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Rivastigmine for vascular cognitive impairment

  1. Jacqueline Birks1,*,
  2. Bernadette McGuinness2,
  3. David Craig3

Editorial Group: Cochrane Dementia and Cognitive Improvement Group

Published Online: 31 MAY 2013

Assessed as up-to-date: 12 FEB 2013

DOI: 10.1002/14651858.CD004744.pub3

How to Cite

Birks J, McGuinness B, Craig D. Rivastigmine for vascular cognitive impairment. Cochrane Database of Systematic Reviews 2013, Issue 5. Art. No.: CD004744. DOI: 10.1002/14651858.CD004744.pub3.

Author Information

  1. 1

    University of Oxford, Centre for Statistics in Medicine, Oxford, UK

  2. 2

    National University of Ireland, School of Medicine, Galway, Ireland

  3. 3

    Queen's University Belfast, Department of Geriatric Medicine, Belfast, Northern Ireland, UK

*Jacqueline Birks, Centre for Statistics in Medicine, University of Oxford, Wolfson College, Linton Road, Oxford, OX2 6UD, UK. jacqueline.birks@csm.ox.ac.uk.

Publication History

  1. Publication Status: New search for studies and content updated (no change to conclusions)
  2. Published Online: 31 MAY 2013

SEARCH

 

Background

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Index terms

As the older population increases, the number of dementia sufferers increases proportionally. Vascular dementia represents the second most common subtype of dementia and may exist in 'pure' form or 'mixed' with Alzheimer's disease or other common dementias. As not all of those affected fulfil strict criteria for dementia, and may be significantly cognitively impaired without memory loss, the term vascular cognitive impairment (VCI) is useful.

Several forms of vascular damage can lead to cognitive impairment. Traditional concepts based on stroke and multi-infarct dementia are limited, as VCI can arise from a broad range of pathologies. Mixed vascular dementia with Alzheimer's disease is the commonest form of VCI (MRC CFAS 2001). Vascular dementia and Alzheimer's disease share risk factors (Black 2011), some histopathological changes (O'Brien 2003), and may even represent different subtypes of the same entity (Bullock 2004).

In the absence of Alzheimer's disease, VCI may result from large cortical infarcts (death of brain tissue caused by a blocked artery) or more subtle white matter ischaemia (lack of oxygen) (O'Brien 2003). Between these extremes lie small infarcts or lacunae. The clinical presentation varies according to the location and nature of the neuropathology (damage to the brain): single strategic infarcts present abruptly, while the onset of symptoms and signs due to subcortical damage from lacunae or white matter disease may be more insidious. Memory impairment is usually mild, and patients characteristically present with abnormalities in attention and executive functioning. The underlying damage is often to the neuronal circuitry of the prefrontal region rather than of the mesial temporal lobe (Cummings 1993; Erkinjuntti 2000). Non-cognitive features such as depression, apathy and emotional lability may also be prominent (O'Brien 2000). Physical impairment such as gait disorder or imbalance may be a concomitant feature (Pohjasvaara 2003). Radiological changes associated with VCI are common, most obviously following an overt event such as stroke, but also silently in a majority of the older population (up to 95% demonstrate white matter ischaemia, or small lacunar defects (Black 2011)).

Currently, there is no established standard treatment for VCI, so clinicians must extrapolate from large primary and secondary prevention trials in ischaemic heart disease, hypertension and stroke. Cholinesterase inhibitors effectively improve a broad range of symptoms in some patients with Alzheimer's disease through enhancement of cholinergic neurotransmission. Reductions in acetylcholine and acetyltransferase activity are common to both Alzheimer's disease and VCI, raising the possibility that these drugs may also be beneficial for the latter (Perry 1997; Toghi 1996).

The three internationally-established cholinesterase inhibitors for the treatment of Alzheimer's disease are donepezil, rivastigmine and galantamine. Methodologically robust, placebo-controlled trials involving large numbers of participants have demonstrated clear cognitive benefit in Alzheimer's disease with each drug (Hansen 2008). Additional gain has also been demonstrated in other areas, such as activities of daily living, global functioning and neuropsychiatric symptoms. The efficacy of cholinesterase inhibitors in VCI is less clear. A Cochrane review of the role of donepezil in VCI noted improvements in cognitive function and activities of daily living as well as more global measures of change (Malouf 2004).

Rivastigmine is a 'pseudo-irreversible' inhibitor of acetylcholinesterase (AChE) and butyryl-cholinesterase (BuChE). The additional inhibition of BuChE may be relevant in VCI, as rivastigmine is reasoned to have particular activity in affected regions of the brain associated with executive dysfunction and reduced attention (Moretti 2004).

 

Objectives

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Index terms

To assess the efficacy of rivastigmine compared with placebo in the treatment of people with vascular cognitive impairment (VCI), vascular dementia (VaD) or mixed dementia.

 

Methods

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Index terms
 

Criteria for considering studies for this review

 

Types of studies

All unconfounded, randomized, double-blind trials involving participants with vascular dementia, VCI or mixed dementia in which treatment with rivastigmine was compared with placebo were eligible for inclusion.

 

Types of participants

Patients diagnosed as having VCI, dementia or mixed dementia on a basis of standardized diagnostic criteria such as the ADDTC (California State Alzheimer's disease Diagnostic and Treatment Center) (Chui 1992), NINDS/AIREN (National Institute of Neurological Disorders and Stroke and the Association International pour la Recherche et l' Enseignement en Neurosciences) (Roman 1993), and ICD-10 (International Classification of Diseases of the World Health Organization) (WHO 1992), were eligible for inclusion.

Diagnosis of VCI with no dementia was based on scores on cognitive impairment scales.

 

Types of interventions

Rivastigmine at any dose compared with a parallel, placebo control group.

 

Types of outcome measures

The review assessed the following outcomes:

  • global impression (assessed by GDS, CDR-SB, ADCS-CGIC)
  • functional performance (assessed by means of ADCS-ADL, Chinese ADL)
  • behavioural disturbance (assessed by NPI, GDS)
  • cognitive function (assessed by means of ADAS-Cog, VaDAS, MMSE, Chinese MMSE, FAS, TenPoint Clock Test, Color Trails 1, Color Trails 2)
  • effect on carer
  • death
  • safety and adverse effects

 

Search methods for identification of studies

 

Electronic searches

We searched ALOIS (www.medicine.ox.ac.uk/alois) - the Cochrane Dementia and Cognitive Improvement Group’s Specialized Register on 12 February 2013. The search terms used were: rivastigmine, exelon, "SDZ ENA 713".

ALOIS is maintained by the Cochrane Dementia and Cognitive Improvement Group's Trials Search Co-ordinator and contains studies in the areas of dementia prevention, dementia treatment and cognitive enhancement in healthy people. The studies are identified from:  

  1. Monthly searches of a number of major healthcare databases: MEDLINE, EMBASE, CINAHL, PsycINFO and LILACS.
  2. Monthly searches of a number of trial registers: ISRCTN; UMIN (Japan's Trial Register); the WHO portal (which covers ClinicalTrials.gov; ISRCTN; the Chinese Clinical Trials Register; the German Clinical Trials Register; the Iranian Registry of Clinical Trials and the Netherlands National Trials Register, plus others).
  3. Quarterly search of The Cochrane Library’s Central Register of Controlled Trials (CENTRAL).
  4. Six-monthly searches of a number of grey literature sources: ISI Web of Knowledge Conference Proceedings; Index to Theses; Australasian Digital Theses.

