Cognitive Outcomes of Long-term Benzodiazepine and Related Drug (BDZR) Use in People Living With Mild to Moderate Alzheimer's Disease: Results From NILVAD

Adam H. Dyer; Claire Murphy; Brian Lawlor; Sean P. Kennelly; Ricardo Segurado; Sean Kennelly; Marcel G. M. Olde Rikkert; Robert Howard; Florence Pasquier; Anne Brjesson-Hanson; Magda Tsolaki; Ugo Lucca; D. William Molloy; Robert Coen; Matthias W. Riepe; Janos Kalman; Rose Anne Kenny; Fiona Cregg; Sarah O'Dwyer; Cathal Walsh; Jessica Adams; Rita Banzi; Laetitia Breuilh; Leslie Daly; Suzanne Hendrix; Paul Aisen; Siobhan Gaynor; Ali Sheikhi; Diana G. Taekema; Frans R. Verhey; Raffaello Nemni; Flavio Nobili; Massimo Franceschi; Giovanni Frisoni; Orazio Zanetti; Anastasia Konsta; Orologas Anastasios; Styliani Nenopoulou; Fani Tsolaki-Tagaraki; Magdolna Pakaski; Olivier Dereeper; Vincent de la Sayette; Olivier Senechal; Isabelle Lavenu; Agnes Devendeville; Gauthier Calais; Fiona Crawford; Michael Mullan; Pauline Aalten; Maria A. Berglund; NILVAD Study Grp

doi:10.1016/j.jamda.2019.08.006

Cognitive Outcomes of Long-term Benzodiazepine and Related Drug (BDZR) Use in People Living With Mild to Moderate Alzheimer's Disease: Results From NILVAD

Adam H. Dyer^*, Claire Murphy, Brian Lawlor, Sean P. Kennelly, Ricardo Segurado, Sean Kennelly, Marcel G. M. Olde Rikkert, Robert Howard, Florence Pasquier, Anne Brjesson-Hanson, Magda Tsolaki, Ugo Lucca, D. William Molloy, Robert Coen, Matthias W. Riepe, Janos Kalman, Rose Anne Kenny, Fiona Cregg, Sarah O'Dwyer, Cathal WalshJessica Adams, Rita Banzi, Laetitia Breuilh, Leslie Daly, Suzanne Hendrix, Paul Aisen, Siobhan Gaynor, Ali Sheikhi, Diana G. Taekema, Frans R. Verhey, Raffaello Nemni, Flavio Nobili, Massimo Franceschi, Giovanni Frisoni, Orazio Zanetti, Anastasia Konsta, Orologas Anastasios, Styliani Nenopoulou, Fani Tsolaki-Tagaraki, Magdolna Pakaski, Olivier Dereeper, Vincent de la Sayette, Olivier Senechal, Isabelle Lavenu, Agnes Devendeville, Gauthier Calais, Fiona Crawford, Michael Mullan, Pauline Aalten, Maria A. Berglund, NILVAD Study Grp

^*Corresponding author for this work

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Abstract

Objective: Benzodiazepines and related drugs (BDZRs) have been associated with an increased risk of Alzheimer's disease (AD) in later life. Despite this, it remains unclear whether ongoing BDZR use may further accelerate cognitive decline in those diagnosed with mild to moderate AD.

Design: This study was embedded within NILVAD, a randomized controlled trial of nilvadipine in mild to moderate AD. Cognition was measured at baseline and 18 months using the Alzheimer Disease Assessment Scale, Cognitive Subsection (ADAS-Cog). We assessed predictors of long-term BDZR use and analyzed the effect of ongoing BDZR use on ADAS-Cog scores at 18 months. Additionally, the impact of BDZR use on adverse events, incident delirium, and falls over 18-month follow-up was assessed adjusting for relevant covariates.

Setting and Participants: 448 participants with mild to moderate AD recruited from 23 academic centers in 9 European countries.

