CoChat
Sign Up
Cited by 534Cholinesterase and Neurodegenerative DiseasesDementia and Cognitive Impairment ResearchAlzheimer's disease research and treatments

The DOI matches its Crossref record; 136 of the 147 references it cites were found in a registry or an index, and 1 are not checked yet.

Rivastigmine for Alzheimer’s disease.

Open access
Birks, Jacqueline S, Chong, Lee-Yee, Grimley Evans, John·2015·Cochrane Database of Systematic Reviews
DOI 10.1002/14651858.cd001191.pub4PMC PMC7050299
Open this paper in CoChat — free accountOpen PDF

Abstract

BACKGROUND: 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. OBJECTIVES: To determine the clinical efficacy and safety of rivastigmine for patients with dementia of Alzheimer's type. SEARCH METHODS: 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). 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 dropou

Overview

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1002/14651858.cd001191.pub4

Cites

136 of 137 references verified0 citation errors · 0 not checkable

Statistics

Verification

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Citations

Cites

Show all 147 references

Research works printed but not linked: 70

  1. Anand, 1996, Efficacy and safety results of the early phase studies with Exelon (ENA-713) in Alzheimer's Disease: an overview, Journal of Drug Development and Clinical Practice, 8, 109
  2. Anand, 1996, Efficacy and safety results of the early phase studies with Exelon (ENA-713) in Alzheimer's Disease: an overview, Journal of Drug Development and Clinical Practice, 8, 109
  3. Anand, 2001, Effects of Alzheimer's disease severity on activities of daily living with long-term rivastigmine treatment, Journal of the American Geriatrics Society, 49, S151
  4. Anand R Messina J Veach J Hartman R Effects of rivastigmine in patients with moderately severe Alzheimer's disease Sixth International Stockholm/Springfield Symposium on Advances in Alzheimer Therapy; April 5-8, 2000; Stockholm, Sweden 2000 199
  5. Farlow M Anand R Messina J Hartman R Increased cognitive efficacy of rivastigmine in patients with moderate to severe Alzheimer's disease with co-existing vascular risk Sixth International Stockholm/Springfield Symposium on Advances in Alzheimer Therapy; April 5-8, 2000; Stockholm, Sweden 2000 206
  6. Kumar V Messina J Hartman R Anand R Long-term cognitive benefits of rivastigmine in Alzheimer's disease patients with vascular risk Sixth International Stockholm/Springfield Symposium on Advances in Alzheimer Therapy; April 5-8, 2000; Stockholm, Sweden 2000 215
  7. Rösler, 1997, A double-blind placebo controlled study of ENA 713 in Alzheimer's disease (DAT), Pharmacopsychiatry, 30, 212
  8. Rösler, 1998, Effects of two-year treatment with the cholinesterase inhibitor rivastigmine on behavioural symptoms in Alzheimer's disease, Behavioural-Neurology, 11, 211, 10.1155/1999/168023 · DOI
  9. Vincent S Andrews C Lane R Rivastigmine shows particular efficacy in Alzheimer patients with concomitant hypertension Proceedings of the 7th International Geneva/Springfield Symposium on Advances in Alzheimer therapy, 2002 Apr 3-6, Geneva 2002 253
  10. Burns, 2004, Efficacy of rivastigmine in subjects with moderately severe Alzheimer's disease, International Journal of Geriatric Psychiatry, 19, 243, 10.1002/gps.1058 · DOI
  11. Farlow, 2003, Analysis of outcome in retrieved dropout patients in a rivastigmine vs placebo, 26-week, Alzheimer disease trial, Archives of Neurology, 60, 843, 10.1001/archneur.60.6.843 · DOI
  12. Burns, 2004, Efficacy of rivastigmine in subjects with moderately severe Alzheimer's disease, International Journal of Geriatric Psychiatry, 19, 243, 10.1002/gps.1058 · DOI
  13. Doraiswamy M The effects of rivastigmine on the Alzheimer's disease assessment scale-cognitive subscale items scores of patients with Alzheimer's disease Health in aging the challenge and promise of new decade. Proceedings of the annual scientific meeting of the American Geriatrics Society and the American Federation for Aging Research; 2000 May 17-21, Nashville 2000 173
