{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,4]],"date-time":"2026-11-04T18:05:31Z","timestamp":1793815531820,"version":"4.6.1"},"reference-count":32,"publisher":"BMJ","issue":"4","license":[{"start":{"date-parts":[[2022,4,25]],"date-time":"2022-04-25T00:00:00Z","timestamp":1650844800000},"content-version":"unspecified","delay-in-days":24,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Tier 2 Canada Research Chair in Knowledge Synthesis","award":["N\/A"],"award-info":[{"award-number":["N\/A"]}]},{"name":"CIHR Banting Postdoctoral Fellowship Program","award":["139157"],"award-info":[{"award-number":["139157"]}]},{"name":"CIHR Drug Safety and Effectiveness Network","award":["137713"],"award-info":[{"award-number":["137713"]}]},{"name":"European Union's Horizon 2020","award":["754936"],"award-info":[{"award-number":["754936"]}]},{"name":"Tier 1 Canada Research Chair in Knowledge Translation","award":["N\/A"],"award-info":[{"award-number":["N\/A"]}]}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["BMJ Open"],"accepted":{"date-parts":[[2022,3,25]]},"published-print":{"date-parts":[[2022,4]]},"abstract":"<jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>To examine the comparative efficacy and safety of cognitive enhancers by patient characteristics for managing Alzheimer\u2019s dementia (AD).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Design<\/jats:title>\n                    <jats:p>Systematic review and individual patient data (IPD) network meta-analysis (NMA) based on our previously published systematic review and aggregate data NMA.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Data sources<\/jats:title>\n                    <jats:p>MEDLINE, Embase, Cochrane Methodology Register, CINAHL, AgeLine and Cochrane Central Register of Controlled Trials up to March 2016.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Participants<\/jats:title>\n                    <jats:p>80 randomised controlled trials (RCTs) including 21 138 adults with AD, and 12 RCTs with IPD including 6906 patients.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Interventions<\/jats:title>\n                    <jats:p>Cognitive enhancers (donepezil, rivastigmine, galantamine and memantine) alone or in any combination against other cognitive enhancers or placebo.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Data extraction and synthesis<\/jats:title>\n                    <jats:p>We requested IPD from authors, sponsors and data sharing platforms. When IPD were not available, we used aggregate data. We appraised study quality with the Cochrane risk-of-bias. We conducted a two-stage random-effects IPD-NMA, and assessed their findings using CINeMA (Confidence in Network Meta-Analysis).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Primary and secondary outcomes<\/jats:title>\n                    <jats:p>We included trials assessing cognition with the Mini-Mental State Examination (MMSE), and adverse events.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Our IPD-NMA compared nine treatments (including placebo). Donepezil (mean difference (MD)=1.41, 95% CI: 0.51 to 2.32) and donepezil +memantine (MD=2.57, 95%\u2009CI: 0.07 to 5.07) improved MMSE score (56 RCTs, 11\u2009619 participants; CINeMA score: moderate) compared with placebo. According to P-score, oral rivastigmine (OR=1.26, 95%\u2009CI: 0.82 to 1.94, P-score=16%) and donepezil (OR=1.08, 95%\u2009CI: 0.87 to 1.35, P-score=30%) had the least favourable safety profile, but none of the estimated treatment effects were sufficiently precise when compared with placebo (45 RCTs, 15\u2009649 patients; CINeMA score: moderate to high). For moderate-to-severe impairment, donepezil, memantine and their combination performed best, but for mild-to-moderate impairment donepezil and transdermal rivastigmine ranked best. Adjusting for MMSE baseline differences, oral rivastigmine and galantamine improved MMSE score, whereas when adjusting for comorbidities only oral rivastigmine was effective.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>The choice among the different cognitive enhancers may depend on patient\u2019s characteristics. The MDs of all cognitive enhancer regimens except for single-agent oral rivastigmine, galantamine and memantine, against placebo were clinically important for cognition (MD larger than 1.40 MMSE points), but results were quite imprecise. However, two-thirds of the published RCTs were associated with high risk of bias for incomplete outcome data, and IPD were only available for 15% of the included RCTs.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>PROSPERO registration number<\/jats:title>\n                    <jats:p>CRD42015023507.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1136\/bmjopen-2021-053012","type":"journal-article","created":{"date-parts":[[2022,5,17]],"date-time":"2022-05-17T08:10:10Z","timestamp":1652775010000},"page":"e053012","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":33,"title":["Comparative safety and efficacy of cognitive enhancers for Alzheimer\u2019s dementia: a systematic review with individual patient data network meta-analysis"],"prefix":"10.1136","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6388-4825","authenticated-orcid":false,"given":"Areti Angeliki","family":"Veroniki","sequence":"first","affiliation":[{"name":"Institute of Health Policy Management and Evaluation, University of Toronto, Toronto, Ontario, Canada"},{"name":"Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, Ontario, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huda M","family":"Ashoor","sequence":"additional","affiliation":[{"name":"Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, Ontario, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patricia","family":"Rios","sequence":"additional","affiliation":[{"name":"Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, Ontario, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0856-1892","authenticated-orcid":false,"given":"Georgios","family":"Seitidis","sequence":"additional","affiliation":[{"name":"Department of Primary Education, University of Ioannina, Ioannina, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lesley","family":"Stewart","sequence":"additional","affiliation":[{"name":"Centre for Reviews and Dissemination, University of York, York, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2926-7257","authenticated-orcid":false,"given":"Mike","family":"Clarke","sequence":"additional","affiliation":[{"name":"Northern Ireland Hub for Trials Methodology Research, Queen\u2019s University Belfast, Belfast, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Catrin","family":"Tudur-Smith","sequence":"additional","affiliation":[{"name":"Department of Biostatistics, University of Liverpool, Liverpool, Merseyside, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1041-4592","authenticated-orcid":false,"given":"Dimitris","family":"Mavridis","sequence":"additional","affiliation":[{"name":"Department of Primary Education, University of Ioannina, Ioannina, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brenda R","family":"Hemmelgarn","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Alberta, Edmonton, Alberta, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jayna","family":"Holroyd-Leduc","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Calgary, Calgary, Alberta, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sharon E","family":"Straus","sequence":"additional","affiliation":[{"name":"Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, Ontario, Canada"},{"name":"Department of Geriatric Medicine, University of Toronto, Toronto, Ontario, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4114-8971","authenticated-orcid":false,"given":"Andrea C","family":"Tricco","sequence":"additional","affiliation":[{"name":"Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, Ontario, Canada"},{"name":"Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"239","published-online":{"date-parts":[[2022,4,26]]},"reference":[{"key":"2025101810505796000_12.4.e053012.1","unstructured":"Health NCCfM . 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