Cholinesterase inhibitors and falls, syncope and injuries in patients with cognitive impairment: a systematic review and meta-analysis.

BACKGROUND: Cholinesterase inhibitors are commonly used to treat patients with neurocognitive disorders, who often have an elevated risk of falling. Effective use of these medications requires a thoughtful assessment of risks and benefits. OBJECTIVE: To provide an update on previous reviews and determine the association between cholinesterase inhibitors and falls, syncope, fracture and accidental injuries in patients with neurocognitive disorders. METHODS: Embase, MEDLINE, Cochrane Central Register of Controlled Trials, Cumulative Index of Nursing and Allied Health Literature and AgeLine were systematically searched through March 2023 to identify all randomised controlled trials of cholinesterase inhibitors (donepezil, galantamine, rivastigmine) in patients with cognitive impairment. Corresponding authors were contacted for additional data necessary for meta-analysis. Inclusion criteria consisted of adults ≥19 years, with a diagnosis of dementia, Parkinson's disease, mild cognitive impairment or traumatic brain injury. Data were extracted in duplicate for the aforementioned primary outcomes and all outcomes were analysed using random-effects meta-analysis. RESULTS: Fifty three studies (30 donepezil, 14 galantamine, 9 rivastigmine) were included providing data on 25, 399 patients. Cholinesterase inhibitors, compared to placebo, were associated with reduced risk of falls (risk ratio [RR] 0.84 [95% confidence interval [CI] = 0.73-0.96, P = 0.009]) and increased risk of syncope (RR 1.50 [95% CI = 1.02-2.21, P = 0.04]). There was no association with accidental injuries or fractures. CONCLUSION: In patients with neurocognitive disorders, cholinesterase inhibitors were associated with decreased risk of falls, increased risk of syncope and no association with accidental trauma or fractures. These findings will help clinicians better evaluate risks and benefits of cholinesterase inhibitors.

Acetylcholinesterase inhibitors for autistic spectrum disorders.

