based on our previously published systematic review and aggregate data NMA.DATA SOURCES: MEDLINE, Embase, Cochrane Methodology Register, CINAHL, AgeLine and Cochrane Central Register of Controlled Trials up to March 2016.PARTICIPANTS: 80 randomised controlled trials (RCTs) including 21 138 adults with AD, and 12 RCTs with IPD including 6906 patients.INTERVENTIONS: Cognitive enhancers (donepezil, rivastigmine, galantamine and memantine) alone or in any combination against other cognitive enhancers or placebo.DATA EXTRACTION AND SYNTHESIS: We requested IPD from authors, sponsors and data sharing platforms. When IPD were not available, we used aggregate data. We appraised study quality with the Cochrane risk-of-bias. We conducted a two-stage random-effects IPD-NMA, and assessed their findings using CINeMA (Confidence in Network Meta-Analysis).PRIMARY AND SECONDARY OUTCOMES: We included trials assessing cognition with the Mini-Mental State Examination (MMSE), and adverse events.RESULTS: Our IPD-NMA compared nine treatments (including placebo). Donepezil (mean difference (MD)=1.41, 95% CI: 0.51 to 2.32) and donepezil +memantine (MD=2.57, 95% CI: 0.07 to 5.07) improved MMSE score (56 RCTs, 11 619 participants; CINeMA score: moderate) compared with placebo. According to P-score, oral rivastigmine (OR=1.26, 95% CI: 0.82 to 1.94, P-score=16%) and donepezil (OR=1.08, 95% CI: 0.87 to 1.35, P-score=30%) had the least favourable safety profile, but none of the estimated treatment effects were sufficiently precise when compared with placebo (45 RCTs, 15 649 patients; CINeMA score: moderate to high). For moderate-to-severe impairment, donepezil, memantine and their combination performed best, but for mild-to-moderate impairment donepezil and transdermal rivastigmine ranked best. Adjusting for MMSE baseline differences, oral rivastigmine and galantamine improved MMSE score, whereas when adjusting for comorbidities only oral rivastigmine was effective.CONCLUSIONS: The choice among the different cognitive enhancers may depend on patient's characteristics. The MDs of all cognitive enhancer regimens except for single-agent oral rivastigmine, galantamine and memantine, against placebo were clinically important for cognition (MD larger than 1.40 MMSE points), but results were quite imprecise. However, two-thirds of the published RCTs were associated with high risk of bias for incomplete outcome data, and IPD were only available for 15% of the included RCTs.PROSPERO REGISTRATION NUMBER: CRD42015023507.

AB - OBJECTIVE: To examine the comparative efficacy and safety of cognitive enhancers by patient characteristics for managing Alzheimer's dementia (AD).DESIGN: Systematic review and individual patient data (IPD) network meta-analysis (NMA) based on our previously published systematic review and aggregate data NMA.DATA SOURCES: MEDLINE, Embase, Cochrane Methodology Register, CINAHL, AgeLine and Cochrane Central Register of Controlled Trials up to March 2016.PARTICIPANTS: 80 randomised controlled trials (RCTs) including 21 138 adults with AD, and 12 RCTs with IPD including 6906 patients.INTERVENTIONS: Cognitive enhancers (donepezil, rivastigmine, galantamine and memantine) alone or in any combination against other cognitive enhancers or placebo.DATA EXTRACTION AND SYNTHESIS: We requested IPD from authors, sponsors and data sharing platforms. When IPD were not available, we used aggregate data. We appraised study quality with the Cochrane risk-of-bias. We conducted a two-stage random-effects IPD-NMA, and assessed their findings using CINeMA (Confidence in Network Meta-Analysis).PRIMARY AND SECONDARY OUTCOMES: We included trials assessing cognition with the Mini-Mental State Examination (MMSE), and adverse events.RESULTS: Our IPD-NMA compared nine treatments (including placebo). Donepezil (mean difference (MD)=1.41, 95% CI: 0.51 to 2.32) and donepezil +memantine (MD=2.57, 95% CI: 0.07 to 5.07) improved MMSE score (56 RCTs, 11 619 participants; CINeMA score: moderate) compared with placebo. According to P-score, oral rivastigmine (OR=1.26, 95% CI: 0.82 to 1.94, P-score=16%) and donepezil (OR=1.08, 95% CI: 0.87 to 1.35, P-score=30%) had the least favourable safety profile, but none of the estimated treatment effects were sufficiently precise when compared with placebo (45 RCTs, 15 649 patients; CINeMA score: moderate to high). For moderate-to-severe impairment, donepezil, memantine and their combination performed best, but for mild-to-moderate impairment donepezil and transdermal rivastigmine ranked best. Adjusting for MMSE baseline differences, oral rivastigmine and galantamine improved MMSE score, whereas when adjusting for comorbidities only oral rivastigmine was effective.CONCLUSIONS: The choice among the different cognitive enhancers may depend on patient's characteristics. The MDs of all cognitive enhancer regimens except for single-agent oral rivastigmine, galantamine and memantine, against placebo were clinically important for cognition (MD larger than 1.40 MMSE points), but results were quite imprecise. However, two-thirds of the published RCTs were associated with high risk of bias for incomplete outcome data, and IPD were only available for 15% of the included RCTs.PROSPERO REGISTRATION NUMBER: CRD42015023507.

KW - Adult

KW - Alzheimer Disease/drug therapy

KW - Donepezil/therapeutic use

KW - Galantamine/therapeutic use

KW - Humans

KW - Memantine/therapeutic use

KW - Network Meta-Analysis

KW - Nootropic Agents/adverse effects

KW - Rivastigmine/therapeutic use

U2 - 10.1136/bmjopen-2021-053012

DO - 10.1136/bmjopen-2021-053012

M3 - Article

C2 - 35473731

SN - 2044-6055

VL - 12

JO - BMJ Open

JF - BMJ Open

IS - 4

M1 - e053012

ER -