  14. Doraiswamy, 2000, Cognitive effects of rivastigmine in patients with mild to moderate alzheimer's disease compared to those with moderately-severe to severe AD, Clinical Neuropschological Assessment, 1, 12
  15. Doraiswamy, 2000, Long term cognitive effects in Alzheimer's disease patients stratified by vascular risk score and treated for 1 year with rivastigmine, Clinical Neuropschological Assessment, 1, 14
  16. Farlow M Messina J Anand R Long term cognitive benefits associated with the use of rivastigmine in the treatment of Alzheimer's disease results following two years of treatment Proceedings of the Annual Scientific Meeting of the American Geriatric Society and the American Federation for Aging Research; 2000 May 17-21, Nashville 2000 172
  17. Farlow, 2003, Analysis of outcome in retrieved dropout patients in a rivastigmine vs placebo, 26-week, Alzheimer disease trial, Archives of Neurology, 60, 843, 10.1001/archneur.60.6.843 · DOI
  18. Farlow, 2001, Response of patients with Alzheimer disease to rivastigmine treatment is predicted by the rate of disease progression, Archives of Neurology, 58, 417, 10.1001/archneur.58.3.417 · DOI
  19. Ferris S Improving day to day functioning in patients with AD Proceedings of the Ninth Congress of the International Psychogeriatric Association; 1999 Aug 15-20, Vancouver 1999 77
  20. Krishnan, 1999, Rivastigmine slows stage specific global deterioration in Alzheimer's disease, Journal of the American Geriatrics Society, 47, S3
  21. Veach KR Doraiswamy PM Rivastigmine slows stage-specific global deterioration in Alzheimer's disease Proceedings of the 152nd Annual Meeting of the American Psychiatric Association; 1999 May 15-20, Washington DC 1999 SR-HANDSRCH
  22. Alva G Grossberg G Schmitt F Olin J Influence of rivastigmine on activities of daily living: item responder analyses targeting improvement and atability Annals of Neurology 2009 S49
  23. Orgogozo J-M Clinical studies investigating dose-related outcomes of cholinesterase inhibition with rivastigmine patch European Journal of Neurology 2012
  24. Tai, 2000, The safety and efficacy of Exelon in Alzheimer's patients: A multicentre, randomized, 26-week study in Taiwan, International Journal of Neuropsychopharmacology, 3 Suppl 1, S356
  25. Farlow, 2013, Long-term safety, tolerability and efficacy of 13.3 mg/24 h rivastigmine patch in patients with severe Alzheimer's disease, Clinical Pharmacology in Drug Development, Conference: 201, 43
  26. Farlow, 2013, Efficacy of 13.3 mg/24 h rivastigmine patch on global functioning and behavior in severe Alzheimer's disease, Annals of neurology, Conference: 138, S91
  27. Grossberg, 2013, Efficacy, safety and tolerability of 13.3 mg/24 h rivastigmine patch in patients with severe alzheimer's disease with and without concomitant memantine, Clinical Pharmacology in Drug Development, Conference: 201, 42
  28. Anand, 1996, Efficacy and safety results of the early phase studies with Exelon (ENA-713) in Alzheimer's disease: an overview, Journal of Drug Development and Clinical Practice, 8, 109
  29. Cutler, 1995, Safety and tolerance of ENA 713 in patients with Alzheimer's disease, Biological Psychiatry, 37, 643
  30. Cummings, 2000, Abstract S79.002, Neurology, 54, A468
  31. Edwards K Goddman W Anand R Koumars B Hartman R Effect of Alzheimer's disease severity on psychotropic drug use and behavior in nursing home patients treated with rivastigmine The 8th conference on Alzheimer's disease and related disorders, July 20-25, 2002, Stockholm, Sweden 2002 296
  32. Anon Double-blind trial will compare two anti-Alzheimer's drugs Journal of Dementia Care 2001c 6
  33. Bullock, 2005, Rivastigmine and donepezil treatment in moderate to moderately-severe Alzheimer's disease over a 2-year period, Current Medical Research and Opinion, 21, 1317, 10.1185/030079905X56565 · DOI
  34. Bullock, 2002, Rationale and design of EXCEED, a 24-month, double-blind study comparing rivastigmine and donepezil, Annals of Neurology, 52, 30
  35. Feldman H Scheltens E Hermann N Ferris S Mesenbrink P Satlin A Mancione L Behavioral symptoms in mild cognitive impairment findings from the InDDEx study The 8th conference on Alzheimer's Disease and Related Disorders, July 20-25, 2002, Stockholm, Sweden 2002 522