To view a list of all sources searched for ALOIS see About ALOIS on the ALOIS website.

Details of the search strategies used for the retrieval of reports of trials from the healthcare databases, CENTRAL and conference proceedings can be viewed in the ‘methods used in reviews’ section within the editorial information about the Dementia and Cognitive Improvement Group.

Additional searches were performed in many of the sources listed above to cover the period after the last searches were performed for ALOIS, to ensure that the search for the review was as up-to-date and as comprehensive as possible. The search strategies used can be seen in Appendix 1 (the pre-publication search), and in Appendix 2.

The latest search (February 2013) retrieved a total of 652 results. The latest search identified no new studies for inclusion in the review.

 

Data collection and analysis

The two review authors independently discarded publications deemed to be irrelevant on the basis of title and abstract. Disagreements between the authors about final inclusion of trials were resolved by discussion, or by involving outside expert advice.

 

Quality assessment

The methodological quality of eligible trials was assessed, as low, unclear or high risk of bias using the Cochrane Collaboration handbook (Higgins 2011).

 

Data extraction

Data were extracted from the published reports. For each outcome assessed on a continuous scale the following statistics were required for each treatment group within each trial: mean change from baseline at endpoint, standard deviation of the mean change, and number of participants. Where changes from baseline were not reported, the mean, standard deviation and number of participants for each treatment group at each time point were extracted.

For binary data the numbers in each treatment group and the numbers experiencing the outcome of interest were sought.

The baseline assessment was defined as the latest available assessment prior to randomization, but not longer than two months prior.

Data were sought for each outcome measure on every participant randomized. To allow an intention-to-treat analysis all randomized patients were included irrespective of compliance, whether or not the patient was subsequently deemed ineligible or otherwise excluded from treatment or follow up. If intention-to-treat data were not available in the publications, the data of those on treatment, or who complete the trial, were sought and indicated as such.

 

Data analysis

The outcomes measured in clinical trials of dementia and cognitive impairment often arise from ordinal rating scales. Where the rating scales used in trials had a reasonably large number of ordered categories (more than 10), the data were treated as continuous outcomes arising from a normal distribution.

Summary statistics (number of participants, mean and standard deviation) for change from baseline are required for each rating scale at each assessment time for each treatment group in each trial.

When change from baseline results are not reported, the required summary statistics are calculated from the baseline and assessment time treatment group means and standard deviations. In this case a zero correlation between the measurements at baseline and assessment time is assumed. This method overestimates the standard deviation of the change from baseline, but this conservative approach is considered to be preferable in a meta-analysis.

Meta-analysis requires the combination of data from trials that may not use the same rating scale to assess an outcome. The measure of treatment difference used for any outcome in the review will be the weighted mean difference when pooled trials used the same rating scale or test, and the standardised mean difference (i.e. the absolute mean difference divided by the standard deviation) when they used different rating scales or tests.

The duration of trials may vary considerably. In future, if the range is considered too great to combine all trials into one meta-analysis, it will be divided into smaller time periods, and a separate meta-analysis conducted for each period. Some trials may contribute data to more than one time period, if multiple assessments have been done.

For binary outcomes, such as clinical improvement or no clinical improvement, the odds ratio has been used to measure treatment effect. A weighted estimate of the typical treatment effect across trials will be calculated.

In future, it is planned that overall estimates of the treatment difference will be presented. In all cases the overall estimate from a fixed-effect model will be presented and a test for heterogeneity using a standard Chi2 or the I2 statistic will be performed. If, however, there is evidence of heterogeneity of the treatment effect between trials then only homogeneous results will be pooled or a random-effects model will be used (in which case the confidence intervals would be broader than those of a fixed-effect model).

 

Subgroup analysis

Where relevant, and if data are available, future subgroup analyses will include age, sex, type and severity of impairment, and duration of treatment.

 

Results

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Index terms
 

Description of studies

 

Results of the search

The latest search performed in February 2013 did not identify any new studies for inclusion.

 

Included studies

Three randomized placebo-controlled trials were identified with 800 participants - Mok 2007, Ballard 2008 and Narasimhalu 2010. For full details see Characteristics of included studies.

The 26-week study of Mok 2007 included participants aged 40 to 90 years (mean ages 75.7 years in the rivastigmine arm and 74.1 years in the placebo arm) with subcortical vascular dementia, diagnosed according to standard criteria (Erkinjuntti 2000). Forty participants were randomized. Average MMSE (mini-mental state examination) scores were 13 and 13.4 in the active arm and placebo arm, respectively.

Ballard 2008, a 24-week trial, included 710 participants with large and small vessel vascular dementia diagnosed according to NINDS-AIREN and DSM-IV criteria (Roman 1993; WHO 1992). The majority met criteria for subcortical dementia as defined by Erkinjuntti 2000 according to MRI criteria (69.9% in the rivastigmine arm and 72.5% in the placebo arm). Age ranged from 50 to 85 years (mean ages 72.9 years in the rivastigmine group and 72.7 years in the placebo group). The average MMSE in both arms was 19.2.

The Narasimhalu 2010 trial included 50 participants with ischaemic stroke who failed to meet standard criteria for dementia, but exhibited some cognitive impairment. Their ages ranged from 48 to 84 years (mean ages 68.1 years in the rivastigmine group and 69.4 years in the placebo group). Trial duration was 24 weeks. The MMSE in the rivastigmine arm was 23.7 and 23.9 in the placebo arm.

Particpants were recruited from a variety of settings. Mok 2007 included people from a Chinese background, Ballard 2008 included people from different centres across the world including Europe, Asia, Russia and USA. Narasimhalu 2010 included participants from Singapore.

Study screening in all cases excluded people with a diagnosis of dementia other than that due to a vascular cause, and cases of depression and physical illness of an unstable nature that might potentially limit involvement in all phases of the study.

 

Outcome measures and rating scales

 

1. Alzheimer's Disease Assessment Scale - Cognitive (ADAS-Cog)

The Alzheimer's Disease Assessment Scale is comprised of 11 individual tests (Rosen 1984): spoken language ability (unless indicated otherwise these tests are scored from 0 to 5), comprehension of spoken language, recall of test instructions, word finding difficulty, following commands, naming objects, construction drawing, ideational praxis, orientation (0 to 8), word recall (0 to 10) and word recognition (0 to 12). The total score ranges from 0 to 70, with higher scores indicating greater impairment.

 

2. Global Deterioration Scale (GDS)

The Global Deterioration Scale is a global assessment of severity of dementia carried out by a clinician with access to all information about a patient (Reisberg 1982). Scores range from 1 to 7, with 1 indicating normal and 7 indicating severe dementia.

 

3. Mini Mental State Examination (MMSE)

The Mini Mental State Examination evaluates cognition in five domains (Folstein 1975); orientation, immediate recall, attention and calculation, delayed recall and language. The test takes 15 minutes to administer. Scores range from 0 (severe impairment) to 30 (normal).

 

4. Alzheimer's Disease Cooperative Study activities of daily living scale (ADCS-ADL)

The Alzheimer's Disease Cooperative Study activities of daily living is a 19-item scale assessing basic and complex abilities in people with dementia (Galasko 1997). Items include activities such as eating, bathing, operating taps, and switching of lights. Scores range from 0 (severe impairment) to 54 (no impairment).

