Cholinesterase inhibitors for vascular dementia and other vascular cognitive impairments: a network meta-analysis (Review)

Ceri E. Battle, Azmil H. Abdul-Rahim, Susan Deborah Shenkin, Jonathan Hewitt, Terry J Quinn

Research output: Contribution to journalReview articlepeer-review


Vascular cognitive impairment (VCI) describes a broad spectrum of cognitive impairments caused by cerebrovascular disease, ranging from
mild cognitive impairment to dementia. There are currently no pharmacological treatments recommended for improving either cognition
or function in people with VCI. Three cholinesterase inhibitors (donepezil, galantamine, and rivastigmine) are licenced for the treatment
of dementia due to Alzheimer's disease. They are thought to work by compensating for reduced cholinergic neurotransmission, which is
also a feature of VCI. Through pairwise comparisons with placebo and a network meta-analysis, we sought to determine whether these
medications are eEective in VCI and whether there are diEerences between them with regard to eEicacy or adverse events.
(1) To assess the eEicacy and safety of cholinesterase inhibitors in the treatment of adults with vascular dementia and other VCI.
(2) To compare the eEects of diEerent cholinesterase inhibitors on cognition and adverse events, using network meta-analysis.
Search methods
We searched ALOIS, the Cochrane Dementia and Cognitive Improvement Group's register, MEDLINE (OvidSP), Embase (OvidSP), PsycINFO
(OvidSP), CINAHL (EBSCOhost), Web of Science Core Collection (ISI Web of Science), LILACS (BIREME),, and the World
Health Organization International Clinical Trials Registry Platform on 19 August 2020.
Selection criteria
We included randomised controlled trials in which donepezil, galantamine, or rivastigmine was compared with placebo or in which the
drugs were compared with each other in adults with vascular dementia or other VCI (excluding cerebral autosomal dominant arteriopathy
with subcortical infarcts and leukoencephalopathy (CADASIL)). We included all drug doses and routes of administration.
Data collection and analysis
Two review authors independently identified eligible trials, extracted data, assessed risk of bias, and applied the GRADE approach to assess
the certainty of the evidence. The primary outcomes were cognition, clinical global impression, function (performance of activities of daily
living), and adverse events. Secondary outcomes were serious adverse events, incidence of development of new dementia, behavioural disturbance, carer burden, institutionalisation, quality of life and death. For the pairwise analyses, we pooled outcome data at similar time
points using random-eEects methods. We also performed a network meta-analysis using Bayesian methods.
Main results
We included eight trials (4373 participants) in the review. Three trials studied donepezil 5 mg or 10 mg daily (n= 2193); three trials studied
rivastigmine at a maximum daily dose of 3 to 12 mg (n= 800); and two trials studied galantamine at a maximum daily dose of 16 to 24 mg
(n= 1380). The trials included participants with possible or probable vascular dementia or cognitive impairment following stroke. Mean
ages were between 72.2 and 73.9 years. All of the trials were at low or unclear risk of bias in all domains, and the evidence ranged from
very low to high level of certainty.
For cognition, the results showed that donepezil 5 mg improves cognition slightly, although the size of the eEect is unlikely to be clinically
important (mean diEerence (MD) −0.92 Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) points (range 0 to 70), 95%
confidence interval (CI) −1.44 to −0.40; high-certainty evidence). Donepezil 10 mg (MD −2.21 ADAS-Cog points, 95% CI −3.07 to −1.35;
moderate-certainty evidence) and galantamine 16 to 24 mg (MD −2.01 ADAS-Cog point, 95%CI −3.18 to −0.85; moderate-certainty evidence)
probably also improve cognition, although the larger eEect estimates still may not be clinically important. With low certainty, there may
be little to no eEect of rivastigmine 3 to 12 mg daily on cognition (MD 0.03 ADAS-Cog points, 95% CI −3.04 to 3.10; low-certainty evidence).
Adverse events reported in the studies included nausea and/or vomiting, diarrhoea, dizziness, headache, and hypertension. The results
showed that there was probably little to no diEerence between donepezil 5 mg and placebo in the number of adverse events (odds ratio
(OR) 1.22, 95% CI 0.94 to 1.58; moderate-certainty evidence), but there were slightly more adverse events with donepezil 10 mg than with
placebo (OR 1.95, 95% CI 1.20 to 3.15; high-certainty evidence). The eEect of rivastigmine 3 to 12 mg on adverse events was very uncertain
(OR 3.21, 95% CI 0.36 to 28.88; very low-certainty evidence). Galantamine 16 to 24 mg is probably associated with a slight excess of adverse
events over placebo (OR 1.57, 95% CI 1.02 to 2.43; moderate-certainty evidence).
In the network meta-analysis (NMA), we included cognition to represent benefit, and adverse events to represent harm. All drugs ranked
above placebo for cognition and below placebo for adverse events. We found donepezil 10 mg to rank first in terms of benefit, but third
in terms of harms, when considering the network estimates and quality of evidence. Galantamine was ranked second in terms of both
benefit and harm. Rivastigmine had the lowest ranking of the cholinesterase inhibitors in both benefit and harm NMA estimates, but this
may reflect possibly inadequate doses received by some trial participants and small trial sample sizes.
Authors' conclusions
We found moderate- to high-certainty evidence that donepezil 5 mg, donepezil 10 mg, and galantamine have a slight beneficial eEect on
cognition in people with VCI, although the size of the change is unlikely to be clinically important. Donepezil 10 mg and galantamine 16 to
24 mg are probably associated with more adverse events than placebo. The evidence for rivastigmine was less certain.
The data suggest that donepezil 10 mg has the greatest eEect on cognition, but at the cost of adverse eEects. The eEect is modest, but
in the absence of any other treatments, people living with VCI may still wish to consider the use of these agents. Further research into rivastigmine is needed, including the use of transdermal patches.
Original languageEnglish
Pages (from-to)CD013306
JournalCochrane Library
Early online date22 Feb 2021
Publication statusE-pub ahead of print - 22 Feb 2021


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