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© David Mumbere Bamusemba, 2020

Caractéristiques des interventions pour déprescrire les benzodiazépines chez les personnes aînées et impacts

sur la santé : Revue systématique

Mémoire

David Mumbere Bamusemba

Maîtrise en sciences pharmaceutiques - avec mémoire

Maître ès sciences (M. Sc.)

Québec, Canada

Caractéristiques des interventions pour déprescrire les benzodiazépines chez les personnes aînées et impacts sur la santé : Revue systématique

Mémoire

David Mumbere Bamusemba

Sous la direction de :

Danielle Laurin, directrice de recherche

Edeltraut Kröger, codirectrice de recherche

iii

Résumé

Le vieillissement de la population s’accompagne d’une augmentation de la

multimorbidité et de la polymédication qui en résulte. Au Canada, deux tiers des

personnes âgées de 65 ans ou plus recevaient au moins cinq classes de

médicaments par année en 2016, malgré le fait que la polymédication soit associée

à des effets indésirables. Plusieurs études ont démontré la possibilité de réduire

significativement le nombre de médicaments chez les personnes dans ce groupe

d’âge grâce aux interventions dites de déprescription. La déprescription des

benzodiazépines (BZD) est d’une importance capitale compte tenu de la prévalence

élevée de cette classe de médicaments chez les personnes aînées. La

déprescription des BZD serait possiblement associée à une réduction des effets

indésirables et une meilleure qualité de vie. Les objectifs de ce projet de recherche

étaient de décrire les caractéristiques des interventions pour déprescrire les BZD

chez les personnes aînées et leurs impacts sur la santé de ces personnes grâce à

une revue systématique. Cette revue décrit les interventions de déprescription de

BZD issues de 11 études et leurs effets sur la santé de 1 042 participants âgés en

moyenne de 71 ans. Les effets des interventions sur la santé des participants des

groupes interventions ont été comparés aux résultats sur la santé des participants

des groupes témoins. Dans l'ensemble, le retrait des BZD est bien sécuritaire et les

impacts négatifs sur le sommeil sont plutôt négligeables et temporaires chez

certains patients. Dans la plupart des études, les patients n'ont pas présenté de

symptômes de sevrage significatifs, sauf dans quelques études où les participants

des groupes d'intervention ont connu plus d'insomnie et d'anxiété à 6 mois par

rapport aux participants des groupes témoins (p <0,0001).

iv

Abstract

People are living longer than ever, but this increase in life expectancy is also

associated with increased multimorbidity and the resulting polypharmacy. In

Canada, two thirds of people aged 65 years or older received at least five prescribed

classes of medications a year in 2016, even though polypharmacy is linked with

increased medication adverse effects and mortality. Several studies demonstrated

the possibility to reduce significantly the number of prescribed drugs in this age

group using deprescribing interventions. Benzodiazepine (BZD) discontinuation is

of paramount importance given the high prevalence of this class of drugs in seniors.

BZD discontinuation may be associated with the reduction of adverse effects and a

better quality of life. The objectives of this research project were to describe the

characteristics of interventions to discontinue BZD in older persons and their impact

on their health through a systematic review. This study describes BZD deprescribing

interventions from 11 BZD discontinuation studies and their impacts on the health

of 1042 participants aged on average 71 years. The health impacts of these

interventions were compared between the intervention and the control groups.

Overall, the withdrawal from BZDs is safe and its adverse impacts on health are

rather negligible and temporary in some patients. In most studies, patients did not

suffer significant withdrawal symptoms, except few studies in which participants in

intervention groups had experienced more insomnia and anxiety at 6 months

compared to participants in the control groups (p<0.0001).

v

Table des matières Résumé .................................................................................................................................................................. iii

Abstract ................................................................................................................................................................... iv

Liste des tableaux .............................................................................................................................................. vii

Liste des figures ................................................................................................................................................ viii

Liste des abréviations ....................................................................................................................................... ix

Special thanks ...................................................................................................................................................... x

Avant-Propos ........................................................................................................................................................ xi

Introduction ............................................................................................................................................................ 1

Chapitre 1. Revue de la littérature ............................................................................................................... 3

1.1 La déprescription ................................................................................................................................. 4

1.2 Les types, les étapes et les objectifs d’interventions de déprescription ........................ 5

1.3 Les médicaments potentiellement inappropriés...................................................................... 6

1.4 La polymédication ............................................................................................................................... 7

1.4.1 La polymédication chez l’aîné .................................................................................................... 8

1.4.2 Les facteurs de risque de la polymédication ........................................................................ 8

1.5 Les benzodiazépines, l’âge et le sexe/genre ........................................................................... 9

1.5.1 La prévalence de l’usage des BZD ....................................................................................... 12

1.5.2 Quelques outils de surveillance des MPI ........................................................................... 13

1.5.3 Les lignes directrices .................................................................................................................. 14

Chapitre 2. Méthodologie .............................................................................................................................. 17

2.1 Objectif général .................................................................................................................................. 17

2.2 Questions de recherche .................................................................................................................. 17

2.3 Devis de l’étude .................................................................................................................................. 17

2.4 Recherche documentaire ............................................................................................................... 17

2.5 La sélection des études .................................................................................................................. 18

2.6 Les critères d'exclusion ................................................................................................................... 19

2.7 L’extraction des données ............................................................................................................... 20

2.8 Synthèse des données .................................................................................................................... 20

Chapitre 3. Résultats ....................................................................................................................................... 21

3.1 Electronic database search, study selection and data extraction .................................. 21

3.2 Settings and Objectives .................................................................................................................. 23

3.3 Quality of the evidence .................................................................................................................... 23

3.4 Study Population ................................................................................................................................ 24

3.5 Description of successful interventions .................................................................................... 28

vi

3.6 Effects of education-based interventions on BZD discontinuation ................................ 34

3.7 Effect of BZD discontinuation on health ................................................................................... 34

3.7.1 Sleep quality and hours of sleep ............................................................................................ 34

3.7.2 Cognitive function ........................................................................................................................ 35

3.7.3 Daily functioning, body stability and depression .............................................................. 36

3.7.4 Adverse events ............................................................................................................................. 37

3.7.5 Withdrawal symptoms ................................................................................................................ 37

3.8 Characteristics of successful deprescribing interventions ................................................ 37

Chapitre 4. Discussion .................................................................................................................................... 41

4.1 Efficacy of interventions to deprescribe BZD ................................................................................. 41

4.2 The health impacts of deprescribing interventions ...................................................................... 42

4.3 Characteristics of successful deprescribing interventions ........................................................ 43

4.4 Acceptability of deprescribing interventions ................................................................................... 44

4.5 Limitation and biases ............................................................................................................................... 45

4.5.1 Selection biases ..................................................................................................................................... 45

4.5.2 Information biases ................................................................................................................................. 45

4.5.3 Confounding biases.............................................................................................................................. 46

4.6 Strengths ...................................................................................................................................................... 46

Conclusion ........................................................................................................................................................... 47

Annexe A. Description complète des rapports d’études retenues ............................................... 48

Annexe B. Outils d’évaluation des biais pour chaque étude incluse (critères RTI et SIGN)

.................................................................................................................................................................................. 57

Annexe C. Les stratégies de recherche et les mots-clés ................................................................. 84

Références .......................................................................................................................................................... 96

vii

Liste des tableaux Tableau 1. Liste des BZD

Tableau 2. Les recommandations sur la gestion sécuritaire des BZD

Tableau 3. Study appraisal

Tableau 4. Description of included studies

Tableau 5. Description of BZD deprescribing interventions

Tableau 6. Common characteristics of successful BZD deprescribing interventions

viii

Liste des figures

Figure 1. Structure chimique de BZD

Figure 2. PRISMA Flow Chart

ix

Liste des abréviations

BZD Benzodiazépines

BWSQ BZD Withdrawal Symptoms Questionnaire

CFF Critical Flicker Fusion Test

CG Control Group

CSP Clinical Stabilometric Platform

EC Échange de connaissances

ECR Essai contrôlé randomisé

FDA Food and Drug Administration

GABA Gamma-Aminobutyric acid

GP General practitioner

GRADE Grading of Recommendations Assessment, Development and Evaluation

HADS Hospital Anxiety and Depression Scale

IC Intervalle de confiance

IG Intervention Group

IIPAS l'intervalle inter-percentile ajusté pour la symétrie

IMA Indice de médicaments appropriés

INESSS Institut national d’excellence en santé et en service sociaux

IRSC Instituts de recherche en santé du Canada

MMSE Mini-Mental State Examination

MPI Médicaments potentiellement inappropriés

NA Not applicable

NA Negative Affect

OPEN Ontario Pharmacy Research Collaboration

PA Positive Affect

PANAS Positive and Negative Affect Schedule

PICOS Population – Intervention – Comparison – Outcomes – Study design

PRISMA Preferred Reporting Items for Systematic Reviews and Meta-Analyses

PROSPERO International prospective register of systematic reviews

RBANS Repeatable Battery for the Assessment of Neuropsychological Status

RC Rapport des cotes

RR Risque relatif

SIF Structured Intervention with Follow-up visits

SIGN Scottish Intercollegiate Guidelines Network

SIW Structured Intervention with Written instruction

START Screening Tool to Alert doctors to the Right Treatment

STOPP Screening Tool of Older Persons' potentially inappropriate Prescriptions

TCC Thérapie cognitivo-comportementale

WAIS-R Wechsler Adult Intelligence Scale-revised

x

Special thanks

I would like to express my special appreciation to my thesis supervisor, Dr.

Danielle Laurin, and co-supervisor, Dr. Edeltraut Kröger, for their scholarly

advice. Thank you both for the encouragement and for corrections during the

entire process.

I would like to thank Mr. Pierre-Hugues Carmichael (biostatistician) and Madam

Martine Marcotte for their valuable cooperation and support.

A special thanks and gratitude to my wife, Ornella L. Mumbere, and my parents,

Celine N. Mabakumba and Maurice C. Chunga, for their loyal support.

xi

Avant-Propos

Ce mémoire a été rédigé sous la co-supervision de Dr Danielle Laurin et Dr

Edeltraut Kroger dans le cadre de mon travail de fin d’étude à l’Université Laval. Au

cours des quatre dernières années, j’ai beaucoup appris sur les méthodes de

recherche en épidémiologie et en pharmaco-épidémiologie. Le travail de recherche

sur l’utilisation de benzodiazépines m’a permis de mettre en pratique plusieurs

aspects de théories sur l’épidémiologie.