  36. Ferris S Feldman P Mesenbrink P Mancione L Satlin A Mild Cognitive impairment and Alzheimer's disease are these distinct study populations clinical trials The 8th conference on Alzheimer's Disease and Related Disorders, July 20-25, 2002, Stockholm, Sweden 2002 570
  37. Kim SY A 24 week trial investigating the safety tolerability and efficacy of rivastigmine in mild to moderately severe Alzheimer's disease patients in Korea The 8th conference on Alzheimer's Disease and Related Disorders, July 20-25, 2002, Stockholm, Sweden 2002 360
  38. Malsch, 2001, [Treatment of Alzheimer's disease: Tolerability of rivastigmine during the initial period], Psychopharmacology, 27, 337
  39. Blesa R Martinez-Lage P Monsch AU Downs P Strohmaier C Caregiver preference for rivastigmine patch in the OPtimising Transdermal exelon In Mild-to-moderate Alzheimer's disease (OPTIMA) Study European Journal of Neurology 2012
  40. Cummings J Froelich L Black SE Bakchine S Bellelli G Molinuevo JL Randomized, double-blind, parallel-group, 48-week study for efficacy and safety of a higher-dose rivastigmine patch (15 vs. 10 cm2) in Alzheimer's disease Dementia & Geriatric Cognitive Disorders 2012 341 53 · DOI
  41. Cummings, 2012, Randomized, double-blind, parallel-group, 48-week study for efficacy and safety of a higher-dose rivastigmine patch (15 vs. 10 cm2) in Alzheimer's disease, Dementia and Geriatric Cognitive Disorders, 33, 341, 10.1159/000340056 · DOI
  42. Frolich L Touchon J Massaia M Callegari F Strohmaier C Safety and tolerability of 9.5mg/24h(10cm2) and 13.3mg/24h (15cm2) rivastigmine patches: results from the optimising transdermal Exelon in mild-to-moderate Alzheimer's disease (OPTIMA) study European Journal of Neurology 2012
  43. Sadowsky, 2013, Effect of body mass index on the efficacy, safety and tolerability of higher-dose 13.3 mg/24 h rivastigmine patch in severe Alzheimer's disease, Clinical Pharmacology in Drug Development, Conference: 201, 42
  44. Potkin SG Wu JC Messina J Fleming K Keator D Bunney WE An R Neuroimaging techniques and applications Proceedings of the 152nd Annual Meeting of the American Psychiatric Association; 1999 May 15-20, Washington DC 1999 SR-HANDSRCH
  45. Rozzini L Bargnani C Bosio A Chia F Franzani S Leonardi R Acetylcholinesterase inhibitors are effective in real world patients with mild to moderate Alzheimer disease evidence from a large population treated with rivastigmine or donepezil The 8th conference on Alzheimer's Disease and Related Disorders, July 20-25, 2002, Stockholm, Sweden 2002 329
  46. Rozzini L Bargnani C Bosio A Chia F Franzoni S Leonardi R Comparison of efficacy and safety of rivastigmine and donepezil in patients with mild to moderate Alzheimer disease: results from a multicentre randomised trial Proceedings of the 7th International Geneva/Springfield Symposium on Advances in Alzheimer Therapy, 2002 Apr 3-6, Geneva 2002 240
  47. Shanks MF Venneri A Staff RT Pestell SJ Forbes KE Gemmell HG Murray AD Cerebral blood flow and cognition enhanced by rivastigmine in a controlled study of Alzheimer's disease Alzheimer's Disease International, 17th International Conference, Christchurch, New Zealand, 25-27 October 2001 2001 37
  48. Shua-Haim J Smith J Potel S A head to study of donepezil (Aricept), rivastigmine (Exelon) and galantamine (Reminyl) for the treatment of Alzheimer's disease safety tolerability clinical and caregiver impression after 4-5 months of treatment: a prospective study The 8th conference on Alzheimer's Disease and Related Disorders, July 20-25, 2002, Stockholm, Sweden 2002 286
  49. Shua-Haim J Smith J Amin S Shua-Haim V Comparison of combination therapy with rivastigmine exelon and donepezil aricept versus rivastigmine alone for treatment of Alzheimer's disease safety tolerability and clinical experience after one year of treatment a cross section study The 8th conference on Alzheimer's Disease and Related Disorders, July 20-25, 2002, Stockholm, Sweden 2002 292
  50. Shua-Haim JR Smith JM Amin S Slow dose escalation of rivastigmine (Exelon®) treatment of agitation in patients with alzheimer disease: an eight month prospective study The International Symposium on Advances in Alzheimer Therapy, 2002, Geneva 2002 242