BACKGROUND: Autism spectrum disorder (autism) is a neurodevelopmental condition characterised by impairments in social communication and interaction, plus restricted, repetitive patterns of behaviour and interests. Whilst some people embrace autism as part of their identity, others struggle with their difficulties, and some seek treatment. There are no current interventions that result in complete reduction of autism features. Acetylcholine is a neurotransmitter for the cholinergic system and has a role in attention, novelty seeking, and memory. Low levels of acetylcholine have been investigated as a potential contributor to autism symptomatology. Donepezil, galantamine, and rivastigmine (commonly referred to as acetylcholinesterase inhibitors) all inhibit acetylcholinesterase, and have slightly different modes of action and biological availability, so their effectiveness and side-effect profiles may vary. The effect of various acetylcholinesterase inhibitor on core autism features across the lifespan, and possible adverse effects, have not been thoroughly investigated. OBJECTIVES: To evaluate the efficacy and harms of acetylcholinesterase inhibitors for people with the core features (social interaction, communication, and restrictive and repetitive behaviours) of autism. To assess the effects of acetylcholinesterase inhibitors on non-core features of autism. SEARCH METHODS: In November 2022, we searched CENTRAL, MEDLINE, Embase, eight other databases, and two trials registers. We also searched the reference lists of included studies and relevant reviews, and contacted authors of relevant studies. SELECTION CRITERIA: Randomised controlled trials (RCTs), comparing acetylcholinesterase inhibitors (e.g. galantamine, donepezil, or rivastigmine) of varying doses, delivered orally or via transdermal patch, either as monotherapy or adjunct therapy, with placebo. People of any age, with a clinical diagnosis of autism were eligible for inclusion. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. Our primary outcomes were core features of autism and adverse effects. Secondary outcomes were language, irritability, hyperactivity, and general health and function. We used GRADE to assess certainty of evidence. MAIN RESULTS: We included two RCTs (74 participants). One study was conducted in Iran, the second in the USA, although exact location in the USA is unclear. Galantamine plus risperidone versus placebo plus risperidone One study compared the effects of galantamine plus risperidone to placebo plus risperidone (40 participants, aged 4 years to 12 years). Primary and secondary outcomes of interest were measured postintervention, using subscales of the Aberrant Behavior Checklist (score 0 to 3; higher scores = greater impairment). Very low-certainty evidence showed there was little to no difference between the two groups postintervention for social communication (mean difference (MD) -2.75, 95% confidence interval (CI) -5.88 to 0.38), and restricted and repetitive behaviour (MD -0.55, 95% CI -3.47 to 2.37). Overall autism features were not assessed. Adverse events may be higher in the galantamine plus risperidone group (75%) compared with the placebo plus risperidone group (35%): odds ratio 5.57, 95% CI 1.42 to 21.86, low-certainty evidence. No serious adverse events were reported. Low-certainty evidence showed a small difference in irritability (MD -3.50, 95% CI -6.39 to -0.61), with the galantamine plus risperidone group showing a greater decline on the irritability subscale than the placebo group postintervention. There was no evidence of a difference between the groups in hyperactivity postintervention (MD -5.20, 95% CI -10.51 to 0.11). General health and function were not assessed. Donepezil versus placebo One study compared donepezil to placebo (34 participants aged 8 years to 17 years). Primary outcomes of interest were measured postintervention, using subscales of the Modified Version of The Real Life Rating Scale (scored 0 to 3; higher scores = greater impairment). Very low-certainty evidence showed no evidence of group differences immediately postintervention in overall autism features (MD 0.07, 95% CI -0.19 to 0.33), or in the autism symptom domains of social communication (MD -0.02, 95% CI -0.34 to 0.30), and restricted and repetitive behaviours (MD 0.04, 95% CI -0.27 to 0.35). Significant adverse events leading to study withdrawal in at least one participant was implied in the data analysis section, but not explicitly reported. The evidence is very uncertain about the effect of donepezil, compared to placebo, on the secondary outcomes of interest, including irritability (MD 1.08, 95% CI -0.41 to 2.57), hyperactivity (MD 2.60, 95% CI 0.50 to 4.70), and general health and function (MD 0.03, 95% CI -0.48 to 0.54) postintervention. Across all analyses within this comparison, we judged the evidence to be very low-certainty due to high risk of bias, and very serious imprecision (results based on one small study with wide confidence intervals). The study narratively reported adverse events for the study as a whole, rather than by treatment group. AUTHORS' CONCLUSIONS: Evidence about the effectiveness of acetylcholinesterase inhibitors as a medication to improve outcomes for autistic adults is lacking, and for autistic children is very uncertain. There is a need for more evidence of improvement in outcomes of relevance to clinical care, autistic people, and their families. There are a number of ongoing studies involving acetylcholinesterase inhibitors, and future updates of this review may add to the current evidence.

Adverse Drug Event Profile Associated with Anti-dementia Drugs: Analysis of a Spontaneous Reporting Database.

Adverse drug events (ADEs) rates associated with anti-dementia acetylcholinesterase inhibitors are estimated to be 5%-20% and show a wide range of symptoms. No report has examined whether there is a difference in the anti-dementia drugs' ADEs profile. This study aimed to establish whether anti-dementia drugs' ADEs profile differed. Data was based on the Japanese Adverse Drug Event Report (JADER) database. The reporting odds ratios (RORs) was used to analyze data for ADEs from April 2004-October 2021. The target drugs were donepezil, rivastigmine, galantamine, and memantine. The top ten most frequently occurring adverse events were selected. The association between the RORs and antidementia drug ADEs was evaluated, and compared the distribution rate of expression age related to ADEs and each ADEs' timing of onset due to anti-dementia drugs. The primary outcome was RORs. Secondary outcome were expression age and time-to-onset of ADE associated with anti-dementia drugs. A total of 705,294 reports were analyzed. The adverse events incidence differed. Bradycardia, loss of consciousness, falls, and syncope incidence were significantly diverse. The Kaplan-Meier curve results for the cumulative ADEs incidence showed that donepezil had the slowest onset, while galantamine, rivastigmine, and memantine had approximately the same timing of onset.