 

5. Neuropsychiatric Instrument (NPI)

The Neuropsychiatric Instrument is a 12-item carer-rated instrument that evaluates behavioural and neuropsychiatric symptoms, including delusions, hallucinations, agitation/aggression, depression/dysphoria, anxiety, elation/euphoria, apathy, disinhibition, irritability, aberrant motor behaviour, night-time behaviour and eating/appetite disorder (Cummings 1993). Frequency is rated from 1 (occasional, less than once a week) to 4 (very frequent). Severity is rated from 1 (mild) to 3 (severe). The product of frequency and severity ranges from 1 to 12 for each item, and total scores range from 12 to 120.

 

6. Clinical Dementia rating scale - sum of boxes (CDR-SB)

Clinical Dementia rating scale - sum of boxes - is derived from ratings in six domains (memory, orientation, judgment and problem solving, community affairs, home and hobbies, and personal care) (Morris 1993); each domain is scored from 0 (normal) to 3 (severe dementia). The sum (0 to 18) is the CDR-SB.

 

7. Vascular Dementia Assessment Scale (VaDAS)

The Vascular Dementia Assessment Scale comprises the 13-item ADAS-Cog plus five additional tests to assess cognitive features that may be more predominant in vascular dementia, such as executive dysfunction (symbol digit modalities test, digit backwards, maze, digit cancellation task, verbal fluency) (Ferris 1999). Total scores range from 0 to 110.

 

8. Alzheimer's Disease Cooperative Study Clinical Global Impression of Change scale (ADCS-CGIC)

The Alzheimer's Disease Cooperative Study Clinical Global Impression of Change scale reports a single global rating of change from baseline using a seven-point scale, where 1 represents marked improvement and 7 represents marked worsening (Schneider 1997).

 

9. Chinese version of MMSE

The Chinese version of the MMSE assesses cognition in five domains in a similar way to the original MMSE. Further details about this version of the MMSE are described in Chiu 1994.

 

10. Frontal Assessment Battery (FAB)

The frontal assessment battery evaluates executive function and consists of six items, each evaluating one executive domain (conceptualization, mental flexibility, motor programming, sensitivity to interference, inhibitory control and environment autonomy) (Dubois 2000; Mok 2004).

 

11. Chinese version of the Instrumental Activities of Daily Living scale (Chinese-IADL)

The Chinese version of the Instrumental Activities of Daily Living scale assess performance of daily activities (use of telephone, transportation, shopping, meal preparation, housework, handyman work, laundry, medication management and money management) (Tong 2002). The score for each item ranges from 0 to 3. Lower scores indicate better function.

 

12. Ten-Point Clock test

The Ten-Point Clock test assesses the correct drawing of a clock showing the time 11.10 (Manos 1994). Maximum score is 10 points, with 0 indicating severe dementia.

 

13. Color Trails 1 and Color Trails 2

The Color Trail 1 test assesses the ability of the patient to connect circles numbered 1 to 25 in the correct sequence with a pencil line (D'elia 1996). The second test is a variation where the patient is asked to alternate between pink and yellow circles. Higher scores indicate more severe dementia.

 

14. Geriatric Depression Scale (GDS)

The Geriatric Depression Scale scores 30 items to assess degree of depression 0 to 30 (severe depression) (Yesavage 1982).

The included trials used a variety of scales/instruments to assess their participants. Mok 2007 assessed participants with the MMSE (Chiu 1994), FAB (Dubois 2000), NPI (Leung 2001), instrumental activities of daily living (IADL) (Tong 2002), and CDR-SB (Morris 1993).

The Ballard 2008 trial based its primary efficacy measures on VaDAS (Ferris 1999), and the ADCS-CGIC (Schneider 1997). Secondary endpoints included the MMSE and NPI as well as ADAS-Cog (Rosen 1984), and ADCS-ADL (Galasko 1997). This study also included the global deterioration scale (GDS) (Reisberg 1982).

Within Narasimhalu 2010, the outcomes included MMSE, ADAS-Cog, FAB, ADCS-ADL, NPI. In this study also used the geriatric depression scale (GDS, Yesavage 1982),along with the Ten-Point Clock test and Color Trails tests 1 and 2.

Treatment in Mok 2007 was started at 1.5 mg rivastigmine twice a day, and increased to 3 mg twice a day after four weeks. In Ballard 2008 treatment began at 1.5 mg rivastigmine twice a day, and increased by 1.5 mg twice a day increments at four-weekly intervals, until the highest well tolerated dose was reached (average daily dose 9.4 mg). The titration regimen of Narasimhalu 2010 was similar, although a ceiling of 4.5 mg twice a day was employed.

All three studies tabulated the extent of adverse side effects.

 

Quality assessment

The Mok 2007 efficacy analysis was performed on an intention-to-treat (ITT) basis. One participant died within the placebo arm after the first assessment. The analysis in Ballard 2008 had an ITT basis for all randomized participants, an observed case analysis for participants available at evaluation, and a last observation carried forward approach (i.e. the DNDP-LOCF, division of neuropharmacological drug products last observation carried forward), where one dose and one evaluation was the minimum engagement. Within this study, 75.3% completed the treatment on rivastigmine and 86.1% completed the placebo arm. Narasimhalu 2010 analysed via ITT and noted one death during the study within the placebo arm.

 

Excluded studies

There were no excluded studies.

 

Risk of bias in included studies

Three randomized, placebo controlled studies were included. For full details see 'risk of bias' tables in the Characteristics of included studies below.

 

Effects of interventions

Data from the three included studies could not be combined because the study populations differed in degree of cognitive impairment (from severe dementia to non-demented), and the target treatment dose of rivastigmine was different.

 

Ballard 2008

 

Cognition

This study showed benefit at 24 weeks associated with rivastigmine (3 mg to 12mg/day) compared with placebo for the VaDAS, ADAS-Cog and MMSE assessments:

VaDAS (MD -1.30, 95% CI -2.62 to 0.02, P value 0.05) ( Analysis 1.1);

MMSE (MD 0.60, 95% CI 0.11 to 1.09, P value 0.02) ( Analysis 1.2);

ADAS-Cog (MD -1.10, 95% CI -2.15 to -0.05, P value 0.04) ( Analysis 1.3).

 

Global

There was no statistically significant difference between rivastigmine (3 mg to 12 mg/day) and placebo groups for the ADCS-CGIC and GDS assessments (MD -0.10, 95% CI -3.68 to 3.48, P value 0.96 ( Analysis 1.4); and MD -0.1, 95% CI -0.21 to 0.01, P value 0.08 ( Analysis 1.5), respectively).

 

Behavioural disturbance

There was no statistically significant difference between rivastigmine (3 mg to 12 mg/day) and placebo groups for the NPI-12 assessments (MD 0.40, 95% CI -1.36 to 2.16, P value 0.66) ( Analysis 1.6).