  51. Sobow T Cholinesterase inhibitors in the real world: donepezil vs rivastigmine tolerability study Proceedings of the 7th International Geneva/Springfield Symposium on Advances in Alzheimer Therapy, 2002 Apr 3-6, Geneva 2002 244
  52. Stefanova E Blennow K Darreh-Shori T Hellstrom-Lindhal E Wall A Almkvist O Evaluation of cerebral glucose metabolism, CSF-TAU and CSF-A342 after long-term rivastigmine and tacrine treatments in Alzheimer disease patients Proceedings of the 7th International Geneva/Springfield Symposium on Advances in Alzheimer Therapy, 2002 Apr 3-6, Geneva 2002 246
  53. Tsolaki M Gerothanassis D Aristotle CP Efficacy and safety of cholinesterase inhibitors a longitudinal comparative study between donepezil and rivastigmine The 8th conference on Alzheimer's Disease and Related Disorders, July 20-25, 2002, Stockholm, Sweden 2002 2038
  54. Venneri A Shanks MF Charting patterns of progression in treated and untreated patients with Alzheimer's disease using SPECT The 8th conference on Alzheimer's Disease and Related Disorders, July 20-25, 2002, Stockholm, Sweden 2002 474
  55. Wang, 2001, The treatment by using rivastigmine for patients with alzheimer disease: results of a multicenter, randomized, open-labeled, controlled clinical trial, Chinese Journal of Neurology, 34, 210
  56. Wang, 2003, [Efficacy of rivastigmine in treating mild to severe alzheimer's disease with different hachinski ischemia index], Chinese Journal of Neurology, 36, 44
  57. Weiser M Davidson M Rotmensch H Korczyn A Hartman R Cicin-Sain A Anand R A pilot randomised open label trial assessing safety and pharmacokinetic parameters of co administration of rivastigmine with risperidone in dementia patients with behavioral disturbances The 8th conference on Alzheimer's Disease and Related Disorders, July 20-25, 2002, Stockholm, Sweden 2002 633
  58. Werber EA Klein C Rabey MJ Evaluation of cholinergic treatment in demented by p300 evoked related potentials The 8th conference on Alzheimer's Disease and Related Disorders, July 20-25, 2002, Stockholm, Sweden 2002 442
  59. Bullock, 2001, The tolerability, ease of use and efficacy of donepezil and rivastigmine in Alzheimer's disease patients: a 12-week, multinational, comparative study, Journal of the American Geriatrics Society, 49, S19
  60. Potocnik FC Smith R Passmore P Hock C Wilkinson D Maud CM Hopker S Tolerability, ease of use, and efficacy of donepezil and rivastigmine in Alzheimer's disease patients Proceedings of the Annual Meeting of the American Psychiatric Association; 2001 May 5-10; New Orleans 2001
  61. Benton, 1974, Revised visual retention test
  62. Brunner, 1990, Eine Validierungsstudie mit der NOSGER (Nurses' Observation Scale for Geriatric Patients), einem neuen Beurteilungsinstrument für die Psychogeriatrie, Zeitschr für Psychologie, XIX, 211
  63. Burns, 2004, Efficacy of rivastigmine in subjects with moderately severe Alzheimer's disease, International Journal of Geriatric Psychiatry, 19, 243, 10.1002/gps.1058 · DOI
  64. Erkinjuntti, 2002, Rivastigmine in patients with Alzheimer's disease and concurrent hypertension, International Journal of Clinical Practice, 56, 791, 10.1111/j.1742-1241.2002.tb11377.x · DOI
  65. Farlow, 2003a, Analysis of outcome in retrieved dropout patients in a rivastigmine vs placebo, 26-week, Alzheimer disease trial, Archives of Neurology, 60, 843, 10.1001/archneur.60.6.843 · DOI
  66. Homma, 1991, Development of a new rating scale for dementia in the elderly: Mental Function Impairment Scale (MENFIS), Japanese Journal of Geriatric Psychiatry, 2, 1217
  67. Reisberg, 1989, Stage specific incidence of potentially remediable behavioral symptoms in aging and AD: a study of 120 patients using the BEHAVE-AD, Bulletin of Clinical Neuroscience, 54, 95
  68. Reisberg, 1994, CIBIC-plus interview guide
  69. Schneider, 1998, Systematic review of the efficacy of rivastigmine for patients with Alzheimer's disease, International Journal of Geriatric Psychopharmacology, 1, S26
  70. Wechsler, 1987, Wechsler Memory Scale-Revised (WMS-R)