Improper Application of a Rivastigmine Patch to the Back of the Neck Induced Toxic Symptoms.

Rivastigmine is a highly effective drug for treating Alzheimer's disease. However, its addiction can be fatal, so proper use of this transdermal drug is needed. We herein report an 85-year-old woman with Alzheimer's disease who inappropriately placed rivastigmine patches on the back of her neck. She suffered from acute cholinergic syndrome, hypersalivation, anorexia, dyspnea, and vomiting. These symptoms disappeared when the improper use of rivastigmine patches was ceased. This case serves as a warning to physicians and pharmacists of the risk associated with the improper placement of rivastigmine patches.

Diphenhydramine-Induced Antimuscarinic Delirium Treated with Physostigmine and Transdermal Rivastigmine.

INTRODUCTION: Recurrent physostigmine shortages present a challenge to healthcare providers treating antimuscarinic delirium. Other centrally acting acetylcholinesterase inhibitors such as rivastigmine may represent a therapeutic alternative or adjunct during physostigmine shortage; however, previous reports of use have not documented serum antimuscarinic toxin concentrations, limiting evaluation of effectiveness. Combination therapy with physostigmine and rivastigmine has not been described. In this report, the authors present a case of diphenhydramine-induced antimuscarinic delirium with elevated diphenhydramine serum concentrations treated with physostigmine and transdermal rivastigmine without observed adverse effect. CASE REPORT: A 48-year-old female presented to an emergency department after ingesting 3.75 g (41.2 mg/kg) of diphenhydramine. She had antimuscarinic delirium with a presenting serum diphenhydramine concentration of 1500 ng/mL (therapeutic range, 25-112 ng/mL) and required two doses of physostigmine to avert intubation prior to intensive care unit (ICU) admission. At hospital hour 22, in the ICU, antimuscarinic delirium persisted but no further physostigmine was available due to hospital shortage. Therefore, a 9.5-mg transdermal rivastigmine patch was applied. By hospital hour 24, her delirium had resolved. A serum diphenhydramine concentration at hospital hour 25 was elevated at 760 ng/mL. Transdermal rivastigmine was discontinued at hospital hour 48 without recurrent delirium. Despite persistent normal mental status after rivastigmine discontinuation, the patient had a dry mouth, difficulty urinating, and mydriasis until hospital day 5. She never developed muscarinic toxicity. DISCUSSION: Transdermal rivastigmine may be a useful treatment alternative or adjunct during physostigmine shortage for antimuscarinic delirium and has a long duration of action without aspiration risk. Muscarinic toxicity was not observed.

Dysphagia Risk in Patients Prescribed Rivastigmine: A Systematic Analysis of FDA Adverse Event Reporting System.

BACKGROUND: Dysphagia has been reported as an adverse event for patients receiving rivastigmine for Alzheimer's disease (AD) treatment. OBJECTIVE: The purpose of this study was to determine the association between dysphagia and the usage of rivastigmine by using the pharmacovigilance data from the FDA Adverse Event Reporting System (FAERS). METHODS: The risk of dysphagia in patients who took rivastigmine was compared with those of patients who took other medications. In addition, this study sought to determine if the dysphagia risk was influenced by sex, age, dosage, and medication routes of administration. RESULTS: When compared to patients prescribed donepezil, galantamine, or memantine, individuals prescribed rivastigmine were almost twice as likely to report dysphagia as an adverse event. The dysphagia risk in individuals prescribed rivastigmine is comparable to individuals prescribed penicillamine but significantly higher than clozapine, drugs of which have been previously shown to be associated with elevated dysphagia likelihood. Individuals older than 80 were 122% more likely to report having dysphagia after being prescribed rivastigmine than patients that were 50-70 years of age. Oral administration of rivastigmine was associated with approximately 2 times greater likelihood of reporting dysphagia relative to users of the transdermal patch. In addition, dysphagia showed higher association with pneumonia than other commonly reported adverse events. CONCLUSION: Patients prescribed rivastigmine were at greater risk of reporting dysphagia as an adverse event than patients prescribed many other medicines. This increase in dysphagia occurrence may be attributed to the dual inhibition of both acetylcholinesterase and butyrylcholinesterase.