Au cours de ce projet de recherche, j'étais responsable de la rédaction et de la

présentation du protocole de recherche, la recherche documentaire, la sélection des

études, l’extraction des données, l’analyse des données et la rédaction des

résultats de recherche sous forme du présent mémoire. Le mémoire est rédigé dans

les deux langues (français et anglais) en se conformant aux règles de la politique

de l’Université Laval sur la rédaction de mémoire de fin d’étude.

Cette revue systématique était entièrement financée par les IRSC pour un montant

de 100 000,00 $ canadiens. Ce montant couvrira toutes les dépenses de la

recherche, y compris ma bourse d’étude, l’accès à l’internet, le traitement ou

salaires des employés exerçant directement les activités de la recherche, les

déplacements, les formations et les frais généraux. Aucun conflit d’intérêt n’est à

signaler.

1

Introduction

La population canadienne semble vieillir de plus en plus vite1. Les aînés de 65

ans et plus devraient, en 2036, constituer 25 % de la population1. Ce

phénomène de vieillissement est inquiétant puisqu’il s’accompagne d’une

croissance de la fréquence des comorbidités et de la polymédication qui en

résulte2. La polymédication constitue un grand problème de santé publique chez

les aînés. Elle est associée aux réactions indésirables3, aux interactions

médicamenteuses et aux hospitalisations4. Plusieurs médicaments,

particulièrement les benzodiazépines (BZD), continuent d'être prescrits de façon

chronique chez les aînés malgré leurs effets indésirables importants5. En 2016,

la prévalence d’utilisation de BZD au Canada était de 14,0 % chez les aînés.6

Étonnamment, les BZD sont inscrites sur toutes les listes validées de

médicaments potentiellement inappropriés (MPI) chez les aînés (Beers7,

STOPP-START8, PRISCUS9). Une étude populationnelle nord-américaine

révèle que l'utilisation de BZD est non conforme aux directives de prescription

appropriée chez environ 30 % des nouveaux utilisateurs des hypnotiques et

20 % des nouveaux utilisateurs des anxiolytiques10. Dans une étude canadienne

de type Delphi réunissant 65 experts dont 36 pharmaciens, les BZD étaient

classées au premier rang des médicaments inappropriés chez les aînés11.

Plusieurs études sur les effets iatrogènes des médicaments encouragent la

déprescription ou l’arrêt des BZD à cause des effets néfastes sur la santé de

cette clientèle plus vulnérable7,12. Par ailleurs, il existe des alternatives

thérapeutiques efficaces13. Les efforts pour une meilleure santé des aînés

doivent entre autres cibler la déprescription des BZD et la promotion des

alternatives thérapeutiques.

Les BZD sont des molécules largement utilisées dans le traitement médical de

l’anxiété, de l’insomnie, des convulsions, des troubles de panique ou lors d’un

sevrage alcoolique14. Leurs effets indésirables sur la santé sont parfois sérieux

et incluent entre autres la dépendance, la toxicomanie15, les troubles cognitifs16,

2

le délirium, les chutes, les fractures et les accidents routiers7. La déprescription

ou l’arrêt des MPI est parfois possible et même, sécuritaire17. Cependant, les

évidences de la littérature sur les impacts des interventions de déprescription

sont basées sur des articles de synthèse qui comprennent entre autres des

études de devis ou de méthodologies de faible qualité18. Pollmann et al. ont

publié en 2015 une revue systématique sur les effets de déprescription sur la

santé, mais plusieurs études sélectionnées avaient moins d’une centaine de

participants et la revue concernait uniquement les adultes vivant dans la

communauté, entre 1984 et 201418. Plus récemment en 2017, Reeve et ses

collègues ont publié une revue sur les interventions de déprescription des BZD,

mais les effets de BZD étaient combinés à ceux d’autres psychotropes, la revue

n’était pas focalisée sur les effets sur la santé de la déprescription et seuls les

articles publiés entre 1995 and 2015 étaient pris en compte19.

L’objectif général du présent projet de maîtrise consiste à déterminer les effets

des interventions de déprescription de BZD sur la santé des aînés de 60 ans et

plus, et de décrire les caractéristiques des interventions efficaces, en faisant une

revue systématique des interventions efficaces de déprescription. Les

connaissances générées par cette revue seront utiles aux décideurs de l’Institut

national d’excellence en santé et en service sociaux (INESSS) et du Conseil

national des Instituts de recherche en santé du Canada (IRSC) sur la gestion

sécuritaire des BZD chez la population âgée, de même qu’aux médecins et

pharmaciens qui avaient exprimé le besoin de directives fondées sur des

données probantes concernant les impacts des interventions de déprescription

des BZD sur la santé des aînés.

3

Chapitre 1. Revue de la littérature

Le groupe des personnes âgées de 65 et plus augmente plus rapidement que

tout autre groupe d’âge de la population canadienne6. La proportion des aînés

a augmenté en moyenne de 3,9 % par année de 2011 à 2016, alors que celle

des autres groupes d’âge a augmenté, pour la même période, en moyenne de

0,9 % par année6. L’augmentation rapide de la proportion des personnes aînées

est à l’origine du phénomène du vieillissement démographique.

En raison des changements physiologiques liés à l’avancement en âge, les

personnes aînées sont plus à risque de multimorbidité, de polymédication et

d'une plus grande vulnérabilité aux effets indésirables des médicaments20. Les

changements des structures des organes et de la circulation sanguine sont à

l’origine de la modification pharmacocinétique chez les aînés21. Avec l’âge, la

quantité du tissu rénal diminue progressivement et les vaisseaux sanguins qui

alimentent les reins peuvent se durcir21. Chez certaines personnes âgées, cette

atteinte de la fonction rénale influence directement la clairance rénale et

augmente par conséquent le risque d’effets indésirables des médicaments22.

Malgré les changements physiologiques augmentant le risque des effets

indésirables, les personnes âgées se font prescrire plus de médicaments que

les autres groupes d’âge23. Une récente étude de cohorte britannique a

démontré qu’à 69 ans, 22,8 % des personnes prenaient plus de cinq différentes

classes de médicaments chaque jour24.

Le phénomène de polymédication s’accompagne aussi fréquemment d’une

augmentation des interactions médicamenteuses, des erreurs de médicaments,

des hospitalisations, de la non adhésion au traitement, du déclin fonctionnel et

cognitif, des chutes et des prescriptions potentiellement inappropriées2,25.

L’amélioration de la qualité de vie des personnes aînées nécessite une approche

axée sur l’utilisation optimale des médicaments prescrits. Une étude sur la

déprescription des médicaments démontre qu’il est possible de réduire le

nombre de médicaments chez les personnes aînées grâce aux interventions de

4

déprescription26. En 1992, Salzman et ses collègues, par exemple, avaient

remarqué une amélioration significative de la mémoire et des performances

cognitives des patients après l'arrêt de BZD26.

1.1 La déprescription

Thompson & Farrell définissent la déprescription comme un « processus planifié

et supervisé de réduction de la dose des médicaments qui pourraient causer des

dommages ou ne plus être bénéfiques »27. La déprescription consiste à réduire

ou arrêter la dose de médicament dont le bénéfice est incertain28,29. Plusieurs

classes de médicaments, y compris les BZD, ont déjà fait l’objet d’études sur la

déprescription. Une étude publiée en 1999 chez des hommes et des femmes

âgés de 65 ou plus qui prenaient couramment des antipsychotiques pour des

indications non précisées avait rapporté que la déprescription des

antipsychotiques réduisait significativement le risque de chutes30. En 2010, les

auteurs d’un essai clinique multicentrique chez 381 adultes âgés de 65 ans ou

plus ayant une espérance de vie de 1 à 12 mois et prenant des statines en

prévention primaire ou secondaire depuis au moins trois mois avaient conclu

que l’arrêt des statines n’avait pas d’impacts négatifs sur leur santé31. Par contre,

un essai clinique randomisé (ECR), incluant un petit effectif de 141 patients âgés

prenant des diurétiques de façon chronique pour l’insuffisance cardiaque,

montrait une légère augmentation des œdèmes et de la pression artérielle chez

les patients du groupe dont les diurétiques étaient remplacés par le placebo par

rapport au groupe des patients qui continuaient à prendre des diurétiques32. Ces

résultats intermédiaires montrant un effet potentiellement bénéfique sur la santé

ne concordaient pas avec ceux d’un autre essai randomisé chez les patients

âgés dont le retrait des diurétiques était susceptible d’augmenter les symptômes

d’insuffisance cardiaque incluant une hausse de la pression artérielle, et que

toute tentative pour retirer les diurétiques nécessitait une surveillance

approfondie33.

5

1.2 Les types, les étapes et les objectifs d’interventions de déprescription

Une intervention de déprescription de médicaments peut-être centrée sur les

patients34, sur les prescripteurs ou sur les pharmaciens17. Certains auteurs se

sont récemment intéressés aux interventions centrées sur les législateurs35, qui

pourraient devenir une autre catégorie importante d’interventions de

déprescription. Les interventions récemment décrites par Reeve et ses

collègues dans une revue systématique sont dites des interventions mixtes, car

elles incluent des programmes éducatifs destinés aux patients et la

sensibilisation des prescripteurs19. Les programmes éducatifs visant la

déprescription des BZD se présentent sous plusieurs formes. Vicens et al. 2016,

par example, propose une formation de trois heures destinée aux prescripteurs

comprenant un atelier sur l'entretien structuré, l'information individualisée du

patient, la gestion de l'arrêt du BZD et la réduction progressive et optimale de la

dose36. La réduction graduelle ou la discontinuation instantanée sont les

interventions de déprescription de BZD les plus fréquentes. Par exemple,

Habraken et ses collègues proposent une réduction graduelle du lorazépam sur

un intervalle de cinq semaines, avec 25 % de réduction par semaine pendant

trois semaines, suivi d’une réduction de 12,5 % pendant deux semaines et enfin,

un arrêt12.

Dans une revue systématique sur les interventions de déprescription dont les

participants avaient au moins un médicament déprescrit, Page et al. (2016) ont

observé que les interventions de déprescription centrées sur les patients

réduisaient significativement le risque de mortalité (rapport de cotes (RC)= 0,62,

intervalle de confiance (IC) à 95 % 0,43-0,88) par rapport aux autres

interventions ciblant le personnel soignant17.