 

Activities of daily living

There was no statistically significant difference between rivastigmine (3 mg to 12 mg/day) and placebo groups for the ADCS-ADL assessments (MD 0.60, 95% CI -1.05 to 2.25, P value 0.48) ( Analysis 1.7)

 

Adverse effects

This study showed a significant difference in withdrawals before the end of treatment, with more participants withdrawing from the rivastigmine group than from the placebo group (rivastigmine 90/365, placebo 48/345, OR 2.02, 95% CI 1.38 to 2.98, P value 0.0003) ( Analysis 1.8). Again, there were more withdrawals before end of treatment due to an adverse event in the rivastigmine group than in the placebo group (rivastigmine 49/365, placebo 19/345, OR 2.66, 95% CI 1.53 to 4.62, P value 0.0005) ( Analysis 1.9).

A greater number of some adverse effects (nausea, vomiting, diarrhoea and anorexia) were documented in the rivastigmine group than in the placebo group:

at least one adverse event of nausea (rivastigmine 96/365, placebo 13/345, OR 9.15, 95% CI 5.02 to 16.70, P value < 0.00001) ( Analysis 1.11);

at least one adverse event of vomiting (rivastigmine 80/365, placebo 8/345, OR 11.87, 95% CI 5.64 to 24.98, P value < 0.00001) ( Analysis 1.12);

at least one adverse event of diarrhoea (rivastigmine 33/365, placebo 15/345, OR 2.19, 95% CI 1.17 to 4.11, P value 0.01) ( Analysis 1.13);

at least one adverse event of anorexia (rivastigmine 19/365, placebo 6/345, OR 3.11, 95% CI 1.23 to 7.89, P value 0.02) ( Analysis 1.19);

However, there was no difference between the rivastigmine and placebo groups for other adverse effects (numbers of deaths, dizziness, falls, hypertension, hypotension, headache, bradycardia, serious adverse events, and at least one serious adverse event due to a cerebrovascular accident):

numbers of deaths (rivastigmine 8/365, placebo 4/345, OR 1.91, 95% CI 0.57 to 6.40, P value 0.29) ( Analysis 1.10);

at least one adverse event of dizziness (rivastigmine 29/363, placebo 17/344, OR 1.67, 95% CI 0.90 to 3.10, P value 0.10) ( Analysis 1.14);

at least one adverse event of a fall (rivastigmine 24/363, placebo 17/344, OR 1.36, 95% CI 0.72 to 2.58, P value 0.34) ( Analysis 1.15);

at least one adverse event of hypertension (rivastigmine 20/363, placebo 10/344, OR 0.95, 95% CI 0.90 to 4.22, P value 0.09) ( Analysis 1.16);

at least one adverse event of hypotension (rivastigmine 5/363, placebo 4/344, OR 1.19, 95% CI 0.32 to 4.46, P value 0.80) ( Analysis 1.17);

at least one adverse event of headache (rivastigmine 19/363, placebo 10/344, OR 1.84, 95% CI (0.85 to 4.03, P value 0.12) ( Analysis 1.18;

at least one adverse event of bradycardia (rivastigmine 5/363, placebo 5/344, OR 0.95, 95% CI 0.27 to 3.30, P value 0.93) ( Analysis 1.20);

at least one serious adverse event (rivastigmine 55/363, placebo 38/344, OR 1.44, 95% CI 0.92 to 2.24, P value 0.11) ( Analysis 1.21);

at least one serious adverse event due to, or potentially due to, a cerebrovascular accident (rivastigmine 20/363, placebo 15/344, OR 1.28, 95% CI 0.64 to 2.54, P value 0.48) ( Analysis 1.22).

 

Mok 2007

 

Cognition

There was no statistically significant difference between the rivastigmine and placebo groups for the MMSE (MD 0.70, 95% CI -1.78 to 3.18, P value 0.58) ( Analysis 2.1), FAB (MD -0.40, 95% CI -1.52 to 0.72, P value 0.48) ( Analysis 2.2), or any of the FAB sub-items (conceptualisation, mental flexibility, programming, sensitivity to interference, inhibitory control, environmental autonomy).

 

Global

There was no statistically significant difference between rivastigmine and placebo groups for CDR-sum of boxes (MD 0.30, 95% CI -3.11 to 3.71, P value 0.86) ( Analysis 2.3).

 

Behavioural disturbance

There was no statistically significant difference between rivastigmine and placebo groups for the NPI (MD -4.50, 95% CI -13.18 to 4.18, P value 0.31) ( Analysis 2.4).

 

Activities of daily living

There was no statistically significant difference between rivastigmine and placebo groups for IADL (MD 0.10, 95% CI -0.12 to 0.32, P value 0.37) ( Analysis 2.5).

 

Adverse effects

There was one death within the placebo arm (haemorrhagic stroke), but none within the rivastigmine arm. There were no significant treatment effects relating to number of withdrawals before end of treatment (rivastigmine 6/20, placebo 3/20, OR 2.43, 95% CI 0.51 to 11.51, P value 0.26) ( Analysis 2.6), or numbers of participants suffering an adverse event (rivastigmine 12/20, placebo 10/20, OR 1.50, 95% CI 0.43 to 5.25, P value 0.53) ( Analysis 2.7).

 

Narasimhalu 2010

 

Cognition

There was no statistically significant difference between rivastigmine (3 mg to 9 mg/d) and placebo groups for clock drawing (MD -0.40, 95% CI -1.58 to 0.78, P value 0.51) ( Analysis 3.1), color trails 1 (MD 8.70, 95% CI -20.16 to 37.56, P value 0.55) ( Analysis 3.2) and 2 (MD -15.50, 95% CI -34.75 to 3.75, P value 0.11) ( Analysis 3.3), and ADAS-Cog (MD 2.20, 95% CI -1.40 to 5.80, P value 0.23) ( Analysis 3.4) assessments.

 

Behavioural disturbance

There was no statistically significant difference between rivastigmine (3 mg to 9 mg/d) and placebo groups for the NPI assessments (MD 0.21, 95% CI -2.61 to 3.03, P value 0.88) ( Analysis 3.5).

 

Activities of daily living

There was no statistically significant difference between rivastigmine (3 mg to 9 mg/d) and placebo groups for the ADCS-ADL assessments (MD -2.00, 95% CI -6.96 to 2.96, P value 0.43) ( Analysis 3.7).

 

Mood

There was no statistically significant difference between rivastigmine (3 mg to 9 mg/d) and placebo groups for the GDS assessments (MD 0.90, 95% CI -0.94 to 2.74, P value 0.34) ( Analysis 3.6).

 