Risk of Serious Adverse Events Associated With Individual Cholinesterase Inhibitors Use in Older Adults With Dementia: A Population-Based Cohort Study.

BACKGROUND AND OBJECTIVE: Cholinesterase inhibitors (ChEIs) are used as first-line pharmacotherapy to manage dementia. However, there are limited data regarding their relative safety. This study evaluated the risk of serious adverse events (SAEs) associated with individual ChEIs in older adults with dementia and also examined sex-based and dose-based effects on this risk. METHODS: This was a retrospective cohort study using 2013-2015 US Medicare claims data involving Parts A, B, and D. Patients aged ≥ 65 years with a dementia diagnosis and incident use of the ChEIs, namely donepezil, galantamine, or rivastigmine, were included. The primary outcome of interest was SAEs defined as emergency department visits, inpatient hospitalizations, or death within 6 months of ChEI initiation. Multivariable Cox proportional hazards regression with propensity score (PS) as a covariate and inverse probability of treatment weighting generated using generalized boosted models was used to assess the risk of SAEs across individual ChEIs. RESULTS: The study included 767,684 older adults with dementia who were incident new users of ChEIs (donepezil 79.42%, rivastigmine 17.67%, galantamine 2.91%). SAEs were observed in 15.5% of the cohort within 6 months of ChEI prescription. Cox regression model with PS as covariate found that patients prescribed rivastigmine (adjusted hazard ratio [aHR] 1.12; 95% CI 1.03-1.33) and galantamine (aHR 1.51; 95% CI 1.24-1.84) were at increased risk of SAEs compared with patients on donepezil. Stratified analyses revealed that rivastigmine was associated with an 18% increased risk for SAEs in females (aHR 1.18; 95% CI 1.06-1.31), and galantamine was associated with a 71% increased risk in males (aHR 1.71; 95% CI 1.17-2.51) compared with donepezil. High and recommended index doses of rivastigmine and galantamine were associated with an increased risk of SAEs compared with donepezil. The findings were consistent in sensitivity analyses. CONCLUSION: The study found that the risk of SAEs varied across individual ChEIs, with sex and dose moderating these effects. Therefore, these moderating effects should be carefully considered in personalizing dementia care.

Bioavailability Study of a Transdermal Patch Formulation of Rivastigmine Compared with Exelon in Healthy Subjects.

BACKGROUND AND OBJECTIVES: Rivastigmine is a reversible cholinesterase inhibitor indicated for the treatment of all stages of Alzheimer's disease (AD). Transdermal patch formulation allows smooth and continuous drug delivery. Its tolerability, efficacy and convenience of use increase treatment compliance. This study was designed to evaluate the bioavailability and to assess the bioequivalence of two rivastigmine transdermal patches at steady state (RIV-TDS Test Product versus Exelon Marketed Reference Product), with a release rate of 13.3 mg/24 h, after multiple patch applications. As secondary objectives, safety, patch adhesion and skin irritation were evaluated. METHODS: This was an open-label, randomized, balanced, two-period, two-sequence, cross-over study of healthy adults (n = 31). The treatment period consisted of two 5-day study periods during which consecutive daily application of the investigational patches with a release rate of 13.3 mg/24 h rivastigmine took place. Serial blood samples were collected to measure plasma concentrations. Adhesion and skin irritation assessments were performed after application of patches. RESULTS: Point estimates and 90% confidence intervals of pharmacokinetic parameters at steady state, viz. area under the plasma concentration versus time curve from dosing time to the end of the dosing interval τ (profile day) at steady state [AUC0-τ,ss] (97.4; 88.8-106.9), maximum plasma concentration within the dosing interval τ (profile day) at steady state [Cmax,ss] (99.6; 90.4-109.7) and trough plasma concentration at the end of the dosing interval τ (profile day) at steady state [Cτ,ss] (96.8; 86.2-108.9), demonstrated that both patches were bioequivalent. Evaluation of patch adhesion showed better skin adherence for RIV-TDS as well as dermal response scores (skin tolerability after removal). CONCLUSIONS: For both products, bioequivalence was shown and systemic tolerability was in accordance with the safety profile of the drug substance. The trial is registered in ClinicalTrials.gov: NCT03573050 and EudraCT: 2018-000968-28.