Reeve et al. (2014) distinguent cinq étapes essentielles d’une intervention de

déprescription centrée sur les patients : les revues complètes des antécédents

médicaux, l’identification des médicaments potentiellement inappropriés, la

détermination de la faisabilité de déprescription, la planification de la posologie

6

de sevrage et une surveillance documentée des effets indesirables34. En plus

des interventions centrées sur les patients, les programmes éducatifs destinés

aux prescripteurs, les revues complètes des antécédents médicaux et

l’identification des médicaments potentiellement inappropriés par des

pharmaciens, la mise en place des outils informatiques d’aide à la prise de

décision clinique, les programmes d’incitatifs financiers visant les changements

dans les pratiques médicales et les interventions législatives d’un gouvernement

destinées à améliorer la prescription35 font également partie des interventions

qui visent la réduction d’usage des médicaments inappropriés.

L’objectif central des interventions de déprescription est de réduire ou d’arrêter

les doses de médicaments inappropriés17. Plusieurs ECR ont démontré que les

interventions de déprescription pouvaient réduire le nombre des médicaments

inappropriés chez les aînés. Une récente étude de déprescription centrée sur

les patients incluant des participants a permis d’arrêter 59 % des médicaments

ciblés, soit en moyenne 4,4 médicaments (écart-type ± 3,4) par personne, et a

démontré que la différence de la mortalité était réduite dans le groupe

d’intervention, bien que non significative (hazard ratio (HR)= 0,60, IC à 95 %,

0,30-1,22)37. Une étude prospective qui évaluait l'effet d'une intervention centrée

sur les prescripteurs avait observé une légère réduction du nombre moyen des

médicaments inappropriés chez les patients selon les critères établis de

« Screening tool of older people's prescriptions » (STOPP) dans le groupe

intervention comparativement au groupe témoin (1,29 ± 1,56 contre 0,81 ± 1,13

médicaments)38, mais la différence n’était pas statistiquement significative.

1.3 Les médicaments potentiellement inappropriés

Les MPI sont des médicaments dont le rapport bénéfices/risques est

défavorable ou qui possèdent une efficacité moindre par rapport à d’autres

options thérapeutiques39. Ces médicaments sont souvent administrés sans

indications claires et prédisposent les aînés aux effets indésirables, aux

gaspillages des ressources et aux interactions médicamenteuses40,41. Certains

facteurs de risque de la prise de médicaments inappropriés sont la

7

polymédication, le nombre de visites chez différents médecins spécialistes au

cours des 12 derniers mois ou les troubles du sommeil42. Plusieurs pays ont

établi des critères pour l’identification des médicaments inappropriés et des

algorithmes en vue d’aider les médecins à choisir les meilleures options

thérapeutiques et à améliorer la qualité de la prescription39. Certains critères dits

explicites sont des critères clairement énoncés, facilement applicables, et qui

donnent lieu à des mesures objectives de la qualité d’utilisation des

médicaments, alors que les critères dits implicites sont des critères plus vagues

référant au jugement clinique des intervenants, mais qui laissent un choix

d’interprétation. Parmi les critères explicites, on retrouve entre autres ceux de

Beers aux États-Unis7, de STOPP-START pour l’Europe de l’Ouest8, la liste

PRISCUS en Allemagne9, les critères de McLeod au Canada43 et l’adaptation

des critères de Beers par Laroche et al. en France39. L’indice de médicaments

appropriés (IMA) est un exemple de critères implicites44.

1.4 La polymédication

La polymédication peut être définie sur la base du nombre de médicaments ou

selon la pertinence des médicaments utilisés45. Bushardt et al. (2008)

définissent la polymédication comme la prise d’au moins six médicaments ou

d’un médicament inapproprié46. Certains auteurs définissent la polymédication

comme la prise de plusieurs médicaments pour traiter une maladie, ou plusieurs

médicaments de la même classe chimique, plusieurs médicaments similaires

pour traiter plusieurs maladies, toute combinaison thérapeutique47 ou encore

l’usage d’au moins deux médicaments pendant au moins 240 jours48. Par

ailleurs, quelques auteurs préfèrent distinguer la polymédication rationnelle de

celle irrationnelle47. La polymédication rationnelle reflète l’hypothèse selon

laquelle certaines circonstances thérapeutiques obligent les médecins à

prescrire des MPI pour prévenir les complications beaucoup plus graves46. La

polymédication inappropriée ou irrationnelle, telle que la cascade

médicamenteuse, décrit l’usage inadapté des médicaments qui ne tiennent pas

compte des critères reconnus.

8

1.4.1 La polymédication chez l’aîné

La polymédication est fréquemment observée chez les aînés à cause des

changements physiologiques qui accompagnent le vieillissement4 tels que le

changement des systèmes sensoriels, neuromusculaires ou cognitifs qui

altèrent le contrôle de l'équilibre et de la démarche49. Dans une étude

rétrospective américaine sur 13 507 résidents de maisons de retraite, la

prévalence de la polymédication en 2004 était d'environ 40 %5051. Les MPI

fréquemment rapportés comprenaient les agents gastro-intestinaux et les

psychotropes50 dont les BZD. En 2012, près des deux tiers (65,9 %) des

personnes aînées participant à des programmes publics canadiens de

médicaments avaient des réclamations pour cinq classes de médicaments ou

plus, 27,2 % avaient des réclamations pour 10 classes ou plus, et 8,6 % des

réclamations pour 15 classes de médicaments ou plus ; 23,9 % parmi eux

utilisaient au moins une prescription potentiellement inappropriée52. Ces

données démontrent bien l’étendue de la gravité de la polymédication chez les

aînés.

1.4.2 Les facteurs de risque de la polymédication

Les facteurs de risque de la polymédication incluent l’âge avancé, le diabète, les

maladies ischémiques coronariennes, l'utilisation de médicaments sans

indication claire48, la faible scolarité et le genre53. Bien que la polymédication soit

inévitable dans la gestion thérapeutique de certaines comorbidités, elle

augmente dangereusement les risques des effets indésirables des

médicaments, des interactions médicamenteuses, des erreurs de médicaments,

des hospitalisations, de la non adhésion au traitement médical, du déclin

fonctionnel et cognitif, des chutes et des prescriptions potentiellement

inappropriées2,25. Les femmes ayant une faible scolarité ont une probabilité

légèrement plus élevée de recevoir une polymédication que les hommes ayant

une faible scolarité53. Par ailleurs, l’association observée entre l’usage des BZD

et le sexe ou le genre féminin n’est pas bien expliquée dans la littérature, mais

9

certaines différences physiologiques telle la ménopause, ou des inégalités

sociales, comme la pauvreté, pourraient expliquer la différence de l’usage de

BZD entre les femmes et les hommes.

1.5 Les benzodiazépines, l’âge et le sexe/genre

En 1955, un chimiste de la compagnie Hoffmann-La Roche, Leo Sternbach, a

découvert le chlordiazépoxyde, la toute première BZD54. En 1960, Hoffmann-

La Roche l'a commercialisée sous le nom de Librium, et a poursuivi des

modifications moléculaires pour créer une autre BZD beaucoup plus avancée

et commercialisée sous le nom de Valium (diazépam) en 196354. Ces deux

découvertes ont provoqué ce que l’on pourrait identifier comme une course à la

découverte des BZD. Les concurrents de Hoffmann-La Roche ont également

entamé des recherches pour trouver des analogues au diazépam54.

Aujourd’hui, les BZD (Tableau 1) sont devenues les psychotropes les plus

prescrits pour traiter des troubles neurospychologiques ou neuropsychiatriques

tels que l’anxiété, l’insomnie, l’épilepsie55, le sevrage de l’alcool, les troubles de

panique,14 les addictions comme la dépendance aux opiacés et la dipsomanie56.

Les BZD possèdent des propriétés anticonvulsivantes, anxiolytiques, sédatives,

hypnotiques, myorelaxantes et amnésiques.58 Les propriétés anxiolytiques et

amnésiques des BZD comportent une utilité importante dans les blocs

opératoires55. Le traitement de l'anxiété est de loin l'indication la plus courante

pour les BZD57.

Les BZD sont des substances pharmacologiques de structure similaire avec un

noyau moléculaire commun : une BZD de base est composée d'un cycle

benzénique fusionné à un cycle diazépine (Figure 1). L'acide γ-aminobutyrique,

fréquemment abrégé GABA (de gamma-aminobutyric acid), est le

neurotransmetteur principal inhibant le système nerveux central des

mammifères. Une des caractéristiques essentielles des BZD est que ces

molécules agissent comme inhibiteurs des influx nerveux en se fixant au

récepteur GABA-A du neurone post-synaptique55. La fixation d’une molécule de

10

BZD sur GABA-A augmente l’affinité de GABA au récepteur GABA-A et la durée

d’ouverture du canal chloré55. L'influx intracellulaire de chlore provoque à son

tour l’hyperpolarisation de la membrane et inhibe l’activité neuronale du neurone

post-synaptique55, ce qui provoque les effets connus des BZD. Les BZD les plus

courantes comprennent entre autres le diazépam (Valium), l'alprazolam

(Xanax), le clonazépam (Rivotril) et lorazépam (Ativan)58.

Les BZD sont devenues de plus en plus populaires dans le traitement de

l’insomnie et de l’anxiété comme remplacement des barbituriques ayant un

profil thérapeutique moins avantageux en raison de leur toxicité55. Laurier et al.

(1990) a estimé qu’environ 10 à 20 % de la population nord-américaine

utilisaient régulièrement des psychotropes pour une période de plus de 12 mois

et que 80 % de ces psychotropes étaient des BZD59. Ce phénomène est

préoccupant à cause du vieillissement accéléré des populations occidentales et

l’abondance des évidences sur l’association entre les BZD et les effets négatifs

sur la santé1.

Les premières BZD (chloridiazépoxide et diazépam ) ont été approuvées par la

Food and Drug Administration (FDA) des États-Unis parce qu’elles

représentaient une alternative sécuritaire aux barbituriques qui pouvaient

entraîner un surdosage mortel, en particulier lorsqu’elles étaient combinées

avec de l’alcool60. Mais l’efficacité thérapeutique des BZD s’accompagne aussi

d’effets indésirables tels que l’amnésie antérograde massive et transitoire61, la

dépendance, la toxicomanie15, la déficience cognitive, le délirium, les chutes, les

fractures et les accidents routiers7. Dans les années ’70, plus de 30 % des

surdoses impliquant des opioïdes étaient reliées à l’usage concomitant de BZD.

Bien qu'elles soient utilisées depuis les années ’60 pour la gestion de l'insomnie

et de l'anxiété, une étude récente a démontré qu’avec une utilisation prolongée,

les BZD peuvent contribuer à l'aggravation de ces symptômes7.