Adverse events

There was no statistically significant difference between rivastigmine compared with placebo for:

numbers of deaths (rivastigmine 1/25, placebo 1/25, OR 1.00, 95% CI 0.06 to 16.93, P value 1.00) ( Analysis 3.11);

numbers of participants suffering at least one adverse event (rivastigmine 9/25, placebo 10/25, OR 0.84, 95% CI 0.27 to 2.65, P value 0.77) ( Analysis 3.9);

numbers of participants suffering at least one adverse event of nausea (rivastigmine 1/25, placebo 0/25, OR 3.12, 95% CI 0.12 to 80.39, P value 0.49) ( Analysis 3.12);

numbers of participants suffering at least one adverse event of diarrhoea (rivastigmine 1/25, placebo 0/25, OR 3.12, 95% CI 0.12 to 80.39, P value 0.49) ( Analysis 3.16),

numbers of participants suffering at least one adverse event of dizziness (rivastigmine 2/25, placebo 0/25, OR 5.43, 95% CI 0.25 to 118.96, P value 0.28) ( Analysis 3.17);

numbers of participants suffering at least one adverse event of vomiting (rivastigmine 3/25, placebo 0/25, OR 7.93, 95% CI 0.39 to 162.07, P value 0.18) ( Analysis 3.18);

numbers of participants suffering at least one adverse event of gastrointestinal upset (rivastigmine 1/25, placebo 1/25, OR 1.00, 95% CI 0.06 to 16.93, P value 1.00) ( Analysis 3.14);

numbers of participants suffering at least one adverse event of headache (rivastigmine 1/25, placebo 2/25, OR 0.78, 95% CI 0.04 to 5.65, P value 0.56) ( Analysis 3.13);

numbers of participants suffering at least one adverse event of breathlessness (rivastigmine 1/25, placebo 1/25, OR 1.00, 95% CI 0.06 to 16.93, P value 1.00) ( Analysis 3.15);

numbers of participants suffering at least one adverse event of chest pain (rivastigmine 2/25, placebo 0/25, OR 5.43, 95% CI 0.25 to 118.96, P value 0.28) ( Analysis 3.19);

numbers of participants suffering at least one adverse event of accidental fall (rivastigmine 0/25, placebo 1/25, OR 0.32, 95% CI 0.01 to 8.25, P value 0.49) ( Analysis 3.20), and

numbers of participants suffering at least one serious adverse event (rivastigmine 5/25, placebo 5/25, OR 1.00, 95% CI 0.25 to 4.00, P value 1.00) ( Analysis 3.10).

 

Discussion

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Index terms

Two of the three included studies had small numbers of participants: Mok 2007 had 40 participants, and Narasimhalu 2010 had 50, divided equally into active (rivastigmine) and placebo arms. These studies were inadequately powered. Thus, conclusions are necessarily limited and an inability to detect an effect size is a potential weakness.

The Ballard 2008 trial, however, included 710 participants at study commencement. It demonstrated superiority of rivastigmine over placebo for several cognitive measures. It should be noted that the 24-week duration of the trial was short, given that vascular cognitive impairment (VCI) is a chronic illness with an uncertain natural history in terms of both survival and rate of decline (Bruandet 2009).

Unfortunately, trials within the area of VCI or vascular dementia are problematic. Uncertainties around diagnosis make it difficult to identify a target population (Kerola 2010; MRC CFAS 2001). It is recognised increasingly that vascular risk factors influence the development of AD (Kivipelto 2005), and there is a limited knowledge base concerning the effect of coexisting dementias on outcome and response (Black 2011).

Further trials are required before rivastigmine can be recommended for the treatment of vascular dementia or VCI.

 

Authors' conclusions

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Index terms

 

Implications for practice

Only one placebo-controlled, double-blind randomized trial has been conducted that was large enough to detect a clinically significant effect for rivastigmine compared with placebo for important outcomes in vascular dementia or vascular cognitive impairment. This trial demonstrated a positive effect of rivastigmine on cognition, but not on other important outcomes.

 
Implications for research

There is a theoretical basis for believing that rivastigmine may be beneficial in vascular cognitive impairment, but there are limited trial resources that have explored this in depth. Such trials are needed, and accurate trial design depends on further research into the aetiological mechanisms of vascular cognitive impairment, separation of subtypes and knowledge of their natural history, and better clarification of the role of other pharmacological methods of reducing neurovascular morbidity in general.

 

Acknowledgements

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Index terms

We gratefully acknowledge the contributions of the consumer editor Corinne Cavender.

 

Data and analyses

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Index terms
Download statistical data

 
Comparison 1. Rivastigmine (3-12 mg/day) vs placebo for probable vascular dementia

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 VaDAS (change from baseline at 24 weeks) ITT1Mean Difference (IV, Random, 95% CI)Totals not selected

 2 MMSE (change from baseline at 24 weeks) ITT1Mean Difference (IV, Fixed, 95% CI)Totals not selected

 3 ADAS-Cog (change from baseline at 24 weeks) ITT1Mean Difference (IV, Fixed, 95% CI)Totals not selected

 4 ADCS-CGIC 24 weeks ITT1Mean Difference (IV, Fixed, 95% CI)Totals not selected

 5 GDS global deterioration scale (change from baseline at 24 weeks) ITT1Mean Difference (IV, Fixed, 95% CI)Totals not selected

 6 Behavioural disturbance NPI-12 (change from baseline at 24 weeks) ITT1Mean Difference (IV, Fixed, 95% CI)Totals not selected

 7 ADCS-ADL (change from baseline at 24 weeks) ITT1Mean Difference (IV, Fixed, 95% CI)Totals not selected

 8 Withdrawals before end of treatment at 24 weeks1Odds Ratio (M-H, Fixed, 95% CI)Totals not selected

 9 Withdrawals due to adverse event by 24 weeks1Odds Ratio (M-H, Fixed, 95% CI)Totals not selected

 10 Deaths by 24 weeks1Odds Ratio (M-H, Fixed, 95% CI)Totals not selected

 11 At least one adverse event of nausea by 24 weeks1Odds Ratio (M-H, Fixed, 95% CI)Totals not selected

 12 At least one adverse event of vomiting by 24 weeks1Odds Ratio (M-H, Fixed, 95% CI)Totals not selected

 13 At least one adverse event of diarrhoea by 24 weeks1Odds Ratio (M-H, Fixed, 95% CI)Totals not selected

 14 At least one adverse event of dizziness by 24 weeks1Odds Ratio (M-H, Fixed, 95% CI)Totals not selected

 15 At least one adverse event of a fall by 24 weeks1Odds Ratio (M-H, Fixed, 95% CI)Totals not selected

 16 At least one adverse event of hypertension by 24 weeks1Odds Ratio (M-H, Fixed, 95% CI)Totals not selected

 17 At least one adverse event of hypotension by 24 weeks1Odds Ratio (M-H, Fixed, 95% CI)Totals not selected

 18 At least one adverse event of headache by 24 weeks1Odds Ratio (M-H, Fixed, 95% CI)Totals not selected

 19 At least one adverse event of anorexia by 24 weeks1Odds Ratio (M-H, Fixed, 95% CI)Totals not selected

 20 At least one adverse event of bradycardia by 24 weeks1Odds Ratio (M-H, Fixed, 95% CI)Totals not selected

 21 At least one serious adverse event by 24 weeks1Odds Ratio (M-H, Fixed, 95% CI)Totals not selected

 22 At least one serious adverse event due to, or potentially due to a cerebrovascular accident by 24 weeks1Odds Ratio (M-H, Fixed, 95% CI)Totals not selected

 
Comparison 2. Rivastigmine (6 mg/day) vs placebo for subcortical vascular dementia

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 MMSE (change from baseline at 26 weeks) ITT1Mean Difference (IV, Fixed, 95% CI)Totals not selected

 2 FAB (change from baseline at 26 weeks) ITT1Mean Difference (IV, Fixed, 95% CI)Totals not selected

 3 Global function CDR sum of boxes (change from baseline at 26 weeks) ITT1Mean Difference (IV, Fixed, 95% CI)Totals not selected

 4 Behavioural disturbance NPI-12 (change from baseline at 26 weeks) ITT1Mean Difference (IV, Fixed, 95% CI)Totals not selected

