Rivastigmine for people with Alzheimer's disease

Review question

We reviewed evidence comparing the effectiveness and safety of rivastigmine with placebo in people with Alzheimer's disease.


Alzheimer's disease is the commonest cause of dementia affecting older people. As the disease progresses, people lose the ability to remember, communicate, think clearly and perform the usual daily activities. Their behaviour or personality may also change. In severe Alzheimer's disease, the patients lose the ability to care for themselves and require full time care.

Currently, there is no cure available for Alzheimer's disease, but a few pharmacological interventions are available to alleviate symptoms.

The symptoms are caused by the loss of a type of nerve cell in the brain called cholinergic neurons. Rivastigmine, an acetylcholinesterase inhibitor, works by increasing the levels of a brain chemical called acetylcholine which allows the nerve cells to communicate. This may improve the symptoms of dementia. Rivastigmine can be taken orally, either as capsules or a liquid, or by applying a patch on the skin. Its effectiveness in improving the symptoms of Alzheimer's disease and safety were evaluated in this review.

Study characteristics

This review included double-blinded randomised controlled trials, and the evidence was searched for up to March 2015 using the standard Cochrane methods. The review included studies conducted for at least 12 weeks that compared the safety and effectiveness of rivastigmine compared with placebo. Thirteen studies that met these criteria were found. Most of these studies involved people with mild to moderate Alzheimer's disease with an average age of around 75 years.

Key results

Results from seven trials showed that patients on rivastigmine (6 to 12 mg/day by mouth, or 9.5 mg/day by skin patch) were better for three outcomes than those on placebo, after six months of treatment. The differences were quite small for cognitive function (2 points, using the ADAS-Cog which has a range of 70 points) and activities of daily living (standardised mean difference (SMD) of 0.20, which is considered a small effect). Patients on rivastigmine were more likely to show overall improvement compared with those on placebo (odds ratio of 1.47, 95% confidence interval (CI) of 1.25 to 1.72) . However, there was no difference for behavioural changes (reported by three trials) or impact on carers (reported by one trial). Patients on rivastigmine were also about twice as likely to experience adverse events, although this risk might have been slightly less for patients using patches compared with capsules. It was possible that certain types of adverse events were less in people using patches than taking capsules (nausea, vomiting, weight loss, dizziness).

In summary, rivastigmine may be of benefit to people with Alzheimer's disease. It is possible that the using a patch is associated with reduced side effects compared to using oral capsules.

Quality of evidence

The quality of the evidence for most of the outcomes reviewed was moderate. The main factors affecting our confidence in the results included relatively high number of patients dropping out in some of the trials (the rates of dropout in the rivastigmine arms were higher). There were also concerns about the applicability of the evidence for the long term treatment of Alzheimer's disease since data from double-blinded randomised controlled trials were only available for up to 12 months. All the data included in the main analysis of this review came from studies either sponsored or funded by the drug manufacturer (Novartis Pharma).

Authors' conclusions: 

Rivastigmine (6 to 12 mg daily orally or 9.5 mg daily transdermally) appears to be beneficial for people with mild to moderate Alzheimer's disease. In comparisons with placebo, better outcomes were observed for rate of decline of cognitive function and activities of daily living, although the effects were small and of uncertain clinical importance. There was also a benefit from rivastigmine on the outcome of clinician's global assessment. There were no differences between the rivastigmine group and placebo group in behavioural change or impact on carers. At these doses the transdermal patch may have fewer side effects than the capsules but has comparable efficacy. The quality of evidence is only moderate for all of the outcomes reviewed because of a risk of bias due to dropouts. All the studies with usable data were industry funded or sponsored. This review has not examined economic data.

Read the full abstract...

Alzheimer's disease is the commonest cause of dementia affecting older people. One of the therapeutic strategies aimed at ameliorating the clinical manifestations of Alzheimer's disease is to enhance cholinergic neurotransmission in the brain by the use of cholinesterase inhibitors to delay the breakdown of acetylcholine released into synaptic clefts. Tacrine, the first of the cholinesterase inhibitors to undergo extensive trials for this purpose, was associated with significant adverse effects including hepatotoxicity. Other cholinesterase inhibitors, including rivastigmine, with superior properties in terms of specificity of action and lower risk of adverse effects have since been introduced. Rivastigmine has received approval for use in 60 countries including all member states of the European Union and the USA.


To determine the clinical efficacy and safety of rivastigmine for patients with dementia of Alzheimer's type.

Search strategy: 

We searched ALOIS, the Cochrane Dementia and Cognitive Improvement Group Specialized Register, on 2 March 2015 using the terms: Rivastigmine OR  exelon OR ENA OR "SDZ ENA 713". ALOIS contains records of clinical trials identified from monthly searches of a number of major healthcare databases (Cochrane Library, MEDLINE, EMBASE, PsycINFO, CINAHL, LILACS), numerous trial registries and grey literature sources.

Selection criteria: 

We included all unconfounded, double-blind, randomised, controlled trials in which treatment with rivastigmine was administered to patients with dementia of the Alzheimer's type for 12 weeks or more and its effects compared with those of placebo in a parallel group of patients, or where two formulations of rivastigmine were compared.

Data collection and analysis: 

One review author (JSB) applied the study selection criteria, assessed the quality of studies and extracted data.

Main results: 

A total of 13 trials met the inclusion criteria of the review. The trials had a duration of between 12 and 52 weeks. The older trials tested a capsule form with a dose of up to 12 mg/day. Trials reported since 2007 have tested continuous dose transdermal patch formulations delivering 4.6, 9.5 and 17.7 mg/day.

Our main analysis compared the safety and efficacy of rivastigmine 6 to 12 mg/day orally or 9.5 mg/day transdermally with placebo.

Seven trials contributed data from 3450 patients to this analysis. Data from another two studies were not included because of a lack of information and methodological concerns. All the included trials were multicentre trials and recruited patients with mild to moderate Alzheimer's disease with a mean age of about 75 years. All had low risk of bias for randomisation and allocation but the risk of bias due to attrition was unclear in four studies, low in one study and high in two studies.

After 26 weeks of treatment rivastigmine compared to placebo was associated with better outcomes for cognitive function measured with the Alzheimer's Disease Assessment Scale-Cognitive (ADAS-Cog) score (mean difference (MD) -1.79; 95% confidence interval (CI) -2.21 to -1.37, n = 3232, 6 studies) and the Mini-Mental State Examination (MMSE) score (MD 0.74; 95% CI 0.52 to 0.97, n = 3205, 6 studies), activities of daily living (SMD 0.20; 95% CI 0.13 to 0.27, n = 3230, 6 studies) and clinician rated global impression of changes, with a smaller proportion of patients treated with rivastigmine experiencing no change or a deterioration (OR 0.68; 95% CI 0.58 to 0.80, n = 3338, 7 studies).

Three studies reported behavioural change, and there were no differences compared to placebo (standardised mean difference (SMD) -0.04; 95% CI -0.14 to 0.06, n = 1529, 3 studies). Only one study measured the impact on caregivers using the Neuropsychiatric Inventory-Caregiver Distress (NPI-D) scale and this found no difference between the groups (MD 0.10; 95% CI -0.91 to 1.11, n = 529, 1 study). Overall, participants who received rivastigmine were about twice as likely to withdraw from the trials (odds ratio (OR) 2.01, 95% CI 1.71 to 2.37, n = 3569, 7 studies) or to experience an adverse event during the trials (OR 2.16, 95% CI 1.82 to 2.57, n = 3587, 7 studies).