11

Tableau 1. Liste des benzodiazépines

Tiré du « WHO Collaboration Centre for Drug Statistics Methodology »1

Nom Codes ATC Nom Codes ATC code

Adinazolam N05BA07 Halazépam N05BA13

Alprazolam N05BA12 Kétazolam N05BA10

Bentazépam N05BA24 Loflazépate d'éthyle N05BA18

Bromazépam N05BA08 Loprazolam N05CD11

Brotizolam N05CD09 Lorazépam N05BA06

Camazépam N05BA15 Lormetazépam N05CD06

Chlordiazépoxide N05BA02 Médazépam N05BA03

Cinolazépam N05CD13 Midazolam N05CD08

Clobazam N05BA09 Nitrazépam N05CD02

Clotiazépam N05BA21 Nordazépam N05BA16

Cloxazolam N05BA22 Oxazépam N05BA04

Diazépam N05BA01 Pinazépam N05BA14

Doxefazépam N05CD12 Prazépam N05BA11

Estazolam N05CD04 Quazépam N05CD10

Étizolam N05BA19 Remimazolam N05CD14

Fludiazépam N05BA17 Temazépam N05CD07

Flunitrazépam N05CD03 Tofisopam N05BA23

Flurazépam N05CD01 Triazolam N05CD05

1 https://www.whocc.no/atc_ddd_index/?code=N05BA

12

Figure 1. Structure chimique commune des BZD

Tiré du « National Center for Biotechnology Information. PubChem

Database »63

1.5.1 La prévalence de l’usage des BZD

En France, une étude transversale téléphonique réalisée en 2001 auprès d'un

échantillon représentatif d’adultes non institutionnalisés, a révélé que la

prévalence d'utilisation des BZD était de 7,5 % dans la population générale,

celle-ci étant plus élevée chez les femmes (9,7 %) que chez les hommes

(5,2 %)64. Dans une étude libanaise auprès de 1 000 sujets issus de la

communauté, la prévalence d’usage des BZD était de 9,6 %65. Avant l’an 2000,

la prévalence d’usage des BZD était très élevée en Ontario. En effet, une étude

populationnelle affichait en 1998 une prévalence de 23,2 % parmi les patients

âgés de 65 ans ou plus issus de la Ontario Drug Benefit database66.

Plusieurs études sur la déprescription des BZD affichent une réduction de la

prévalence d’usage de BZD : Au Danemark, la prévalence de l’usage d’au moins

une BZD dans la population a baissé de 12 à 10 % entre 1997 à 2008 (p <

0,0001)67. À Hong Kong, un changement de politique publique indexant les BZD

comme substances dangereuses en 1992 a entraîné une réduction de 50 % du

nombre annuel moyen des ordonnances de BZD par personne dans la

population générale de 1991 à 199468. Au Canada, la Ontario Drug Benefit

database a rapporté chez les personnes aînées une baisse de la prévalence des

ordonnances de BZD de 23,2 % en 1998 à 14,9 % en 201366. Même si la

prévalence d’usage de BZD semble diminuer dans la population générale, cette

prévalence demeure encore trop élevée chez les personnes âgées chez qui les

13

changements physiologiques dus à l’âge les prédisposent aux effets

indésirables des BZD. Au Danemark, par exemple, environ le quart des patients

âgés de 75 à 85 ans prennent au moins une BZD chaque jour67.

1.5.2 Quelques outils de surveillance des MPI

1.5.2.1 Les critères de Beers

Les critères de Beers, des critères explicites d’identification des MPI, regroupent

35 conditions sine qua non de définition des médicaments à éviter chez les

aînés, ainsi que les doses ou les fréquences à ne pas dépasser chez les

personnes âgées atteintes de certaines maladies fréquentes7. Ces critères de

Beers, bien validés, stipulent que toutes les BZD augmentent le risque de

troubles cognitifs, de délirium, de chutes, de fractures et des accidents de la

route chez les aînés7. Beers affirme que des médicaments comme l’alprazolam,

l’estazolam, le lorazépam, l’oxazépam, le témazépam et le triazolam ne

devraient absolument pas être prescrits aux aînés7. Les médicaments comme

le chlordiazépoxide, le chlordiazépoxide-amitriptyline, le clorazépate, le

clidinium-chlordiazépoxide, le clonazépam, le diazépam, le lorazépam et le

quazépam peuvent être prescrits seulement pour les troubles d’épilepsie, les

troubles du sommeil liés aux mouvements oculaires rapides, au sevrage des

BZD, au sevrage de l'éthanol, pour les troubles d’anxiété généralisée (TAG)

sévère, à l'anesthésie péri-oculaire et lors des soins de fin de vie71.

1.5.2.2 Les critères START-STOPP

Les critères de STOPP et du Screening tool to alert to right treatment (START)

comprennent 114 critères explicites d’alerte aux traitements inappropriés chez

les aînés8. Ces outils interdisent la prescription des BZD au-delà de quatre

semaines pour éviter les risques de sédation prolongée, de confusion, des

chutes et des accidents de la route72. Ces outils créés par des auteurs irlandais

recommandent le retrait progressif des BZD après deux semaines pour éviter

les risques de sevrage75.

14

1.5.2.3 La liste de PRISCUS

Contrairement aux critères de Beers, PRISCUS n'est pas une liste de

substances interdites en termes de contre-indication, mais une liste des critères

implicites qui contient des informations pertinentes sur les risques des

médicaments individuels chez les aînés. PRISCUS sensibilise la communauté

médicale quant aux problèmes potentiels liés à l’utilisation d’un médicament

spécifique9. Il contient environ 83 MPI dont 18 (21 %) sont des BZD74. Les BZD

ciblées par PRISCUS incluent les BZD à action prolongée, telles que le

diazépam, le clobazam, le nitrazépam et certains BZD à action courte telles que

l’alprazolam74. PRISCUS recommande de remplacer les BZD à action prolongée

par les BZD à action courte, par des neuroleptiques de faible puissance tels que

le melperone et le pipamperone ou par des antidépresseurs sédatifs comme le

mirtazapine74. Le traitement non-pharmacologique des perturbations du

sommeil telle l’hygiène du sommeil est aussi suggéré74.

1.5.3 Les lignes directrices

En 2018, l'Institut de recherche Bruyère et ses collaborateurs a publié des lignes

directrices et un algorithme fondé sur des données probantes détaillant les

étapes à suivre pour déprescrire les BZD80. Les directives recommandaient

entre autres une stratégie basée sur la réduction graduelle des doses, les soins

non-pharmacologiques pour des difficultés de sommeil et la thérapie cognitivo-

comportementale75. Le volet de soins non-pharmacologiques recommandait

notamment d’aller se coucher seulement lorsqu’on a sommeil, d’utiliser le lit ou

la chambre à coucher uniquement pour dormir ou pour les activités intimes,

d’utiliser l’alarme pour se réveiller à la même heure chaque matin, de ne pas

faire de sieste, d’éviter la caféine l’après-midi, d’éviter l’exercice, la nicotine,

l’alcool et les repas copieux dans les deux heures précédant le coucher75.

Récemment, la Coalition canadienne pour la santé mentale des personnes

âgées a aussi produit des lignes directrices pour la prévention, l’identification,

l’évaluation et la gestion de BZD (Tableau 2).

15

Tableau 2. Les recommandations canadiennes sur la gestion sécuritaire des BZD

Tiré du « Canadian Guidelines on Benzodiazepine Receptor Agonist Use Disorder Among Older Adults, 2019 »

1 L'utilisation à long terme des BZD (> 4 semaines) chez les personnes âgées doit être évitée pour la plupart des indications en raison de leur efficacité minimale et du risque de préjudice.

2 Les options non pharmacologiques de première intention pour le traitement de l'insomnie et des troubles anxieux telles que les thérapies cognitivo-comportementales (TCC) sont proposées sous divers formats.

3 Une BZD ne devrait être envisagée pour la prise en charge de l'insomnie ou de l'anxiété qu'après avoir essayé les interventions non pharmacologiques ou options pharmacologiques plus sûres ou pour un pontage à court terme jusqu'à ce qu'un traitement plus approprié devienne efficace.

4 Une évaluation du risque de trouble lié à l'utilisation d’une BZD et d'autres effets indésirables potentiels doit être effectuée avant de prescrire une BZD.

5 Si une BZD est envisagée, la personne âgée doit être informée à la fois des avantages et des risques limités associés à son utilisation, ainsi que d’autres options, avant de décider d'un plan de gestion.

6 L'initiation de BZD devrait être une décision partagée entre le prescripteur et la personne âgée (ou son mandataire spécial).

7 Les personnes âgées qui reçoivent une BZD devraient être encouragées à ne prendre la BZD que pendant une courte période, surveillées au cours de leur prescription, soutenues dans l'arrêt du médicament jusqu'à l'arrêt.

8 Les fournisseurs de soins de santé et les organisations devraient envisager de mettre en œuvre des interventions pour réduire l'utilisation inappropriée des BZD dans leur milieu de pratique.

9 Les établissements de soins de santé devraient mettre en œuvre des protocoles qui minimisent les nouvelles ordonnances de BZD en raison du risque de préjudice et du risque que cela entraîne à long terme.

10 Les professionnels de la santé, les personnes âgées et leurs familles devraient plaider pour un accès et un financement adéquat à des alternatives non pharmacologiques efficaces pour la gestion de l'insomnie et des troubles anxieux.

16

11 Les cliniciens doivent savoir que les BZD sont prescrites plus fréquemment aux femmes et les biais implicites potentiels qui peuvent conduire à une utilisation inappropriée.

12 Toutes les personnes âgées devraient être interrogées sur la consommation actuelle et passée de BZD.

13 L'évaluation des personnes âgées soupçonnées d'avoir un trouble lié à l'utilisation de BZD comprend l'indication, la dose, la durée, les caractéristiques indiquant un trouble lié à l'utilisation de BZD.

14 La consommation de plusieurs substances est courante et doit être envisagée et demandée chez toutes les personnes âgées souffrant d'un trouble lié à l'utilisation de BZD. Les professionnels de la santé devraient éviter de prescrire des BZD simultanément avec des opioïdes dans la mesure du possible.

15 Une approche de soins centrée sur la personne visant le retrait progressif et l'arrêt des BZD doit être utilisée. Les cliniciens et les patients devraient partager la planification et le plan d'un programme de réduction progressive de la dose soutenue par une éducation appropriée du patient.

16 L'arrêt brusque d'une BZD après une utilisation à long terme (> 4 semaines) chez les personnes atteintes d'un trouble lié à l'utilisation du BZD doit être évité en raison du risque de symptômes de sevrage, du renforcement de la dépendance à la substance et de phénomènes de rebond.