 5 IADL (change from baseline at 26 weeks) ITT1Mean Difference (IV, Fixed, 95% CI)Totals not selected

 6 Withdrawals before end of treatment at 26 weeks1Odds Ratio (M-H, Fixed, 95% CI)Totals not selected

 7 At least one adverse event by 26 weeks1Odds Ratio (M-H, Fixed, 95% CI)Totals not selected

 8 At least one adverse event of recurrent stroke by 26 weeks1Odds Ratio (M-H, Fixed, 95% CI)Totals not selected

 9 Deaths by 26 weeks1Odds Ratio (M-H, Fixed, 95% CI)Totals not selected

 
Comparison 3. Rivastigmine (3-9 mg/day) vs placebo for MCI and CIND

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Clock drawing (change from baseline at 24 weeks) ITT149Mean Difference (IV, Fixed, 95% CI)-0.4 [-1.58, 0.78]

 2 Color trails 1149Mean Difference (IV, Fixed, 95% CI)8.7 [-20.16, 37.56]

 3 Color trails 21Mean Difference (IV, Fixed, 95% CI)Totals not selected

 4 ADAS-Cog (change from baseline at 24 weeks) ITT1Mean Difference (IV, Fixed, 95% CI)Totals not selected

 5 Behavioural disturbance NPI (change from baseline at 24 weeks) ITT1Mean Difference (IV, Fixed, 95% CI)Totals not selected

 6 GDS depression scale (change from baseline at 24 weeks ) ITT1Mean Difference (IV, Fixed, 95% CI)Totals not selected

 7 ADCS-ADL (change from baseline at 24 weeks) ITT1Mean Difference (IV, Fixed, 95% CI)Totals not selected

 8 Withdrawals before end of treatment at 24 weeks1Odds Ratio (M-H, Fixed, 95% CI)Totals not selected

 9 At least one adverse event by 24 weeks1Odds Ratio (M-H, Fixed, 95% CI)Totals not selected

 10 At least one serious adverse event by 24 weeks1Odds Ratio (M-H, Fixed, 95% CI)Totals not selected

 11 Deaths by 24 weeks1Odds Ratio (M-H, Fixed, 95% CI)Totals not selected

 12 At least one adverse event of nausea by 24 weeks1Odds Ratio (M-H, Fixed, 95% CI)Totals not selected

 13 At least one adverse event of headache by 24 weeks1Odds Ratio (M-H, Fixed, 95% CI)Totals not selected

 14 At least one adverse event of gastrointestinal upset by 24 weeks1Odds Ratio (M-H, Fixed, 95% CI)Totals not selected

 15 At least one adverse event of breathlessness by 24 weeks1Odds Ratio (M-H, Fixed, 95% CI)Totals not selected

 16 At least one adverse event of diarrhoea by 24 weeks1Odds Ratio (M-H, Fixed, 95% CI)Totals not selected

 17 At least one adverse event of dizziness by 24 weeks1Odds Ratio (M-H, Fixed, 95% CI)Totals not selected

 18 At least one adverse event of vomiting by 24 weeks1Odds Ratio (M-H, Fixed, 95% CI)Totals not selected

 19 At least one adverse event of chest pain by 24 weeks1Odds Ratio (M-H, Fixed, 95% CI)Totals not selected

 20 At least one adverse event of accidental fall by 24 weeks1Odds Ratio (M-H, Fixed, 95% CI)Totals not selected

 

Appendices

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Index terms
 

Appendix 1. Pre-publication search: February 2013


Source

 
Search strategyHits retrieved

1. ALOIS (www.medicine.ox.ac.uk/alois)  

2. MEDLINE In-process and other non-indexed citations and MEDLINE 1950-present (12 February 2013) (Ovid SP)1. exp Dementia/

2. Delirium/

3. Wernicke Encephalopathy/

4. Delirium, Dementia, Amnestic, Cognitive Disorders/

5. dement*.mp.

6. alzheimer*.mp.

7. (lewy* adj2 bod*).mp.

8. deliri*.mp.

9. (chronic adj2 cerebrovascular).mp.

10. ("organic brain disease" or "organic brain syndrome").mp.

11. ("normal pressure hydrocephalus" and "shunt*").mp.

12. "benign senescent forgetfulness".mp.

13. (cerebr* adj2 deteriorat*).mp.

14. (cerebral* adj2 insufficient*).mp.

15. (pick* adj2 disease).mp.

16. (creutzfeldt or jcd or cjd).mp.

17. huntington*.mp.

18. binswanger*.mp.

19. korsako*.mp.

20. or/1-19

21. rivastigmin*.ti,ab.

22. exelon.ti,ab.

23. ENA.ti,ab.

24. "SDZ ENA 713".ti,ab.

25. or/21-24

26. 20 and 25

27. randomized controlled trial.pt.

28. controlled clinical trial.pt.

29. random*.ab.

30. placebo.ab.

31. drug therapy.fs.

32. trial.ab.

33. groups.ab.

34. or/27-33

35. (animals not (humans and animals)).sh.

36. 35 not 34

37. 26 and 36

38. (2011* or 2012* or 2013*).ed.

39. 37 and 38

 
4

3. EMBASE

1980-2013 February 10 (Ovid SP)
1. exp dementia/

2. Lewy body/

3. delirium/

4. Wernicke encephalopathy/

5. cognitive defect/

6. dement*.mp.

7. alzheimer*.mp.

8. (lewy* adj2 bod*).mp.

9. deliri*.mp.

10. (chronic adj2 cerebrovascular).mp.

11. ("organic brain disease" or "organic brain syndrome").mp.

12. "supranuclear palsy".mp.

13. ("normal pressure hydrocephalus" and "shunt*").mp.

14. "benign senescent forgetfulness".mp.

15. (cerebr* adj2 deteriorat*).mp.

16. (cerebral* adj2 insufficient*).mp.

17. (pick* adj2 disease).mp.

18. (creutzfeldt or jcd or cjd).mp.

19. huntington*.mp.

20. binswanger*.mp.

21. korsako*.mp.

22. CADASIL.mp.

23. or/1-22

24. RIVASTIGMINE/

25. rivastigmin*.ti,ab.

26. exelon.ti,ab.

27. ENA.ti,ab.

28. "SDZ ENA 713".ti,ab.

29. or/24-28

30. 23 and 29

31. randomized controlled trial/

32. controlled clinical trial/

33. random*.ab.

34. placebo*.ab.

35. trial.ab.

36. groups.ab.

37. or/31-36

38. 30 and 37

39. (2011* or 2012* or 2013*).em.

40. 38 and 39

 
251

4. PSYCINFO

1806-February week 1 2013 (Ovid SP)
1. exp Dementia/

2. exp Delirium/

3. exp Huntingtons Disease/

4. exp Kluver Bucy Syndrome/

5. exp Wernickes Syndrome/

6. exp Cognitive Impairment/

7. dement*.mp.

8. alzheimer*.mp.

9. (lewy* adj2 bod*).mp.

10. deliri*.mp.

11. (chronic adj2 cerebrovascular).mp.

12. ("organic brain disease" or "organic brain syndrome").mp.

13. "supranuclear palsy".mp.

14. ("normal pressure hydrocephalus" and "shunt*").mp.

15. "benign senescent forgetfulness".mp.

16. (cerebr* adj2 deteriorat*).mp.

17. (cerebral* adj2 insufficient*).mp.

18. (pick* adj2 disease).mp.

19. (creutzfeldt or jcd or cjd).mp.