Targeting the Beta-2-Adrenergic Receptor and the Risk of Developing Alzheimer's Disease: A Retrospective Inception Cohort Study.

BACKGROUND: Animal studies suggested that ß2-Adrenergic receptors (ß2AR) may be a potential target for the treatment of Alzheimer's disease (AD). OBJECTIVE: This retrospective inception cohort study aimed to assess the association between antagonists and agonists of the ß2AR and the risk of starting treatment for AD in older adults. METHODS: A retrospective inception cohort study was conducted among older adults who initiated either non-selective ßAR antagonists or selective ß2AR agonists using the University Groningen IADB.nl prescription database (study period 1994-2019). For each exposed cohort, two reference cohorts (A and B) were matched on age at index date. The main outcome was defined as at least two prescriptions for cholinesterase inhibitors (rivastigmine, galantamine, and donepezil) and/or memantine. Cox proportional hazard regression models were used to estimate hazard ratios (HR). RESULTS: The risk of developing AD was elevated among patients exposed to non-selective ßAR antagonists (A: aHR 3.303, 95% CI 1.230-8.869, B: aHR 1.569, 95% CI 0.560-4.394) and reduced among patients exposed to selective ß2AR agonists (A: aHR 0.049, 95% CI 0.003-0.795, B: aHR 0.834, 95% CI 0.075-9.273) compared to reference patients. CONCLUSION: These findings suggest that exposure to non-selective ßAR antagonists is associated with an increased risk for developing AD whereas there may be a decreased risk for developing AD after exposure to selective ß2AR agonists.

Association between long-term usage of acetylcholinesterase inhibitors and lung cancer in the elderly: a nationwide cohort study.

This retrospective cohort study aimed to evaluate the association between acetylcholinesterase inhibitors (AChEI) usage and the risk of lung cancer. Data from 116,106 new users of AChEI and 348,318, at a ratio of 1:3, matched by age, sex, and index-year, between 2000 and 2015 controls were obtained from the Taiwan Longitudinal Health Insurance Database in this cohort study. The Cox regression model was used to compare the risk of lung cancer. The adjusted hazard ratio (aHR) of lung cancer for AChEI users was 1.198 (95% confidence interval [CI] = 0.765-1.774, p = 0.167). However, the adjusted HR for patients aged ≥ 65 was adjusted to HR: 1.498 (95% CI = 1.124-1.798, p < 0.001), in contrast to the comparison groups. In addition, patients with comorbidities such as pneumonia, bronchiectasis, pneumoconiosis, pulmonary alveolar pneumonopathy, hypertension, stroke, coronary artery disease, diabetes mellitus, chronic kidney disease, depression, anxiety, smoking-related diseases, dementia, and seeking medical help from medical centers and regional hospitals, were associated with a higher risk in lung cancer. Furthermore, longer-term usage of rivastigmine (366-730 days, ≥ 731 days) and galantamine (≥ 731 days) was associated with the risk of lung cancer. AChEI increased the risk of lung cancer in the older aged patients, several comorbidities, and a longer-term usage of rivastigmine and galantamine. Therefore, physicians should estimate the risks and benefits of AChEI usage and avoid prescribing antidepressants concurrently.

Risk of overactive bladder associated with cholinesterase inhibitors in dementia.