Results: Overall, 14% (62/448) were prescribed an ongoing BDZR for the study duration. Increasing total number of (non-BDZR) medications was associated with a greater likelihood of BDZR prescription (odds ratio 1.16, 95% confidence interval 1.05-1.29). At 18 months, BDZR use was not associated with greater cognitive decline on the ADAS-Cog controlling for baseline ADAS-Cog scores, age, gender, study arm, and other clinical covariates (beta = 1.62, -1.34 to 4.56). However, ongoing BDZR use was associated with a greater likelihood of adverse events [incidence rate ratio (IRR) 1.19, 1.05-1.34], incident delirium (IRR 2.31, 1.45-3.68), and falls (IRR 1.66, 1.02-2.65) over 18 months that persisted after robust adjustment for covariates.

Conclusions and Implications: This study found no effect of ongoing BDZR use on ADAS-Cog scores in those with mild to moderate AD over 18 months. However, ongoing use of these medications was associated with an increased risk of adverse events, delirium, and falls. Thus, BDZR use should be avoided where possible and deprescribing interventions should be encouraged in older adults with AD. (C) 2019 AMDA - The Society for Post-Acute and Long-Term Care Medicine.

Original language	English
Pages (from-to)	194-200
Number of pages	7
Journal	Journal of the American Medical Directors Association
Volume	21
Issue number	2
DOIs	https://doi.org/10.1016/j.jamda.2019.08.006
Publication status	Published - Feb 2020

Keywords

Dementia
benzodiazepines
cognition
benzodiazepines and related drugs
OLDER-ADULTS
RISK
DEMENTIA
DELIRIUM
DECLINE

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Dyer, A. H., Murphy, C., Lawlor, B., Kennelly, S. P., Segurado, R., Kennelly, S., Rikkert, M. G. M. O., Howard, R., Pasquier, F., Brjesson-Hanson, A., Tsolaki, M., Lucca, U., Molloy, D. W., Coen, R., Riepe, M. W., Kalman, J., Kenny, R. A., Cregg, F., O'Dwyer, S., ... NILVAD Study Grp (2020). Cognitive Outcomes of Long-term Benzodiazepine and Related Drug (BDZR) Use in People Living With Mild to Moderate Alzheimer's Disease: Results From NILVAD. Journal of the American Medical Directors Association, 21(2), 194-200. https://doi.org/10.1016/j.jamda.2019.08.006

@article{d5c6332329284b4ba1f13b6657af555c,

title = "Cognitive Outcomes of Long-term Benzodiazepine and Related Drug (BDZR) Use in People Living With Mild to Moderate Alzheimer's Disease: Results From NILVAD",

abstract = "Objective: Benzodiazepines and related drugs (BDZRs) have been associated with an increased risk of Alzheimer's disease (AD) in later life. Despite this, it remains unclear whether ongoing BDZR use may further accelerate cognitive decline in those diagnosed with mild to moderate AD.Design: This study was embedded within NILVAD, a randomized controlled trial of nilvadipine in mild to moderate AD. Cognition was measured at baseline and 18 months using the Alzheimer Disease Assessment Scale, Cognitive Subsection (ADAS-Cog). We assessed predictors of long-term BDZR use and analyzed the effect of ongoing BDZR use on ADAS-Cog scores at 18 months. Additionally, the impact of BDZR use on adverse events, incident delirium, and falls over 18-month follow-up was assessed adjusting for relevant covariates.Setting and Participants: 448 participants with mild to moderate AD recruited from 23 academic centers in 9 European countries.Results: Overall, 14% (62/448) were prescribed an ongoing BDZR for the study duration. Increasing total number of (non-BDZR) medications was associated with a greater likelihood of BDZR prescription (odds ratio 1.16, 95% confidence interval 1.05-1.29). At 18 months, BDZR use was not associated with greater cognitive decline on the ADAS-Cog controlling for baseline ADAS-Cog scores, age, gender, study arm, and other clinical covariates (beta = 1.62, -1.34 to 4.56). However, ongoing BDZR use was associated with a greater likelihood of adverse events [incidence rate ratio (IRR) 1.19, 1.05-1.34], incident delirium (IRR 2.31, 1.45-3.68), and falls (IRR 1.66, 1.02-2.65) over 18 months that persisted after robust adjustment for covariates.Conclusions and Implications: This study found no effect of ongoing BDZR use on ADAS-Cog scores in those with mild to moderate AD over 18 months. However, ongoing use of these medications was associated with an increased risk of adverse events, delirium, and falls. Thus, BDZR use should be avoided where possible and deprescribing interventions should be encouraged in older adults with AD. (C) 2019 AMDA - The Society for Post-Acute and Long-Term Care Medicine.",