17 Les symptômes de sevrage aigus de la BZD doivent être surveillés attentivement par un outil validé.

18 Les ordonnances impliquant plusieurs BZD doivent être simplifiées et converties en une seule BZD.

19 Le changement de routine d'une BZD à demi-vie courte par une autre ayant une longue demi-vie pour faciliter le retrait des BZD n'est généralement pas recommandé chez les personnes âgées.

20 Les interventions psychologiques telles que la TCC devraient être envisagées lors des efforts de retrait des BZD car elles peuvent améliorer les expériences des personnes âgées et augmenter la probabilité d'arrêter les BZD.

21 La substitution à un médicament pharmacologiquement différent en tant qu'intervention pour atténuer les symptômes de sevrage au BZD lors d'une réduction progressive de la dose n'est pas systématiquement recommandée.

17

Chapitre 2. Méthodologie

2.1 Objectif général

Le projet de recherche de ce mémoire avait pour objectif de décrire les

interventions de déprescription de BZD et leurs effets sur la santé des aînés (60

ans et plus) par le moyen d’une synthèse systématique des interventions de

déprescription.

2.2 Questions de recherche

Chez les personnes de 60 ans et plus :

I. Quels sont les impacts des interventions de déprescription de BZDs sur

la santé ?

II. Quelles sont les caractéristiques des interventions de déprescription de

BZDs, ou des éléments de celles-ci, qui permettent d'obtenir des résultats

positifs ou neutres sur la santé ? En d'autres termes, qu'est-ce qui est

commun aux interventions efficaces de déprescription de BZDs ?

2.3 Devis de l’étude

Il s’agit d’une synthèse systématique dans laquelle les énoncés PRISMA

(« Preferred Reporting Items for Systematic Reviews and Meta-Analyses »),

référence internationale en matière d’informations fiables et de haute qualité, ont

été appliqués76. Ce choix de devis se justifiait par l’existence de nombreux

résultats rapportés dans la littérature quant aux effets des interventions de

déprescription de BZD sur la santé des aînés32,83.

2.4 Recherche documentaire

Les bases de données MEDLINE, EMBASE, CINAHL, PSYCHINFO et

AGELINE ont été consultées en septembre 2018 et en août 2019 pour retrouver

toutes les études éligibles grâce à une stratégie de recherche documentaire

18

élaborée par Mme Carole Brault, bibliothécaire au Centre Hospitalier

Universitaire (CHU) de Québec, et modifiée par Mme Martine Marcotte (MM),

professionnelle de recherche impliquée dans ce projet de recherche et l’étudiant

gradué attitré au projet (DMB), pour cibler uniquement les études sur les BZD.

Tous les mots-clés et les résultats de recherche de chaque base de données se

retrouvent en annexe C.

La plus récente consultation des bases des données a été complétée le 8

novembre 2019 pour la mise à jour des études retenues. Les mots-clés utilisés

pour la recherche documentaire visaient premièrement les études sur tous les

médicaments déprescrits, et les deux réviseurs, DMB et MM, ont ensuite

manuellement sélectionné uniquement les études concernant les BZD.

2.5 La sélection des études

La sélection des études s’est faite en deux étapes. D’abord, les titres et les

résumés ont été examinés pour identifier les études pertinentes, puis une lecture

intégrale des articles a permis d’identifier les études éligibles (cf. Table 3 au

chapitre 3). La sélection des études, l'extraction des données et l'évaluation de

la qualité des études étaient effectuées par deux réviseurs indépendants (MM

ou Mme Daniela Furrer Soliz-Urrutia (DFSU), la professionnelle de recherche

qui a remplacé MM) et l’étudiant gradué (DMB). Les désaccords étaient

généralement résolus en consultant un troisième membre de l’équipe (Mme

Edeltraut Kröger (EK) ou Mme Danielle Laurin (DL)).

La sélection des études a suivi la méthode PICOS pour l’inclusion et l’exclusion

des études :

Population : Toutes les études sur la déprescription de BZD chez les personnes

âgées de 60 ans ou plus, ayant au moins une BZD déprescrite ont été

considérées. Les études étaient prises en compte si 80 % ou plus des

participants étaient âgés d’au moins 60 ans, ou si l'âge moyen des participants

était égal ou supérieur à 60 ans ou si des données pertinentes pour les

19

participants âgés de 60 ans ou plus pouvaient être extraites des articles. Les

études incluant les « z-drugs » ont été exclues.

Intervention : Toutes les interventions visant la déprescription de BZD, c’est-à-

dire, l’arrêt ou la réduction de dose de BZD, quel que soit le milieu d'intervention

(communauté, hôpital, maison de retraite) ou les cibles de l’intervention (patients

ou professionnels de la santé) étaient pris en compte.

Comparaison : Seules les études qui comparent des groupes d’intervention à

des groupes de soins habituels, à la situation avant l’étude (« before-after

study ») ou à un placebo étaient incluses.

« Outcomes » ou Résultats : Dans un premier temps, on s’intéressait au

changement du nombre de médicaments totaux, mesuré par des instruments

objectifs ou validés. On notait les interventions capables de réduire le nombre

de médicaments totaux ou inappropriés, leurs impacts sur la santé et d'autres

issues secondaires, par exemple les réactions indésirables, le contrôle de la

glycémie, la pression artérielle, les lipides sanguins, la qualité de vie, la mortalité,

etc.

« Study type » ou Devis d’étude : Tous les ECR, y compris les ECR en grappes,

les essais cliniques contrôlés non randomisés, les études contrôlées avant et

après, ont été inclus. Les séries chronologiques interrompues étaient

considérées si l'attribution des participants dans les groupes était aléatoire.

2.6 Les critères d'exclusion

Les revues systématiques, les études de cas, les études transversales, les

doublons, les articles disponibles uniquement sous forme de résumés, les

études sur les médicaments non-chroniques, les articles dans des langues

autres que le français, l’anglais et l’allemand étaient exclus.

20

2.7 L’extraction des données

Les données des études étaient extraites dans un formulaire prédéfini (Annexe

A). La sélection des études, l'extraction des données et l’évaluation du risque de

biais étaient effectuées indépendamment par deux réviseurs, d’abord par MM et

DMB, ensuite par DFSU et DMB. Les références, le devis de l’étude, les

caractéristiques des participants (taille de l'échantillon, taux de participation,

données sociodémographiques, etc.), la description de l’intervention (à qui

s’adresse l’intervention, dans quel milieu, médicament(s) ciblé(s)s, durée, etc.),

les analyses statistiques et les résultats (les mesures d’association et les

intervalles de confiance) ont été extraits. L’évaluation du risque de biais pour les

études non-randomisées était réalisée grâce au RTI Item Bank76 alors que les

risques de biais pour les ECR ont été vérifiés en utilisant le Scottish

Intercollegiate Guidelines Network (SIGN).77

2.8 Synthèse des données

Une méthode de synthèse narrative, transparente et reproductible a été utilisée

pour décrire toutes les études78. Un tableau récapitulatif et descriptif de toutes

les études incluses a été réalisé. Une analyse qualitative comparative a été

réalisée pour analyser la contribution causale des différents éléments

d'intervention aux issues de santé chez les aînés. Les différents ensembles de

caractéristiques associés aux résultats spécifiques sont cartographiés et soumis

à une procédure de minimisation en vue d'identifier un ensemble plus simple de

conditions, tenant compte des issues de santé observées, et aboutissant à une

matrice de caractéristiques des interventions et des issues connexes. Les

énoncés généraux basés sur les preuves recueillies sont formulés pour

répondre à la première question de recherche et une matrice résume les

résultats des études pour répondre à la deuxième question de recherche.

21

Chapitre 3. Résultats

3.1 Electronic database search, study selection and data extraction

The search in five electronic databases identified 3174 articles (Figure 2):

MEDLINE (n=894), EMBASE (n=793), CINAHL (n=354), AGELINE (n=114) and

PsycINFO (n=1019). After removing the duplicates (n=1166), two authors (DMB,

MM) independently screened all articles by title and abstract, and further

excluded 1978 articles in order to respect the inclusion and exclusion criteria. If

consensus was not possible, all disagreements at this stage were resolved by

consulting a third author (EK or DL). This third-party arbitration happened more

frequently in the initial stages of the study selection due to moderate interrater

agreement evidenced by a Cohen kappa’s value of 0.55. The two review authors

(DMB and MM) retrieved the full text of the remaining articles (n=30) and

excluded 20 additional articles due to eligibility criteria. One article was added

after hand-searching of reference lists. Finally, 11 articles from 10 studies were

included in this review: Habraken et al. (1997), Vicens et al. (2014), Vicens et al.

(2016), Tsunoda et al. (2010), Tham et al. (1989), Gilbert et al. (1993), Petrovic

et al. (2002), Petrovic et al. (1999), Salzman et al. (1992), Curran et al. (2003)

and Hopkins et al. (1982). Vicens et al. (2016) was the follow-up study to Vicens

et al. (2014) at 36 months. Complete description of included studies is described

in Table 3. Using an excel sheet, data on study characteristics (design, date and

location), participants’ characteristics (age, sex and residency), intervention

description (target, duration and follow up), and outcomes (medication and

health status) were extracted and noted in Annex A.

22

FIGURE 2. PRISMA Flow chart

Records screened

(n = 1023)

Records after duplicates removed

(n = 2008)

Records identified through

database searching

(n = 3174)

Scre

enin

g In

clu

ded

El

igib

ility

Id

enti

fica

tio

n

Additional records identified

through other sources (n = 0 )

Records excluded based

on abstracts

(n = 993)

Full-text articles assessed

for eligibility

(n = 30)

Full-text articles excluded,

with reasons*

(n =20) *Reasons:

Subjects were under 65 years of

age (n=4), no health related

outcomes (n=5), language other

than English, French and

German (n=4), missing date on

exposure (n=2), study combined

the effect of BZD and Z-drugs

(n=5)

Articles included in

qualitative synthesis

(n = 11)

Studies included in

quantitative synthesis

(meta-analysis)

(n=0)

Records excluded

based on title

(n =985)

Based on?Title

Full-text articles

included by hand search

(n = 1)

23

3.2 Settings and Objectives

The included studies on BZD discontinuation were conducted in diverse

healthcare settings: primary care centres or communities (Hopkins et al. 1982,

Vicens et al. 2014, Vicens et al. 2016, Curran et al. 2003), hospitals (Petrovic et

al. 1999, Petrovic et al. 2002, Tham et al. 1989) and nursing homes (Gilbert et

al. 1993, Habraken et al. 1997, Salzman et al. 1992, Tsunoda et al. 2010). All

included studies had somewhat similar study objectives: Habraken et al. (1997)

wanted to study the long-term effect of gradual withdrawal from BZD on daily

functioning of residents of homes for the elderly. Tsunoda et al. (2010) wanted

to assess the feasibility and health benefits of discontinuing BZD-derivative

hypnotics. Salzman et al. (1992) sought to find out if memory improves following

BZD discontinuation in elderly taking BZD on a regular basis for more than 5

months. Hopkins et al. (1982) assessed the effects of withdrawing BZD on mood

and sleep. Gilbert et al. (1993) wanted to demonstrate if their intervention, which

involved relaxation training for patients and education for prescribers, could

reduce the level of chronic BZD use among residents of a nursing home facility.