BACKGROUND: Although cholinesterase inhibitors (ChEIs) are the primary treatment for dementia, they are associated with overactive bladder (OAB), necessitating antimuscarinic use. Limited data exist regarding the risk of OAB across individual ChEIs in dementia. This study evaluated the risk of OAB associated with individual ChEIs in older adults with dementia. METHODS: This was a new user retrospective cohort study using Medicare claims data involving Parts A, B, and D claims dataset from 2013 to 2015. The study included older adults (aged 65 and older) with a diagnosis of dementia using donepezil, galantamine, or rivastigmine. New ChEI claims were identified with a 6-month baseline washout period. Patients with OAB diagnosis or any antimuscarinic or mirabegron use in the baseline period were excluded. The primary outcome of interest was OAB diagnosis or prescription of antimuscarinics or mirabegron within 6 months of ChEI initiation. Multivariable cox proportional hazards regression with propensity scores (PS) as covariates and inverse probability of treatment weighting generated using generalized boosted models was used to assess the risk of OAB among donepezil, galantamine, and rivastigmine users. RESULTS: The study included 524,975 older adults with dementia who were incident users of ChEIs (donepezil 80.72%, rivastigmine 16.41%, galantamine 2.87%). Overall, OAB diagnosis/antimuscarinic/mirabegron prescription was observed in 5.07% of the cohort within 6 months of ChEIs prescription. The Cox regression model with PS as covariate approach found that donepezil use increased the risk of OAB compared to rivastigmine (aHR, 1.13; 95% CI, 1.08-1.28; p < 0.0001). However, there was no differential risk of OAB between galantamine and rivastigmine. The findings were consistent with the generalized boosted models. CONCLUSIONS: The study found that the risk of OAB varies across individual ChEIs with an increased risk of OAB with donepezil compared to rivastigmine. The study findings suggest the need to understand and manage medication-related morbidity in older adults with dementia.

The Association Between Use of Rivastigmine and Pneumonia: Systematic Analysis of FDA Adverse Event Reporting System.

BACKGROUND: Pneumonia is an inflammatory condition induced by infection of the lungs and is frequently a cause of morbidity and mortality among patients with Alzheimer's disease (AD). Some studies have shown an association between acetylcholinesterase inhibitor use and elevated pneumonia risk. OBJECTIVE: The purpose of this study was to perform a comparative analysis of the number of reported pneumonia cases in individuals prescribed rivastigmine relative to the number of reported cases by patients using other therapeutics including over-the-counter drugs and other AD therapeutics, as reported to the FDA Adverse Event Reporting System (FAERS) database. METHODS: A disproportionality analysis was conducted to investigate the association between using rivastigmine and risk of pneumonia. Age, gender, dosage, temporality, and geographic distribution of reported cases were also assessed. RESULTS: Patients prescribed rivastigmine were more likely to report pneumonia as an adverse event than many drugs except galantamine. Males were found to be 46% more likely than females to report pneumonia as an adverse event while likelihood of pneumonia diagnosis increases 3-5-fold in patients older than 65 years of age. CONCLUSION: The observed elevated frequency of aspiration pneumonia in patients prescribed rivastigmine may be due to an induced cholinergic crisis that is selective for the medulla oblongata, resulting in gastrointestinal distress, impaired swallowing, heightened salivation, and labored breathing. The observed elevated frequency of infectious pneumonia in patients prescribed rivastigmine may also be linked to overstimulation of neurons in the medulla oblongata and downstream suppression of localized inflammatory responses.

The Efficacy of Transdermal Rivastigmine in Mild to Moderate Alzheimer's Disease with Concomitant Small Vessel Cerebrovascular Disease: Findings from an Open-Label Study.