keywords = "Dementia, benzodiazepines, cognition, benzodiazepines and related drugs, OLDER-ADULTS, RISK, DEMENTIA, DELIRIUM, DECLINE",

author = "Dyer, {Adam H.} and Claire Murphy and Brian Lawlor and Kennelly, {Sean P.} and Ricardo Segurado and Sean Kennelly and Rikkert, {Marcel G. M. Olde} and Robert Howard and Florence Pasquier and Anne Brjesson-Hanson and Magda Tsolaki and Ugo Lucca and Molloy, {D. William} and Robert Coen and Riepe, {Matthias W.} and Janos Kalman and Kenny, {Rose Anne} and Fiona Cregg and Sarah O'Dwyer and Cathal Walsh and Jessica Adams and Rita Banzi and Laetitia Breuilh and Leslie Daly and Suzanne Hendrix and Paul Aisen and Siobhan Gaynor and Ali Sheikhi and Taekema, {Diana G.} and Verhey, {Frans R.} and Raffaello Nemni and Flavio Nobili and Massimo Franceschi and Giovanni Frisoni and Orazio Zanetti and Anastasia Konsta and Orologas Anastasios and Styliani Nenopoulou and Fani Tsolaki-Tagaraki and Magdolna Pakaski and Olivier Dereeper and {de la Sayette}, Vincent and Olivier Senechal and Isabelle Lavenu and Agnes Devendeville and Gauthier Calais and Fiona Crawford and Michael Mullan and Pauline Aalten and Berglund, {Maria A.} and {NILVAD Study Grp}",

note = "Funding Information: Funding from the NILVAD study was from the European Commission Framework 7 Programme Health Theme Collaborative Project (grant 279093; PI: Brian Lawlor). Publisher Copyright: {\textcopyright} 2019 AMDA – The Society for Post-Acute and Long-Term Care Medicine",

year = "2020",

month = feb,

doi = "10.1016/j.jamda.2019.08.006",

language = "English",

volume = "21",

pages = "194--200",

journal = "Journal of the American Medical Directors Association",

issn = "1525-8610",

publisher = "Elsevier Science",

number = "2",

}

Dyer, AH, Murphy, C, Lawlor, B, Kennelly, SP, Segurado, R, Kennelly, S, Rikkert, MGMO, Howard, R, Pasquier, F, Brjesson-Hanson, A, Tsolaki, M, Lucca, U, Molloy, DW, Coen, R, Riepe, MW, Kalman, J, Kenny, RA, Cregg, F, O'Dwyer, S, Walsh, C, Adams, J, Banzi, R, Breuilh, L, Daly, L, Hendrix, S, Aisen, P, Gaynor, S, Sheikhi, A, Taekema, DG, Verhey, FR, Nemni, R, Nobili, F, Franceschi, M, Frisoni, G, Zanetti, O, Konsta, A, Anastasios, O, Nenopoulou, S, Tsolaki-Tagaraki, F, Pakaski, M, Dereeper, O, de la Sayette, V, Senechal, O, Lavenu, I, Devendeville, A, Calais, G, Crawford, F, Mullan, M, Aalten, P, Berglund, MA & NILVAD Study Grp 2020, 'Cognitive Outcomes of Long-term Benzodiazepine and Related Drug (BDZR) Use in People Living With Mild to Moderate Alzheimer's Disease: Results From NILVAD', Journal of the American Medical Directors Association, vol. 21, no. 2, pp. 194-200. https://doi.org/10.1016/j.jamda.2019.08.006

