Efficacy and adverse effects of cholinesterase inhibitors and memantine in vascular dementia: a meta-analysis of randomised controlled trials

Summary

Background

Cholinesterase inhibitors and memantine do not have regulatory approval in most of the world for treatment of vascular dementia. A systematic review and meta-analysis was undertaken to assess the evidence for efficacy and safety of cholinesterase inhibitors and memantine in vascular dementia.

Methods

PubMed, BIOSIS, International Pharmaceutical Abstracts, and Cochrane registries were searched for randomised, placebo-controlled trials on cholinesterase inhibitors and memantine in patients with vascular dementia. Trial methods, clinical characteristics, outcomes, and adverse events were extracted and checked. Meta-analytic methods using fixed-effects models were used to give summaries of each drug's effects.

Findings

Three donepezil, two galantamine, one rivastigmine, and two memantine trials, comprising 3093 patients on the study drugs and 2090 patients on placebo, met the selection criteria. Trials were of 6-month duration with similar vascular dementia criteria and outcome measures. Cognitive effects on the Alzheimer's Disease Assessment scale were significant for all drugs, ranging from a −1·10 point mean difference (95% CI −2·15 to −0·05) for rivastigmine to −2·17 for 10 mg daily donepezil (95% CI −2·98 to −1·35). Only 5 mg daily donepezil had an effect on the Clinicians' Global Impression of Change scale (odds ratio 1·51 [95% CI 1·11–2·07]). No behavioural or functional benefits were observed, except for a −0·95 point difference (95% CI −1·74 to −0·16) with 10 mg daily donepezil on the Alzheimer's Disease Functional Assessment and Change Scale. Compared with placebo, more dropouts and adverse events (anorexia, nausea, vomiting, diarrhoea, and insomnia) occurred with the cholinesterase inhibitors, but not with memantine.

Interpretation

Cholinesterase inhibitors and memantine produce small benefits in cognition of uncertain clinical significance in patients with mild to moderate vascular dementia. Data are insufficient to support widespread use of these drugs in vascular dementia. Individual patient analyses are needed to identify subgroups of patients with vascular dementia who might benefit.

Introduction

Vascular dementia has an overall prevalence of 1·2–4·2% in people aged 65 years or older,¹ and has been reported to comprise 10–50% of dementia cases, depending on the diagnostic criteria and study population.2, 3, 4 Treatment has been limited to control of the underlying risk factors for cerebrovascular disease, such as hypertension and diabetes mellitus, with the primary goal of slowing clinical progression. The four cholinesterase inhibitors, tacrine, donepezil, galantamine, and rivastigmine, and the uncompetitive NMDA antagonist memantine, are approved in the USA and most of Europe for Alzheimer's disease (AD) but not for vascular dementia. Donepezil is approved for vascular dementia by regulatory agencies in New Zealand, India, Romania, South Korea, and Thailand,⁵ and memantine is approved for vascular dementia in Argentina, Brazil, and Mexico.

Approval for drugs used for the treatment of AD is mainly based on their efficacy on a cognitive assessment scale—the AD Assessment Scale-cognitive subscale (ADAS-cog) for mild to moderate dementia—supported by significant effects on clinicians' global assessments and activities of daily living (ADL) over the course of 6-month trials. The role of cholinesterase inhibitors and memantine for AD has been controversial, with some national formularies restricting their use, and health economists questioning whether the small clinical effects are economically worthwhile.6, 7

Evidence that disruption of cholinergic pathways contributes to the pathophysiology and clinical expression of vascular dementia has led to clinical trials of cholinesterase inhibitors in treatment of vascular dementia.8, 9 Although all cholinesterase inhibitors enhance intrasynaptic acetylcholine, they differ in structural, pharmacodynamic, and pharmacokinetic properties. For example, galantamine modulates nicotinic receptor function, rivastigmine inhibits butyrylcholinesterase, and donepezil has a particularly long elimination half-life.¹⁰ In addition, glutamatergic neurotoxicity may contribute to the pathophysiology of vascular dementia. Clinical trials of memantine suggest modest benefits in vascular dementia, possibly due to its effect in reducing glutamatergic activity.¹¹ Safety concerns have been raised about cholinesterase inhibitors, including increased mortality with galantamine in patients with mild cognitive impairment and with donepezil in patients with vascular dementia.5, 12

Because of the lack of regulatory approval in most of the world and concerns about safety, we did a systematic review of the available clinical trials to clarify the efficacy and adverse events of these drugs in treatment of vascular dementia. Previous reviews included only published trials reports, posing a significant risk for publication bias, and also focused on the individual dementia drugs.13, 14, 15, 16 We sought to include unpublished data from recent trials to achieve a comprehensive and updated review of the evidence. We included the three widely used cholinesterase inhibitors (donepezil, galantamine, and rivastigmine) and the glutamate modulator, memantine, to provide a concise, clinically relevant summary of the commercially available dementia medications in treatment of vascular dementia.