20. huntington*.mp.

21. binswanger*.mp.

22. korsako*.mp.

23. ("parkinson* disease dementia" or PDD or "parkinson* dementia").mp.

24. or/1-23

25. rivastigmin*.ti,ab.

26. exelon.ti,ab.

27. ENA.ti,ab.

28. "SDZ ENA 713".ti,ab.

29. or/25-28

30. 24 and 29

31. (2011* or 2012* or 2013*).up.

32. 30 and 31

 
85

5. CINAHL (EBSCOhost) 45

6. Web of Science and conference proceedingsTopic=(dement* OR alzheimer* OR VAD OR ADD OR lewy OR DLB OR LBD OR "vascular cognitive impairment" OR VCI) AND Topic=(rivastigmin* OR exelon OR ENA) AND Topic=(random* OR placebo* OR trial OR "double-blind*" OR "single-blind*") AND Year Published=(2011-2013)

Timespan=All Years. Databases=SCI-EXPANDED, SSCI, A&HCI, CPCI-S, CPCI-SSH.

Lemmatization=On

 
124

7. LILACS (BIREME)rivastigmine OR exelon [Words]9

8. CENTRAL (The Cochrane Library) (Issue 1 of 2013)#1               MeSH descriptor: [Dementia] explode all trees

#2               MeSH descriptor: [Delirium] this term only

#3               MeSH descriptor: [Wernicke Encephalopathy] this term only

#4               MeSH descriptor: [Delirium, Dementia, Amnestic, Cognitive Disorders] this term only

#5               dement*

#6               alzheimer*

#7               "lewy* bod*"

#8               deliri*

#9               "chronic cerebrovascular"

#10             "organic brain disease" or "organic brain syndrome" or "vascular cognitive impairment"

#11             "normal pressure hydrocephalus" and "shunt*"

#12             "benign senescent forgetfulness"

#13             "cerebr* deteriorat*"

#14             "cerebral* insufficient*"

#15             "pick* disease"

#16             creutzfeldt or jcd or cjd

#17             huntington*

#18             binswanger*

#19             korsako*

#20             #1 or #2 or #3 or #4 or #5 or #6 or #7 or #8 or #9 or #10 or #11 or #12 or #13 or #14 or #15 or #16 or #17 or #18 or #19

#21             rivastigmin* or exelon* or ENA

#22             #20 and #21 in Trials

#23             #22 from 2011 to 2013 (Word variations have been searched)

 
7

9. Clinicaltrials.gov (www.clinicaltrials.gov)Interventional Studies | dementia OR VAD OR VCI OR vascular OR alzheimer OR alzheimer's | rivastigmine OR exelon OR ENA | received from 01/01/2011 to 02/12/201314

10. ICTRP Search Portal (http://apps.who.int/trialsearch) [includes: Australian New Zealand Clinical Trials Registry; ClinicalTrilas.gov; ISRCTN; Chinese Clinical Trial Registry; Clinical Trials Registry – India; Clinical Research Information Service – Republic of Korea; German Clinical Trials Register; Iranian Registry of Clinical Trials; Japan Primary Registries Network; Pan African Clinical Trial Registry; Sri Lanka Clinical Trials Registry; The Netherlands National Trial Register](rivastigmine OR Exelon) AND condition: dementia OR vascular cognitive impairment AND recruitment status: ALL [date restriction: 01/01/2011-12/02/2013]2

TOTAL before de-duplication652



 

Appendix 2. Update search: January 2011


Source

 
Search strategyHits retrieved

1. ALOIS (www.medicine.ox.ac.uk/alois)Advanced [Intervention] search: Study design: RCT AND Intervention: rivastigmine OR exelon OR "SDZ ENA 713" [no date limits applied]69

2. MEDLINE In-process and other non-indexed citations and MEDLINE 1950 - 24 January 2011 (Ovid SP)1. exp Dementia/

2. Delirium/

3. Wernicke Encephalopathy/

4. Delirium, Dementia, Amnestic, Cognitive Disorders/

5. dement*.mp.

6. alzheimer*.mp.

7. (lewy* adj2 bod*).mp.

8. deliri*.mp.

9. (chronic adj2 cerebrovascular).mp.

10. ("organic brain disease" or "organic brain syndrome").mp.

11. ("normal pressure hydrocephalus" and "shunt*").mp.

12. "benign senescent forgetfulness".mp.

13. (cerebr* adj2 deteriorat*).mp.

14. (cerebral* adj2 insufficient*).mp.

15. (pick* adj2 disease).mp.

16. (creutzfeldt or jcd or cjd).mp.

17. huntington*.mp.

18. binswanger*.mp.

19. korsako*.mp.

20. or/1-19

21. rivastigmin*.ti,ab.

22. exelon.ti,ab.

23. ENA.ti,ab.

24. "SDZ ENA 713".ti,ab.

25. or/21-24

26. 20 and 25

27. randomized controlled trial.pt.

28. controlled clinical trial.pt.

29. random*.ab.

30. placebo.ab.

31. drug therapy.fs.

32. trial.ab.

33. groups.ab.

34. or/27-33

35. (animals not (humans and animals)).sh.

36. 35 not 34

37. 26 and 36

 
33

3. EMBASE

1980-2011 week 3 (Ovid SP)
1. exp dementia/

2. Lewy body/

3. delirium/

4. Wernicke encephalopathy/

5. cognitive defect/

6. dement*.mp.

7. alzheimer*.mp.

8. (lewy* adj2 bod*).mp.

9. deliri*.mp.

10. (chronic adj2 cerebrovascular).mp.

11. ("organic brain disease" or "organic brain syndrome").mp.

12. "supranuclear palsy".mp.

13. ("normal pressure hydrocephalus" and "shunt*").mp.

14. "benign senescent forgetfulness".mp.

15. (cerebr* adj2 deteriorat*).mp.

16. (cerebral* adj2 insufficient*).mp.

17. (pick* adj2 disease).mp.

18. (creutzfeldt or jcd or cjd).mp.

19. huntington*.mp.

20. binswanger*.mp.

21. korsako*.mp.

22. CADASIL.mp.

23. or/1-22

24. RIVASTIGMINE/

25. rivastigmin*.ti,ab.

26. exelon.ti,ab.

27. ENA.ti,ab.

28. "SDZ ENA 713".ti,ab.

29. or/24-28

30. 23 and 29

31. randomized controlled trial/

32. controlled clinical trial/

33. random*.ab.

34. placebo*.ab.

35. trial.ab.

36. groups.ab.

37. or/31-36

38. 30 and 37

39. (2009* or 2010* or 2011*).em.

40. 38 and 39

 
221

4. PSYCINFO

1806-February week 3 2011 (Ovid SP)
1. exp Dementia/

2. exp Delirium/

3. exp Huntingtons Disease/

4. exp Kluver Bucy Syndrome/

5. exp Wernickes Syndrome/

6. exp Cognitive Impairment/

7. dement*.mp.

8. alzheimer*.mp.

9. (lewy* adj2 bod*).mp.

10. deliri*.mp.

11. (chronic adj2 cerebrovascular).mp.

12. ("organic brain disease" or "organic brain syndrome").mp.

13. "supranuclear palsy".mp.

14. ("normal pressure hydrocephalus" and "shunt*").mp.

15. "benign senescent forgetfulness".mp.

