Comparative Effectiveness and Safety of Cognitive Enhancers for Treating Alzheimer's Disease: Systematic Review and Network Metaanalysis

Abstract

Background/Objectives To examine the comparative effectiveness and safety of cognitive enhancers for Alzheimer's disease (AD). Design Systematic review and Bayesian network metaanalysis (NMA). Setting MEDLINE, EMBASE, Cochrane Library, CINAHL, Ageline (inception–March 2016). Participants Individuals with AD in randomized controlled trials (RCTs), quasi‐RCTs, and nonrandomized studies. Intervention Any combination of donepezil, rivastigmine, galantamine, or memantine. Measurements Two reviewers independently screened titles, abstracts, and full‐texts; abstracted data; and appraised risk of bias. Results Twenty thousand three hundred forty‐three citations were screened, and 142 studies were included (110 RCTs, 21 non‐RCTs, 11 cohort studies). NMA found that donepezil (Mini‐Mental State Examination: mean difference (MD) = 1.39, 95% credible interval (CrI) = 0.53–2.24), donepezil+memantine (2.59, 95% CrI = 0.12–4.98), and transdermal rivastigmine (2.02, 95% CrI = 0.02–4.08) improved cognition more than placebo. NMA found that donepezil (Alzheimer's Disease Assessment Scale–cognitive: MD = −3.29, 95% CrI = −4.57 to −1.99) and galantamine (MD = −2.13, 95% CrI = −3.91 to −0.27) improved cognition more than placebo. NMA found that donepezil+memantine (MD = −5.23, 95% CrI = −8.72 to −1.56) improved behavior more than placebo. NMA found that donepezil (MD = −0.32, 95% CrI = −0.46 to −0.19), donepezil+memantine (MD = −0.57, 95% CrI = −0.95 to −0.21), oral rivastigmine (MD = −0.38, 95% CrI = −0.56 to −0.17), and galantamine (MD = −3.79, 95% CrI = −6.98 to −0.59) improved global status more than placebo. NMA found that galantamine decreased the odds of mortality (odds ratio = 0.56, 95% CrI = 0.36–0.87). No agent increased risk of serious adverse events, falls, or bradycardia. Some increased risk of headache (oral rivastigmine), diarrhea (oral rivastigmine, donepezil), nausea (oral rivastigmine, donepezil, galantamine), and vomiting (oral rivastigmine, donepezil, galantamine). Conclusion An exhaustive review of the literature involving 142 studies demonstrated that cognitive enhancers in general have minimal effects on cognition according to minimal clinically important difference and global ratings. The drugs appear safe, but this must be interpreted cautiously because trial participants may have less comorbidity and fewer adverse effects than those treated with these drugs in clinical practice.

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

“…15 Compared with previous systematic reviews, we included a larger number of studies and/or studies with shared IPD, compared in a wider range of cognitive enhancers. 6 27 Our results are in agreement with previous studies overall. Access to IPD allowed us to observe minor differences between the original published results and our reanalysis.…”

“…We followed the methods guidelines in the Cochrane Handbook for systematic reviews,26 the reporting guidelines in the PRISMA-NMA and PRISMA-IPD statements7 8 and evaluated credibility of findings using CINeMA 15. Compared with previous systematic reviews, we included a larger number of studies and/or studies with shared IPD, compared in a wider range of cognitive enhancers 6 27. Our results are in agreement with previous studies overall.…”

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

“…15 Compared with previous systematic reviews, we included a larger number of studies and/or studies with shared IPD, compared in a wider range of cognitive enhancers. 6 27 Our results are in agreement with previous studies overall. Access to IPD allowed us to observe minor differences between the original published results and our reanalysis.…”

“…We followed the methods guidelines in the Cochrane Handbook for systematic reviews,26 the reporting guidelines in the PRISMA-NMA and PRISMA-IPD statements7 8 and evaluated credibility of findings using CINeMA 15. Compared with previous systematic reviews, we included a larger number of studies and/or studies with shared IPD, compared in a wider range of cognitive enhancers 6 27. Our results are in agreement with previous studies overall.…”

Efficacy and Safety of Cholinesterase Inhibitors for Mild Cognitive Impairment:A Systematic Review and Meta-Analysis

“…Moreover, treatment with ChEIs was associated with a higher incidence of gastrointestinal adverse events, abnormal dreams, dizziness, headache, insomnia, muscle cramps, and weight loss compared with placebo. The results of these safety outcomes were similar to the effects of previous meta-analyses for MCI or dementia [6, 35]. On the other hand, our meta-analysis showed that ChEIs had a significantly lower incidence of falls compared with placebo.…”

Compliance and persistence with Alzheimer’s disease treatment: a retrospective analysis of multiregional hospital databases in Thailand

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

“…15 Compared with previous systematic reviews, we included a larger number of studies and/or studies with shared IPD, compared in a wider range of cognitive enhancers. 6 27 Our results are in agreement with previous studies overall. Access to IPD allowed us to observe minor differences between the original published results and our reanalysis.…”

“…We followed the methods guidelines in the Cochrane Handbook for systematic reviews,26 the reporting guidelines in the PRISMA-NMA and PRISMA-IPD statements7 8 and evaluated credibility of findings using CINeMA 15. Compared with previous systematic reviews, we included a larger number of studies and/or studies with shared IPD, compared in a wider range of cognitive enhancers 6 27. Our results are in agreement with previous studies overall.…”

Efficacy and Safety of Cholinesterase Inhibitors for Mild Cognitive Impairment:A Systematic Review and Meta-Analysis

“…Moreover, treatment with ChEIs was associated with a higher incidence of gastrointestinal adverse events, abnormal dreams, dizziness, headache, insomnia, muscle cramps, and weight loss compared with placebo. The results of these safety outcomes were similar to the effects of previous meta-analyses for MCI or dementia [6, 35]. On the other hand, our meta-analysis showed that ChEIs had a significantly lower incidence of falls compared with placebo.…”

Compliance and persistence with Alzheimer’s disease treatment: a retrospective analysis of multiregional hospital databases in Thailand

“……”

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

“…15 Compared with previous systematic reviews, we included a larger number of studies and/or studies with shared IPD, compared in a wider range of cognitive enhancers. 6 27 Our results are in agreement with previous studies overall. Access to IPD allowed us to observe minor differences between the original published results and our reanalysis.…”

“…We followed the methods guidelines in the Cochrane Handbook for systematic reviews,26 the reporting guidelines in the PRISMA-NMA and PRISMA-IPD statements7 8 and evaluated credibility of findings using CINeMA 15. Compared with previous systematic reviews, we included a larger number of studies and/or studies with shared IPD, compared in a wider range of cognitive enhancers 6 27. Our results are in agreement with previous studies overall.…”

Efficacy and Safety of Cholinesterase Inhibitors for Mild Cognitive Impairment:A Systematic Review and Meta-Analysis

“…Moreover, treatment with ChEIs was associated with a higher incidence of gastrointestinal adverse events, abnormal dreams, dizziness, headache, insomnia, muscle cramps, and weight loss compared with placebo. The results of these safety outcomes were similar to the effects of previous meta-analyses for MCI or dementia [6, 35]. On the other hand, our meta-analysis showed that ChEIs had a significantly lower incidence of falls compared with placebo.…”

Compliance and persistence with Alzheimer’s disease treatment: a retrospective analysis of multiregional hospital databases in Thailand

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