BACKGROUND: Rivastigmine is used to treat cognitive impairment in Alzheimer's disease (AD); however, the efficacy of Rivastigmine in patients with AD and concomitant small vessel cerebrovascular disease (svCVD) remains unclear. We investigated the effectiveness of Rivastigmine Patch in patients with AD and svCVD. METHODS: In this open-label study, 100 patients with AD and MRI confirmed svCVD received 9.5mg/24 hours Rivastigmine transdermal treatment for 24 weeks. The primary outcome was global cognition indexed using the ADAS-Cog. Secondary outcomes included clinical-rated impression of change (indexed using (ADCS-CGIC), activities of daily living (indexed using ADCS-ADL) and side effects. RESULTS: Overall, performance on the ADAS-Cog after 24 weeks deteriorated by 1.78 (SD = 5.29) points. Fifty-two percent of the sample demonstrated improvement or remained stable, while 48% demonstrated worsening of ADAS-Cog scores. Of the 52%, significant improvement (2 or more-point decline) on the ADAS-Cog was observed in 25% of the sample, with a mean change of -5.08 (SD = 3.11). A decline on the ADAS-Cog was observed in 48% of the sample, with a mean change of 6 (SD = 2.98) points. Cognitive outcome did not interact with severity of svCVD. ADCS-ADL scores remained stable from baseline to week 24 and ADCS-CGIC reports indicated that 81% of the patients remained stable after treatment. Side effects were reported by 16% of the patients, with contact dermatitis being the most common. CONCLUSION: Our findings suggest that Rivastigmine may have a role in the management of patients having AD and concomitant mild-severe svCVD, with minimal side effects.

Cholinesterase inhibitors for vascular dementia and other vascular cognitive impairments: a network meta-analysis.

BACKGROUND: 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 effective in VCI and whether there are differences between them with regard to efficacy or adverse events. OBJECTIVES: (1) To assess the efficacy and safety of cholinesterase inhibitors in the treatment of adults with vascular dementia and other VCI. (2) To compare the effects of different 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), ClinicalTrials.gov, 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-effects 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 effect is unlikely to be clinically important (mean difference (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 effect estimates still may not be clinically important. With low certainty, there may be little to no effect 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 difference 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 effect 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 effect 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 effect on cognition, but at the cost of adverse effects. The effect 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.

Withdrawal or continuation of cholinesterase inhibitors or memantine or both, in people with dementia.