Cited by

Sorted by citations

Related

See all

Metadata

Authors
Birks, J. S., Chong, L.-Y., & Grimley Evans, J.
Affiliations
  • University of Oxford (GB)
  • Cochrane (GB)
  • University of Oxford; Division of Clinical Geratology, Nuffield Department of Clinical Medicine; Radcliffe Infirmary Woodstock Road Oxford UK OX2 6HE
ORCID
Birks, Jacqueline S
Venue
Cochrane Database of Systematic Reviews
Publisher
Wiley
Published
2015-09-22
Volume
38
Issue
2
Pages
15-6
ISSN
  • 1361-6137 (ISSN-L)
  • 1465-1858
DOI
10.1002/14651858.cd001191.pub4
PMC
PMC7050299
OpenAlex
W2098999434
Cited by
534
References
147
Citations by year
2026: 10 · 2025: 15 · 2024: 24 · 2023: 25 · 2022: 23 · 2021: 29 · 2020: 28 · 2019: 30 · 2018: 30 · 2017: 21 · 2016: 25 · 2015: 18
FWCI
3.93
Type
journal article
Language
en
Open access
Locations
  • Cochrane Database of Systematic Reviews (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Topics
  • Health Sciences › Medicine › Pharmacology (medical) › Cholinesterase and Neurodegenerative Diseases
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
Keywords
rivastigmine, Alzheimer's disease, dementia, cholinesterase inhibitors, acetylcholinesterase inhibition, transdermal patch, oral dosage forms, cognitive function, functional status, adverse effects, hepatotoxicity, tacrine, placebo comparison, treatment efficacy and safety, older adults, dose comparison
MeSH terms
Rivastigmine, Alzheimer Disease, Carbamates, Cholinesterase Inhibitors, Humans, Randomized Controlled Trials as Topic, Neuroprotective Agents, Phenylcarbamates

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review