16. (cerebr* adj2 deteriorat*).mp.

17. (cerebral* adj2 insufficient*).mp.

18. (pick* adj2 disease).mp.

19. (creutzfeldt or jcd or cjd).mp.

20. huntington*.mp.

21. binswanger*.mp.

22. korsako*.mp.

23. ("parkinson* disease dementia" or PDD or "parkinson* dementia").mp.

24. or/1-23

25. rivastigmin*.ti,ab.

26. exelon.ti,ab.

27. ENA.ti,ab.

28. "SDZ ENA 713".ti,ab.

29. or/25-28

30. 24 and 29

31. (2009* or 2010* or 2011*).up.

32. 30 and 31

 
88

5. CINAHL (EBSCOhost)S1 (MH "Dementia+")  

S2 (MH "Delirium") or (MH "Delirium, Dementia, Amnestic, Cognitive Disorders")

S3 (MH "Wernicke's Encephalopathy")  

S4 TX dement*  

S5 TX alzheimer* 

S6 TX lewy* N2 bod*  

S7 TX deliri* 

S8 TX chronic N2 cerebrovascular  

S9 TX "organic brain disease" or "organic brain syndrome"  

S10 TX "normal pressure hydrocephalus" and "shunt*"  

S11 TX "benign senescent forgetfulness" 

S12 TX cerebr* N2 deteriorat* 

S13 TX cerebral* N2 insufficient*  

S14 TX pick* N2 disease

S15 TX creutzfeldt or jcd or cjd  

S16 TX huntington* 

S17 TX binswanger*  

S18 TX korsako* 

S19 S1 or S2 or S3 or S4 or S5 or S6 or S7 or S8 or S9 or S10 or S11 or S12 or S13 or S14 or S15 or S16 or S17 or S18

S20 (MH "Rivastigmine") 

S21 TX rivastigmin*

S22 TX exelon*

S23 TX ENA 

S24 TX "SD2 ENA 713"

S25 S20 OR S21 OR S22 OR S23 OR S24 

S26 S19 and S25 

S27 EM 2009 

S28 EM 2010 

S29 EM 2011 

S30 S27 or S28 or S29 

S31 S26 and S30 
52

6. ISI Web of Knowledge – all databases [includes: Web of Science (1945-present); BIOSIS Previews (1926-present); MEDLINE (1950- 12 Feb 2013); Journal Citation Reports]Topic=(dement* OR alzheimer* OR VAD OR ADD OR lewy OR DLB OR LBD OR "vascular cognitive impairment" OR VCI) AND Topic=(rivastigmin* OR exelon OR ENA) AND Topic=(random* OR placebo* OR trial OR "double-blind*" OR "single-blind*") AND Year Published=(2009-2011)

 
146

7. LILACS (BIREME)rivastigmine OR exelon7

8. CENTRAL (The Cochrane Library) (Issue 4 of 4, Oct 2010)#1 MeSH descriptor Dementia explode all trees

#2 MeSH descriptor Delirium, this term only

#3 MeSH descriptor Wernicke Encephalopathy, this term only

#4 MeSH descriptor Delirium, Dementia, Amnestic, Cognitive Disorders, this term only

#5 dement*

#6 alzheimer*

#7 "lewy* bod*"

#8 deliri*

#9 "chronic cerebrovascular"

#10 "organic brain disease" or "organic brain syndrome" OR “vascular cognitive imapairment”

#11 "normal pressure hydrocephalus" and "shunt*"

#12 "benign senescent forgetfulness"

#13 "cerebr* deteriorat*"

#14 "cerebral* insufficient*"

#15 "pick* disease"

#16 creutzfeldt or jcd or cjd

#17 huntington*

#18 binswanger*

#19 korsako*

#20 (#1 OR #2 OR #3 OR #4 OR #5 OR #6 OR #7 OR #8 OR #9 OR #10 OR #11 OR #12 OR #13 OR #14 OR #15 OR #16 OR #17 OR #18 OR #19)

#21 rivastigmin* OR exelon* OR ENA

#22 (#20 AND #21)

#23 (#22), from 2009 to 2011

 
24

9. Clinicaltrials.gov (www.clinicaltrials.gov)dementia OR VAD OR VCI OR vascular OR alzheimer OR alzheimer's | rivastigmine OR exelon OR ENA40

10. ICTRP Search Portal (http://apps.who.int/trialsearch) [includes: Australian New Zealand Clinical Trials Registry; ClinicalTrilas.gov; ISRCTN; Chinese Clinical Trial Registry; Clinical Trials Registry – India; Clinical Research Information Service – Republic of Korea; German Clinical Trials Register; Iranian Registry of Clinical Trials; Japan Primary Registries Network; Pan African Clinical Trial Registry; Sri Lanka Clinical Trials Registry; The Netherlands National Trial Register]Intervention: (rivastigmine OR Exelon) AND condition: dementia OR vascular cognitive impairment AND recruitment status: ALL [date restriction: 01/01/2009-25/01/2011]2

TOTAL before de-duplication682


TOTAL after de-duplication and first-assessment74



 

What's new

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Index terms

Last assessed as up-to-date: 12 February 2013.


DateEventDescription

8 April 2013New citation required but conclusions have not changedConclusions unchanged

12 February 2013New search has been performedA pre-publication search was performed for this review on 12 February 2013



 

History

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Index terms

Protocol first published: Issue 2, 2004
Review first published: Issue 2, 2005


DateEventDescription

24 January 2011New search has been performedAn update search was performed for this review on 24 January 2011. New studies were identified for inclusion and exclusion within the review

28 October 2008Amendedconverted to new review format

27 March 2008New search has been performedAn update search was performed on 27 March 2008. Two studies were retrieved for possible inclusion within or exclusion from the review

7 June 2006New search has been performedJune 2006: an update search was run and no new trials were found

24 February 2004New citation required and conclusions have changedSubstantive amendment



 

Contributions of authors

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Index terms

DC: drafted the review, and dealt with all correspondence.
JB: drafted the review.

Consumer editor: Corinne Cavender.
Contact editor: Rupert McShane.

This review has been peer reviewed anonymously.

 

Declarations of interest

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Index terms

None known

 

Sources of support

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Index terms
 

Internal sources

  • No sources of support supplied

 

External sources

  • The Health Research Board, Dublin and the R&D Office for the Health and Social Services, Belfast, Ireland.

References

References to studies included in this review

  1. Top of page
  2. AbstractRésumé
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Characteristics of studies
  18. References to studies included in this review
  19. Additional references
  20. References to other published versions of this review
Ballard 2008 {published data only}
  • Ballard C, Sauter M, Scheltens P, He Y, Barkhof F, van Straaten EC, et al. Efficacy, safety and tolerability of rivastigmine capsules in patients with probable vascular dementia: the VantagE study. Current medical research and opinion 2008;24(9):2561-74. [PUBMED: 18674411]
Mok 2007 {published data only}
  • Mok V, Wong A, Ho S, Leung T, Lam WWM, Wong KS. Rivastigmine in Chinese patients with subcortical vascular dementia. Neuropsychiatric Disease and Treatment 2007;3(6):943-8.
Narasimhalu 2010 {published data only}

Additional references

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  2. AbstractRésumé
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Characteristics of studies
  18. References to studies included in this review
  19. Additional references
  20. References to other published versions of this review
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