Tham et al. (1989) wanted to compare the effects of abrupt versus gradual

withdrawal on sleep. Petrovic et al. (2002) studied the differential effects of

transitional lormetazepam versus placebo on withdrawal success rate and

symptoms. Petrovic et al. (1999) tried to test the hypothesis that a short-term

programme for withdrawal of benzodiazepines (BZD) is feasible in hospitalized

geriatric patients. Curran et al. (2003) wanted to demonstrate if withdrawing from

BZD led to change in patients' cognitive function, quality of life, mood and sleep.

Vicens et al. (2014) and (2016) aimed to compare the effectiveness of two

structured interventions intended to physicians, patients, and nurses on BZD

discontinuation.

3.3 Quality of the evidence

This review included seven RCTs (Vicens et al. 2014, Vicens et al. 2016, Curran

et al. 2003, Gilbert et al. 1993, Habraken et al. 1997, Tham et al. 1989, Petrovic

24

et al. 2002) and four before and after studies (Hopkins et al. 1982, Petrovic et al.

1999, Salzman et al. 1992, Tsunoda et al. 2010). The description of the studies

are included in Table 4. This review has three quality studies (Vicens et al. 2014,

Vicens et al. 2016, Curran et al. 2003) according to SIGN guidelines. Urine

samples were obtained from participants to confirm BZD withdrawal. The

remaining eight study reports were considered of low quality according to SIGN

guidelines or the Research Triangle Institute (RTI) Item bank for non-randomised

controlled trials. The common characteristics of the low-quality studies included

small sample size (n<100), high dropout rates (>10%), lack of appropriate

concealment and other methodological concerns (Table 3). One study

(Habraken et al. 1997) did not indicate whether the experimental and the control

groups were similar at baseline. Petrovic et al. (1999) did not report information

on how they allocated patients to study groups and they failed to provide

sufficient characteristics of participants. Five of the 10 included studies had small

sample sizes (Salman et al.1992 had 25 participants, Tham et al. 1989 had 30

participants, and Tsunoda et al. 2010 had 31 participants). Only the three studies

of good quality, two of which from the same population, had more than 100

participants (Vicens et al. 2014 and 2016, and Curran et al. 2003). Three studies

had a significant number of patients lost to follow up. Indeed, 10% of participants

were lost to follow up in Hopkins et al. (1982); 25% of participants were lost to

follow up in Gilbert et al. (1993), including 12% decedents and 13% relocated to

different accommodations. The highest proportion of participants lost to follow

up was 35% in Habraken et al. (1997).

3.4 Study Population

The total number of participants included in the 10 studies was 1042 and the

average of the mean age of these participants was 70.6 years, mostly female

(70.5%), ranging from 25% to 97%, and they were using BZD for at least 3

months (Table 4). Over three quarters of the participants (n=798) were living in

the community and were recruited from primary care centres through general

practicians. The remaining participants (n=244) were living in institutionalized

25

settings such as nursing homes and hospitals. Ninety percent of participants

were from Europe, including the United Kingdom, Belgium, and Spain.

Potentially eligible patients in Curran et al. (2003) were sent letters signed by

their general practitioners inviting them to attend an appointment with a research

psychologist to discuss their use of sleeping tablets. Patients who had been

taking BZD for at least 3 months were invited to participate in the study upon

admission to the geriatric ward in Petrovic et al. (1999). All residents of a nursing

home who were taking BZD were identified by Salzman et al. (1992), and their

clinicians were asked whether or not discontinuation of BZD was clinically

appropriate and feasible. In Hopkins’ study, eligible patients were identified when

they requested a repeat prescription, at consultation or from receptionists

(Hopkins et al. 1982). Using a semi-structural interview, patients in Curran et al.

(2003) were interviewed and assessed at four time points: week 0 (baseline),

week 12, week 24 and a proportion of patients were followed up and re-assessed

at week 52. In all studies, informed consent was required and obtained from the

participants. All participants could be considered as relatively healthy at

baseline: For example, patients with severe anxiety, senile dementia, severe

psychiatric illness and severe physical illness were excluded (Hopkins et al.

1982). Another study excluded patients if they had a history of substance abuse

within six months or had a significant medical condition that required an

immediate referral to specialists (Tsunoda et al. 2010). Salzman et al. (1992)

excluded patients who were moderately or severely demented at clinical

screening interview. Gilbert et al. (1993) excluded all participants acutely ill,

restricted to bed or diagnosed with dementia. A diagnosis of dementia was the

only exclusion criterion for Petrovic et al. (2002). Patients with dementia, severe

deafness, severe visual impairment, major psychiatric disorders, histories of

seizures and those receiving terminal care were excluded from Curran et al.

(2003).

26

Table 3. Appraisal of study reports

Study reference Study design Quality Comments

Curran 2003 RCT HIGH None.

Gilbert 1993 RCT LOW Small sample size, lack of randomization, inclusion criteria poorly described. Methodology was poorly described, and there is a lack of information on how deprescribing was processed.

Habraken 1997 RCT LOW No indication on whether the experimental and control groups were similar at baseline. There is possibly some measurements errors.

Hopkins 1982 Before and after MEDIUM The authors say that outcome assessment was blinded. However, they do not explain in details how blinding of outcome evaluators has been performed.

Petrovic 1999 Before and after LOW Lack of information on how allocation to groups was done, no baseline characteristics of patients, no data to verify confounding variables.

Petrovic 2002 RCT LOW Small sample size, high dropout rate, lack of multivariate analysis and on how randomization and concealment were done.

Salzman 1992 Before and after LOW Small sample size, lack of randomization, lack of multivariate analysis and poor blinding are serious limitations to this study.

Tham 1989 RCT LOW Small sample size, lack of multivariate analysis, and very short study duration (10 days).

Tsunoda 2010 Before and after LOW Small sample size, lack of multivariate analysis, no subgroup analysis, open label procedure and lack of any control group.

Vicens 2014 RCT HIGH None.

Vicens 2016 RCT HIGH None.

27

Table 4. Description of included studies (study reports)

2 The participants in both Vincens 2014 and Vicens 2016 are the same and were only counted once in the total.

First author, year

Country

Sample Size

Age (Mean)

Female (%) Follow-up (months)

Design Settings

Curran 2003 UK 132 76.6 71 13 RCT General pratices

Gilbert 1993 Australia 69 84 97 4 RCT Nursing Home

Habraken 1997 Belgium 56 84 81 12 RCT Community

Hopkins 1982 NA 78 60 71 5 Before and after Primary care centres

Petrovic 1999 Belgium 49 81.4 83 1.5 Before and after Hospital

Petrovic 2002 Belgium 40 81 81 12 RCT Hospital

Salzman 1992 USA 25 86 80 12 Before and after Nursing Home

Tham 1989 UK 31 82 26 0.55 RCT Hospital

Tsunoda 2010 Japan 30 79.1 43 2 Before and after Nursing Home

Vicens 2014 Spain 532 64 72 12 RCT Primary care centres

Vicens 2016 2 Spain 532 66 72 36 RCT Primary care centres

Total/Average 1042 70.7 72.8 22.2

28

3.5 Description of successful interventions

The review includes four modes of BZD deprescribing interventions (gradual

withdrawal, abrupt withdrawal, education-based interventions and mixed

interventions). Within the gradual withdrawal process, the BZD discontinuation

took place progressively, slowly or by degrees, whereas abrupt withdrawal

suddenly replaced patients’ BZD by non-BZD medications (e.g. placebo,

antidepressant) or discontinued BZD without any replacement. Education-based

interventions, as illustrated by Vicens et al. (2014) and Vicens et al. (2016), were

the educational programmes intended to healthcare workers or patients with the

goal to reduce BZD prescriptions or intakes. Detailed characteristics of

deprescribing interventions are described in Table 5.

3.5.1 Gradual withdrawal

Three studies assessed the effects of a gradual BZD withdrawal programme:

Habraken et al. (1997), Tsunoda et al. (2010), and Tham et al. (1989). The

process of gradual withdrawal was slightly different between the studies.

Habraken and colleagues, for example, replaced lorazepam progressively by

placebo over 5 weeks (25% reduction per week for 3 weeks and then 12.5%

reduction for 2 weeks) until discontinuation. Tsunoda et al. (2010) gradually

discontinued flurazepam by tapering the usual dose over 3 weeks (25% weekly

reduction regimen), allowing trazodone in case of increased insomnia at any

time. Tham et al. (1989) implemented the gradual withdrawal from temazepam

(5 mg for the first 4 nights, 2 mg for the next 4 nights and then placebo for the

last 2 nights). The gradual withdrawal in the study by Habraken et al. (1997) was

quite unique in the sense that the discontinuation involved a transitional period

of one week, where the usual medication was replaced by a sedative

antidepressant (trazodone 50 mg), administered at bedtime before

discontinuation. The gradual withdrawal programs from BZD appeared to be

diverse in type but feasible in diverse health care settings (community, nursing

homes and hospitals). Results from Tsunoda et al. (2010) demonstrated that a

29

gradual withdrawal led to BZD discontinuation; 26 out of 30 participants

completed the gradual withdrawal programme successfully. The elderly long-

term hospitalised patients in Tham et al. (1989) successfully discontinued

temazepam 10 mg daily following the strategy to withdraw from BZD gradually

or abruptly in few days. In Petrovic et al. (2002), BZD discontinuation success

rate was significantly higher in the lormetazepam substitution group (80%),

corroborating the earlier report from Petrovic et al. (1999).

3.5.2 Abrupt withdrawal

Four studies assessed the effectiveness of BZD abrupt withdrawal (Tham et al.

1989, Petrovic et al. 2002, Petrovic et al. (1999) and Salzman et al. 1992).