Cognitive Outcomes of Long-term Benzodiazepine and Related Drug (BDZR) Use in People Living With Mild to Moderate Alzheimer's Disease: Results From NILVAD. / Dyer, Adam H.; Murphy, Claire; Lawlor, Brian et al.
In: Journal of the American Medical Directors Association, Vol. 21, No. 2, 02.2020, p. 194-200.

Research output: Contribution to journal › Article › Academic › peer-review

TY - JOUR

T1 - Cognitive Outcomes of Long-term Benzodiazepine and Related Drug (BDZR) Use in People Living With Mild to Moderate Alzheimer's Disease

T2 - Results From NILVAD

AU - Dyer, Adam H.

AU - Murphy, Claire

AU - Lawlor, Brian

AU - Kennelly, Sean P.

AU - Segurado, Ricardo

AU - Kennelly, Sean

AU - Rikkert, Marcel G. M. Olde

AU - Howard, Robert

AU - Pasquier, Florence

AU - Brjesson-Hanson, Anne

AU - Tsolaki, Magda

AU - Lucca, Ugo

AU - Molloy, D. William

AU - Coen, Robert

AU - Riepe, Matthias W.

AU - Kalman, Janos

AU - Kenny, Rose Anne

AU - Cregg, Fiona

AU - O'Dwyer, Sarah

AU - Walsh, Cathal

AU - Adams, Jessica

AU - Banzi, Rita

AU - Breuilh, Laetitia

AU - Daly, Leslie

AU - Hendrix, Suzanne

AU - Aisen, Paul

AU - Gaynor, Siobhan

AU - Sheikhi, Ali

AU - Taekema, Diana G.

AU - Verhey, Frans R.

AU - Nemni, Raffaello

AU - Nobili, Flavio

AU - Franceschi, Massimo

AU - Frisoni, Giovanni

AU - Zanetti, Orazio

AU - Konsta, Anastasia

AU - Anastasios, Orologas

AU - Nenopoulou, Styliani

AU - Tsolaki-Tagaraki, Fani

AU - Pakaski, Magdolna

AU - Dereeper, Olivier

AU - de la Sayette, Vincent

AU - Senechal, Olivier

AU - Lavenu, Isabelle

AU - Devendeville, Agnes

AU - Calais, Gauthier

AU - Crawford, Fiona

AU - Mullan, Michael

AU - Aalten, Pauline

AU - Berglund, Maria A.

AU - NILVAD Study Grp

N1 - Funding Information: Funding from the NILVAD study was from the European Commission Framework 7 Programme Health Theme Collaborative Project (grant 279093; PI: Brian Lawlor). Publisher Copyright: © 2019 AMDA – The Society for Post-Acute and Long-Term Care Medicine