BACKGROUND: Dementia is a progressive syndrome characterised by deterioration in memory, thinking and behaviour, and by impaired ability to perform daily activities. Two classes of drug - cholinesterase inhibitors (donepezil, galantamine and rivastigmine) and memantine - are widely licensed for dementia due to Alzheimer's disease, and rivastigmine is also licensed for Parkinson's disease dementia. These drugs are prescribed to alleviate symptoms and delay disease progression in these and sometimes in other forms of dementia. There are uncertainties about the benefits and adverse effects of these drugs in the long term and in severe dementia, about effects of withdrawal, and about the most appropriate time to discontinue treatment. OBJECTIVES: To evaluate the effects of withdrawal or continuation of cholinesterase inhibitors or memantine, or both, in people with dementia on: cognitive, neuropsychiatric and functional outcomes, rates of institutionalisation, adverse events, dropout from trials, mortality, quality of life and carer-related outcomes. SEARCH METHODS: We searched the Cochrane Dementia and Cognitive Improvement Group's Specialised Register up to 17 October 2020 using terms appropriate for the retrieval of studies of cholinesterase inhibitors or memantine. The Specialised Register contains records of clinical trials identified from monthly searches of a number of major healthcare databases, numerous trial registries and grey literature sources. SELECTION CRITERIA: We included all randomised, controlled clinical trials (RCTs) which compared withdrawal of cholinesterase inhibitors or memantine, or both, with continuation of the same drug or drugs. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed citations and full-text articles for inclusion, extracted data from included trials and assessed risk of bias using the Cochrane risk of bias tool. Where trials were sufficiently similar, we pooled data for outcomes in the short term (up to 2 months after randomisation), medium term (3-11 months) and long term (12 months or more). We assessed the overall certainty of the evidence for each outcome using GRADE methods. MAIN RESULTS: We included six trials investigating cholinesterase inhibitor withdrawal, and one trial investigating withdrawal of either donepezil or memantine. No trials assessed withdrawal of memantine only. Drugs were withdrawn abruptly in five trials and stepwise in two trials. All participants had dementia due to Alzheimer's disease, with severities ranging from mild to very severe, and were taking cholinesterase inhibitors without known adverse effects at baseline. The included trials randomised 759 participants to treatment groups relevant to this review. Study duration ranged from 6 weeks to 12 months. There were too few included studies to allow planned subgroup analyses. We considered some studies to be at unclear or high risk of selection, performance, detection, attrition or reporting bias. Compared to continuing cholinesterase inhibitors, discontinuing treatment may be associated with worse cognitive function in the short term (standardised mean difference (SMD) -0.42, 95% confidence interval (CI) -0.64 to -0.21; 4 studies; low certainty), but the effect in the medium term is very uncertain (SMD -0.40, 95% CI -0.87 to 0.07; 3 studies; very low certainty). In a sensitivity analysis omitting data from a study which only included participants who had shown a relatively poor prior response to donepezil, inconsistency was reduced and we found that cognitive function may be worse in the discontinuation group in the medium term (SMD -0.62; 95% CI -0.94 to -0.31). Data from one longer-term study suggest that discontinuing a cholinesterase inhibitor is probably associated with worse cognitive function at 12 months (mean difference (MD) -2.09 Standardised Mini-Mental State Examination (SMMSE) points, 95% CI -3.43 to -0.75; moderate certainty). Discontinuation may make little or no difference to functional status in the short term (SMD -0.25, 95% CI -0.54 to 0.04; 2 studies; low certainty), and its effect in the medium term is uncertain (SMD -0.38, 95% CI -0.74 to -0.01; 2 studies; very low certainty). After 12 months, discontinuing a cholinesterase inhibitor probably results in greater functional impairment than continuing treatment (MD -3.38 Bristol Activities of Daily Living Scale (BADLS) points, 95% CI -6.67 to -0.10; one study; moderate certainty). Discontinuation may be associated with a worsening of neuropsychiatric symptoms over the short term and medium term, although we cannot exclude a minimal effect (SMD - 0.48, 95% CI -0.82 to -0.13; 2 studies; low certainty; and SMD -0.27, 95% CI -0.47 to -0.08; 3 studies; low certainty, respectively). Data from one study suggest that discontinuing a cholinesterase inhibitor may result in little to no change in neuropsychiatric status at 12 months (MD -0.87 Neuropsychiatric Inventory (NPI) points; 95% CI -8.42 to 6.68; moderate certainty). We found no clear evidence of an effect of discontinuation on dropout due to lack of medication efficacy or deterioration in overall medical condition (odds ratio (OR) 1.53, 95% CI 0.84 to 2.76; 4 studies; low certainty), on number of adverse events (OR 0.85, 95% CI 0.57 to 1.27; 4 studies; low certainty) or serious adverse events (OR 0.80, 95% CI 0.46 to 1.39; 4 studies; low certainty), and on mortality (OR 0.75, 95% CI 0.36 to 1.55; 5 studies; low certainty). Institutionalisation was reported in one trial, but it was not possible to extract data for the groups relevant to this review. AUTHORS' CONCLUSIONS: This review suggests that discontinuing cholinesterase inhibitors may result in worse cognitive, neuropsychiatric and functional status than continuing treatment, although this is supported by limited evidence, almost all of low or very low certainty. As all participants had dementia due to Alzheimer's disease, our findings are not transferable to other dementia types. We were unable to determine whether the effects of discontinuing cholinesterase inhibitors differed with baseline dementia severity. There is currently no evidence to guide decisions about discontinuing memantine. There is a need for further well-designed RCTs, across a range of dementia severities and settings. We are aware of two ongoing registered trials. In making decisions about discontinuing these drugs, clinicians should exercise caution, considering the evidence from existing trials along with other factors important to patients and their carers.