Experimental patients had their BZD doses suddenly replaced by placebo or

non-BZD medication. Tham et al. (1989) compared the efficacy of the abrupt and

gradual withdrawal in patients taking temazepam 10 mg and there was no

difference between the two. Twenty-six patients (83%) were able to complete a

deprescribing programme lasting few nights. Petrovic et al. (2002) compared two

withdrawal programmes: abrupt withdrawal with a transitional placebo versus an

abrupt withdrawal with a transitional lormetazepam, the habitual BZD was

replaced by a low dose of lormetazepam (1 mg), and then discontinued one

week later. The BZD discontinuation success rate was significantly higher in the

lormetazepam substitution group than in the placebo group (80% vs 50%). The

major difference between Petrovic et al. (1999) and Petrovic et al. (2002) is that

in the latter, placebo group was replaced by trazodone.

3.5.3 Education-based interventions

Two studies assessed the impacts of education-based interventions on BZD

discontinuation and health (Vicens et al. 2014, 2016, and Gilbert et al. 1993). A

three-hour educational workshop for healthcare professionals on structured

interviews, individualised patient information, BZD discontinuation management,

and dose-reduction follow-up were organized by Vicens et al. (2014, 2016).

Since follow-up visits to patients could generate more cost, follow-up letters were

30

sent out to patients or follow-up calls were organized. The content of the

educational interview included information on BZD dependence, abstinence,

withdrawal symptoms, the risks of long-term BZD use, the risk of memory and

cognitive impairment, accident and falls due to BZD. The participants also

received reassurance about reducing medication and a self-help leaflet to

improve sleep quality if patients were taking BZD for insomnia (Vicens et al.

2016).

In Gilbert et al. (1993), a relaxation training and a sleep hygiene education were

provided to patients in nursing homes while their staff and caregivers were

instructed on alternative strategies for the management of sleep disturbance and

the use of BZD. Patients were issued an audio recording of relaxation

procedures, information about sleep, anxiety and medication use. Members of

the staff, particularly those on night shift, were instructed about the likely

consequences of BZD withdrawal and how to help residents having trouble with

sleep.

The efficacy of the two education-based interventions in Vicens et al. (2014) was

assessed at 12 months. Nearly half (45%) of the patients (76 out of 168) in the

intervention groups who received follow-up letters successfully discontinued

their BZD use. Similarly, 86 out of 191 patients (45%) in the other intervention

group who received follow up calls also discontinued BZD use compared with 26

out of 173 patients (15%) in the control group. There was no statistically

significant difference in efficacy between the structured intervention with follow-

up visits (SIF) and the structured intervention with written instruction (SIW)

groups. The relative risks (RR) for BZD discontinuation were 3.01 (95% CI 2.03–

4.46) for structured intervention with SIW and 3.00 (95% CI 2.04–4.40) for the

structured intervention with SIF. The structured interventions with follow-up

appointments or written instruction were up to three times more effective than

routine care in discontinuing long-term BZD use in patients without severe

comorbidity. The relaxation training and sleep hygiene education for patients in

nursing homes significantly reduced BZD intake in Gilbert et al. (1993) study.

31

The proportion of participants taking BZD in the intervention group declined from

70% to 35% at 3-month follow-up, while the number of users or the used dose

did not significantly change in the control group. All three education-based

programmes significantly decreased BZD in exposed patients as compared with

usual care.

32

Table 5. Description of BZD deprescribing interventions

# Study reference Descriptions of the interventions

1 Habraken et al. (1997)

Patients taking BZD other than lorazepam were switched to lorazepam as per the equivalence table published by the National Health and Medical research council of Australia, then dose tapering with lorazepam replaced by placebo over 5 weeks (25% reduction per week for 3 weeks and then 12.5% reduction for 2 weeks) and discontinuation.

2 Vicens et al. (2014)

Three-hour workshop on structured interview, individualised patient information, BZD discontinuation and optimal gradual dose reduction. In addition, physicians were assigned to attend a 30-min workshop on how to standardise the dose-reduction follow-up visits or patients were sent instructions reinforcing the educational information.


Three-hour workshop on structured interview, individualised patient information, BZD discontinuation and optimal gradual dose reduction. In addition, physicians were assigned to attend a 30-min workshop on how to standardise the dose-reduction follow-up visits or patients were sent instructions reinforcing the educational information.

4 Tsunoda et al. (2010)

All daily doses of a BZD-derivative converted to flurazepam equivalent. BZD dose tapering over 3 weeks with 25% weekly reduction regimen. Trazodone was allowed for the relief of increased insomnia at any time.

5 Tham et al. (1989)

Gradual withdrawal from temazepam (5 mg for the first 4 nights, 2 mg for the next 4 nights and then placebo for the last 2 nights).

6 Gilbert et al. (1993)

Relaxation training and hygiene education provided to patients in nursing homes. Staff and caregiver were instructed about alternative strategies to manage sleep disturbance and the use of BZD. Physicians were sent a letter encouraging them to reduce the use of BZD. Two registered psychologists conducted the relaxation training of eight 40-minute sessions over 3 weeks. Patients were issued audio recordings of relaxation procedures. Relaxation was encouraged to control anxiety. Staff on night shift was instructed about the likely consequences of BZD withdrawal and how to help residents having trouble.

7 Petrovic et al. (2002)

Abrupt withdrawal with or without placebo.

33

8 Petrovic et al. (1999)

Transitional period of 1 week, where the usual BZD was replaced by a sedative antidepressant agent (trazodone 50 mg) or low-dose BZD (lormetazepam 1 mg) before discontinuation, administered at bedtime.

9 Hopkins et al. (1982)

The participants were explained the danger of BZD long term treatment, and were instructed to reduce the dosage of and frequency of medication according to a predetermined regimen. In patients taking medication more than once daily, withdrawal was planned to take four weeks, and where medication were taken less frequently or only in response to emotional upset treatment was stopped abruptly. Patients complaining of increased anxiety or insomnia were encouraged to continue withdrawal.

10 Salzman et al. (1992)

Following the initial baseline testing, BZDs were gradually tapered in experimental group.

11 Curran et al. (2003)

Patients who wished to withdraw were randomly allocated to one of two groups under double-blind,

placebo controlled conditions: group A’s BZD dose was tapered from week 1 of the trial; group B

were given their usual dose for 12 weeks and then it was tapered. An additional group (C) of patients

who did not wish to withdraw from BZDs participated as ‘continuers ’.

34

3.6 Effects of education-based interventions on BZD discontinuation

The RR of discontinuing BZD was 3.01 (95% CI 2.04 – 4.40) in patients exposed to

education-based interventions that consisted of a 3-hour workshop on structured

interview, individualised patient information, BZD discontinuation management,

optimal gradual dose reduction, and dose-reduction follow-up visits, in comparison

to patients in usual care at 12 months (Vicens et al. 2014). Even at 36 months, this

RR remained statistically significant at 1.51 (95% CI 1.10 -2.05) in the intervention

groups (Vicens et al. 2016). In Gilbert et al. (1993), the proportion of participants

who used BZD declined significantly from 70% to 35% following a BZD

deprescribing intervention. This intervention involved relaxation training and

hygiene education provided to patients in nursing homes, instruction to staff and

caregiver on alternative strategy to manage sleep disturbance and the use of BZD,

and sending letters to physicians to encourage them to reduce the use of BZD

(Gilbert et al.1993).

3.7 Effect of BZD discontinuation on health

The most frequently reported health outcomes were sleep quality, withdrawal

symptoms and mortality. Cognitive functioning, anxiety, memory status, activities of

daily living, falls, emotional responsiveness, well-being and mood were reported

less frequently.

3.7.1 Sleep quality and hours of sleep

Nine studies assessed the impacts of BZD withdrawal on sleep: Habraken et al.

(1997), Vicens et al. (2014, 2016), Tsunoda et al. (2010), Tham et al. (1989), Gilbert

et al. (1993), Petrovic et al. (2002), Petrovic et al. (1999), Salzman et al. (1992), and

Curran et al. (2003). However, these studies used diverse tools or scales to assess

sleep quality (n=5), sleep satisfaction (n=1) and sleep quantity (n=2). The sleep

quality was measured using the Groningen scale (Habraken et al. 1997 and Petrovic

et al. 1999), the subscale of the Oviedo Sleep Questionnaire (Vicens et al. 2014) or

the Leeds Sleep Evaluation Questionnaire (LSEQ). Hours of sleep were measured

35

with patients’ records (Tham et al. 1989) and a sleep diary (Curran et al. 2003).

Tsunoda et al. (2010) reported no worsening in the subjective evaluation of sleep

after the intervention in terms of getting to sleep, quality of sleep and awakening

from sleep. However, Habraken and colleagues reported that the subjective sleep

quality decreased in the placebo group compared to baseline, while it increased in

the lorazepam group (Habraken et al. 1997). Considering the number of sleep

hours, Tham et al. (1989) found no difference in hours of sleep between the baseline

period (5.9 hours (95% CI 5.3 – 6.5) and abrupt withdrawal period (5.6 hours (95%

CI 5.0 – 6.3)) or gradual withdrawal period (5.6 hours (95% CI 5.1-6.1)). Gilbert et

al. (1993) mentioned there were no significant differences between the sleep

satisfaction scores over time. Salzman et al. (1992) found no significant change in

either the discontinuers or the continuers regarding sleep following BZD

discontinuation. Curran et al. (2003) corroborated the finding that withdrawers and

continuers did not differ for sleep quality. Petrovic et al. (2002) favorably noted that

the sleep quality of subjects under investigation substantially improved in

intervention groups after the substitution period. Hopkins et al. (1982) reported a

temporary deterioration in sleep quality in the withdrawal process in form of

insomnia. Nevertheless, the benefit of BZD withdrawal out weighted risk, as Hopkins

and colleagues reported: « the withdrawal appeared to have little effect on waking

and several patients noted increased alertness and a sense of well-being on waking,

once BZD were discontinued » (Hopkins et al. 1982).

3.7.2 Cognitive function

Three studies assessed the effects of withdrawing BZD on cognitive function using

different scales. Using the Wechsler Adult Intelligence Scale-revised (WAIS-R) and

the vigilance test paradigm, Salzman et al. (1992) observed a significant

improvement of memory and cognitive performance following BZD discontinuation

without an increase in anxiety, agitation or sleeplessness. Subjects who

discontinued BZD, as compared with non-discontinuing controls, showed a

significant improvement in total memory (p < 0.004), immediate recall (p < 0.03),

and total digits (p < 0.05). Clinically, patients appeared more alert and less forgetful.

36

The authors reported that improvement in cognitive function was noticeable to

nursing staff and family members. Gilbert et al. (1993) assessed global cognitive

function using the Mini-Mental State Examination (MMSE) and observed no

significant difference between MMSE scores. Using the Repeatable Battery for the

Assessment of Neuropsychological Status (RBANS), Tsunoda et al. (2010) reported

that the discontinuation of BZD led to an improvement in cognitive functions during

the daytime, including immediate memory, language and attention index scores.