PY - 2020/2

Y1 - 2020/2

N2 - Objective: Benzodiazepines and related drugs (BDZRs) have been associated with an increased risk of Alzheimer's disease (AD) in later life. Despite this, it remains unclear whether ongoing BDZR use may further accelerate cognitive decline in those diagnosed with mild to moderate AD.Design: This study was embedded within NILVAD, a randomized controlled trial of nilvadipine in mild to moderate AD. Cognition was measured at baseline and 18 months using the Alzheimer Disease Assessment Scale, Cognitive Subsection (ADAS-Cog). We assessed predictors of long-term BDZR use and analyzed the effect of ongoing BDZR use on ADAS-Cog scores at 18 months. Additionally, the impact of BDZR use on adverse events, incident delirium, and falls over 18-month follow-up was assessed adjusting for relevant covariates.Setting and Participants: 448 participants with mild to moderate AD recruited from 23 academic centers in 9 European countries.Results: Overall, 14% (62/448) were prescribed an ongoing BDZR for the study duration. Increasing total number of (non-BDZR) medications was associated with a greater likelihood of BDZR prescription (odds ratio 1.16, 95% confidence interval 1.05-1.29). At 18 months, BDZR use was not associated with greater cognitive decline on the ADAS-Cog controlling for baseline ADAS-Cog scores, age, gender, study arm, and other clinical covariates (beta = 1.62, -1.34 to 4.56). However, ongoing BDZR use was associated with a greater likelihood of adverse events [incidence rate ratio (IRR) 1.19, 1.05-1.34], incident delirium (IRR 2.31, 1.45-3.68), and falls (IRR 1.66, 1.02-2.65) over 18 months that persisted after robust adjustment for covariates.Conclusions and Implications: This study found no effect of ongoing BDZR use on ADAS-Cog scores in those with mild to moderate AD over 18 months. However, ongoing use of these medications was associated with an increased risk of adverse events, delirium, and falls. Thus, BDZR use should be avoided where possible and deprescribing interventions should be encouraged in older adults with AD. (C) 2019 AMDA - The Society for Post-Acute and Long-Term Care Medicine.

AB - Objective: Benzodiazepines and related drugs (BDZRs) have been associated with an increased risk of Alzheimer's disease (AD) in later life. Despite this, it remains unclear whether ongoing BDZR use may further accelerate cognitive decline in those diagnosed with mild to moderate AD.Design: This study was embedded within NILVAD, a randomized controlled trial of nilvadipine in mild to moderate AD. Cognition was measured at baseline and 18 months using the Alzheimer Disease Assessment Scale, Cognitive Subsection (ADAS-Cog). We assessed predictors of long-term BDZR use and analyzed the effect of ongoing BDZR use on ADAS-Cog scores at 18 months. Additionally, the impact of BDZR use on adverse events, incident delirium, and falls over 18-month follow-up was assessed adjusting for relevant covariates.Setting and Participants: 448 participants with mild to moderate AD recruited from 23 academic centers in 9 European countries.Results: Overall, 14% (62/448) were prescribed an ongoing BDZR for the study duration. Increasing total number of (non-BDZR) medications was associated with a greater likelihood of BDZR prescription (odds ratio 1.16, 95% confidence interval 1.05-1.29). At 18 months, BDZR use was not associated with greater cognitive decline on the ADAS-Cog controlling for baseline ADAS-Cog scores, age, gender, study arm, and other clinical covariates (beta = 1.62, -1.34 to 4.56). However, ongoing BDZR use was associated with a greater likelihood of adverse events [incidence rate ratio (IRR) 1.19, 1.05-1.34], incident delirium (IRR 2.31, 1.45-3.68), and falls (IRR 1.66, 1.02-2.65) over 18 months that persisted after robust adjustment for covariates.Conclusions and Implications: This study found no effect of ongoing BDZR use on ADAS-Cog scores in those with mild to moderate AD over 18 months. However, ongoing use of these medications was associated with an increased risk of adverse events, delirium, and falls. Thus, BDZR use should be avoided where possible and deprescribing interventions should be encouraged in older adults with AD. (C) 2019 AMDA - The Society for Post-Acute and Long-Term Care Medicine.

KW - Dementia

KW - benzodiazepines

KW - cognition

KW - benzodiazepines and related drugs

KW - OLDER-ADULTS

KW - RISK

KW - DEMENTIA

KW - DELIRIUM

KW - DECLINE

U2 - 10.1016/j.jamda.2019.08.006

DO - 10.1016/j.jamda.2019.08.006

M3 - Article

C2 - 31604674

SN - 1525-8610

VL - 21

SP - 194

EP - 200

JO - Journal of the American Medical Directors Association

JF - Journal of the American Medical Directors Association

IS - 2

ER -

Cognitive Outcomes of Long-term Benzodiazepine and Related Drug (BDZR) Use in People Living With Mild to Moderate Alzheimer's Disease: Results From NILVAD

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