Curran et al. (2003) assessed the memory and cognitive function using the Spot the

Word test, the Digit span and the speed of information processing tasks, and

reported that the performance of the withdrawers on several cognitive/psychomotor

tasks showed relative improvements at 24 and 52 weeks. These results corroborate

Gilbert and colleagues’ findings of significantly increased positive affect (PA) and

negative affect (NA) scores at the intervention group over the comparison setting

(PA=5.59, NA=5.58, p<0.05) using the Positive and Negative affect schedule

(PANAS) (Gilbert at al.1993). This latter scale measures emotional responsiveness.

3.7.3 Daily functioning, body stability and depression

Using the Geriatric behavior observation scale, patients’ daily functioning improved

by 4 points with 95% confidence interval (-1.3, 9.3) after six months in the

intervention group, while the daily functioning score of patients in the control group

actually significantly deteriorated by 4.2 points (-10.9, -1.2) after six months

(Habraken et al. 1997). Vicens et al. (2014) assessed the impact of BZD

deprescribing at 36 months, and reported that there was no difference in depression

between the control and the intervention groups. Using the Clinical Stabilometric

Platform (CSP) and the Critical Flicker Fusion Test (CFF), Tsunoda et al. (2010)

reported that discontinuation of BZD led to an improvement in body stability, as

demonstrated by total length and a range of trunk motion with eyes closed

(baseline,: 5.49 cm2 ± 3.94; and endpoint: 3.98 cm2 ±3.66, p=0.10).

37

3.7.4 Adverse events

In the study of Tham et al. (1989), patients in the gradual withdrawal group had

between two to five restless nights with poor sleep. In another before and after

study, all subjects had mild insomnia (Salzman et al.1992). Many patients in the

study by Hopkins et al. (1989) reported agitation or tension during the withdrawal,

which usually settled within one or two weeks after the intervention, and which often

settled with reassurance. However, 13 patients out of 78 were unable to tolerate

these symptoms and their withdrawal was terminated.

3.7.5 Withdrawal symptoms

Four studies assessed withdrawal symptoms due to BZD discontinuation: Habraken

et al. (1997), Vicens et al. (2014; 2016), and Petrovic et al. (2002). These studies

used two methods to assess the occurrence of withdrawal symptoms: the BZD

Withdrawal Symptoms Questionnaire (BWSQ) was used in Habraken et al. (1997),

Curran et al. (2003) and Petrovic et al. (2002). Vicens and colleagues (2014, 2016)

used a list of frequent symptoms. Habraken and colleagues (1997) found no major

withdrawal symptoms and noted a small fluctuation of symptoms. Vicens et al.

(2014) reported some cases of severe irritability at six months after the intervention

in 19 out of 345 participants in the intervention group, severe insomnia in 52 out of

345, and severe anxiety in 29 out of 345 participants. Vicens et al. (2014) noted that

the most frequent withdrawal symptoms at 6 months were insomnia, anxiety and

irritability. Petrovic et al. (2002) reported that the BWSQ score increased during the

withdrawal period and decreased to the baseline level 10 to 15 days later. This result

corroborates Hopkins and colleagues’ conclusion that the sleep disturbance after

the BZD discontinuation is temporary and may last up to two weeks (Hopkins et al.

1982).

3.8 Characteristics of successful deprescribing interventions

All of the included interventions were successful in reducing the dosage of

prescribed BZDs due to this review’s inclusion criteria. They either discontinued or

38

significantly reduced BZD in more than 50% of the exposed participants with minor

or no withdrawal symptoms (Gilbert et al.1993, Habraken et al.1997, Petrovic et

al.1999). The characteristics of successful interventions are defined in term of

impacts on health. In most studies, the processes of BZD deprescribing were

gradual and patient centered (Gilbert et al.1993, Curran at al.2023, Habraken et al.

1997, Hopkins et al.1982,, Salzmann et al. 1992, Tham et al. 1989, Vicens et al.

2014/2016). Most of the included studies (n=8) involved multi-faceted components

(intervention involving both education and gradual withdrawal). The abrupt

withdrawal was not recommended in patients taking high doses of BZD for long

time. The successful interventions involved several professional specializations

such as physicians, nurses, psychologists, and patients (Habraken et al. 1997,

Salzmann et al.1992).

Patients’ characteristics are also an important factor of a successful intervention.

The BZD discontinuation rate at 12 months was greater for less anxious patients,

as assessed by the Hospital Anxiety and Depression Scale (HADS) (Hopkins et al.

1982). There was no relationship between successful withdrawal and either age,

sex and which health professional had started the treatment (e.g. general

practitioner) or the reason for continuing treatment (Hopkins et al. 1982). The

previous BZD dose was correlated with successful intervention in one study

(Hopkins et al. 1982). The discontinuation rate of BZD at 12 months was significantly

greater for patients taking less than 10 mg of diazepam equivalent versus patients

taking more than 10 mg. Some intervention designs were more successful than

others. For example, the withdrawal success rate was higher in the lormetazepam

substitution group than with placebo (80% versus 50%, p<0.05), supporting the

evidence that gradual withdrawal is more efficient than an abrupt withdrawal. The

likelihood of withdrawal was related to the duration of previous treatment when

successful withdrawers were compared with unsuccessful withdrawers in Hopkins

et al. (1982).

This review corroborates with the existing evidence that BZD discontinuation does

not negatively affect sleep, and at no point did the withdrawal groups differ from the

39

group who stayed on medication in terms of sleep ratings (Curran et al. 2003),

suggesting that BZDs do not help people sleep when taken for a long time.

Correlations between measures of BZD intake (dose, cumulative dose) and

patients’ ratings of sleeping problems also suggest the ineffectiveness of BZDs in

aiding sleep (Curran et al. 2003).

40

Table 6. Common characteristics of successful BZD deprescribing intervention reports

First author, Year Study design Gradual withdrawal

Educational intervention

Non Pharmacologic alternatives

Multi Disciplinary intervention

Patient centered

Curran 2003 RCT

Gilbert 1993 RCT

Habraken 1997 RCT

Hopkins 1982 Before and after

Petrovic 1999 Before and after

Petrovic 2002 RCT

Salzman 1992 Before and after

Tham 1989 RCT

Tsunoda 2010 Before and after

Vicens 2014 RCT

Vicens 2016 RCT

41

Chapitre 4. Discussion

The aim of the present research project was to evaluate the effects of BZD

discontinuation on the health of older adults and to describe the characteristics of

successful deprescribing interventions by using data from a systematic review of

deprescribing interventions on patients aged 60 years or older. To this end, five

databases were systematically searched for eligible BZD deprescribing studies.

Eleven articles met the inclusion criteria and were included in this review. Given the

heterogeneity between the included studies, a quantitative review of results, i.e. a

meta-analysis, was not possible. Instead, a narrative and transparent synthesis

method was used to report the results while respecting the PRISMA reporting

protocol.

In general, BZD deprescribing interventions included BZD withdrawal (gradual or

abrupt) and either multi-disciplinary teams (doctors, nurses or caregiver),

educational activities (workshop, training) or non-pharmacological alternatives such

as cognitive behaviour therapy or relaxation. Most of the included interventions

(n=9) were gradual, multidisciplinary, patient-centered and educational (Table 6).

The main findings of this research project were the differences between those who

withdrew from BZDs and those who continued to use BZDs in term of changes of

health outcomes (sleep quality, anxiety, depression and more). The qualitative

review of the 11 epidemiological articles included in this review clearly demonstrated

that BZD discontinuation is feasible in the majority of patients without major negative

health impacts.

4.1 Efficacy of interventions to deprescribe BZD

The purpose of this review was not to demonstrate the efficacy of the interventions

but their impacts on health, therefore, only the interventions that were effective in

deprescribing or reducing the number of medications were included. The efficacy of

deprescribing interventions in terms of medication discontinuation were previously

demonstrated in a systematic review and meta-analysis by Page et al. (2016).

42

Deprescribing was shown to have reduced both the total number of medications

(mean difference of −0.99, 95% CI −1.83 to −0.14) and the number of potentially

inappropriate medications taken (mean difference of −0.49, 95% CI −0.70 –−0.28)

but data concerning BZD was not easily accessible (Page et al. 2016). In one study

that focused on BZD, a structured intervention with follow-up visits or a structured

intervention with written instruction were up to three times more effective than

routine care in discontinuing long-term BZD use in patients without severe

comorbidity at 12 months (Vicens et al. 2014). Even after 36 months, the BZD

discontinuation rate was 59% higher in the intervention group as compared with the

control group (Vicens et al. 2016). Although, there was no difference in efficacy

between the intervention groups, the structured intervention with written instruction

was somehow easier to implement than the structured intervention with follow-up.

Furthermore, both interventions had similar effects on BZD discontinuation, despite

the fact that sleep satisfaction was significantly higher in the intervention with follow-

up visits. Of all patients beginning the trial in Curran et al. 2003, 80% had

successfully withdrawn 6 months later. In Gilbert et al. (1993), a relaxation training

combined sleep hygiene education to patients, prescribers and caregivers in nursing

homes significantly reduced the proportion of participants taking BZD in the

intervention group from 70% to 35% after three months, while the used dose did not

change in the control group.

4.2 The health impacts of deprescribing interventions

Positive impacts on the health of the participants in the included BZD discontinuation

studies have been observed. At 24 weeks, the measure of speed of information

processing showed that withdrawn groups were performing more accurately than

those who continued to use BZDs, and the accuracy of information processing

improved in those who withdrew compared with a decline in performance by those

who continued taking their BZDs (Curran et al. 2003). Patients who withdrew from

BZDs had improved working memory as assessed by total Digit span while those

who stayed on medication showed a slight decline in performance (Curran et al.

2003). Improvement in cognitive performance is clearly an advantage of BZD

43

withdrawal as observed by Tsunoda et al. (2010) and evidenced by significant

improvement of immediate memory and attention. Using the Geriatrics Behaviour

Observation scale, patients’ daily functioning improved by 4 points in the

intervention group while the parameter actually decreased by 4.2 points in the

control group (Habraken et al. 1997). Discontinuation of BZD led to an improvement

in the stability of body and a recovery in cognitive functions such as memory,

language and attention (Tsunoda et al. 2010). The benefits of BZD withdrawal need

to be assessed in light of fewer road traffic accidents, fewer falls and fewer fractures

(Curran et al. 2003). As Curran and colleagues (2003) correctly noted: « although

the costs of BZD medication are fairly small, there are very substantial costs in

treating fractures and other injuries associated with accidents and falls ».

Nevertheless, the cost to implement BZD deprescribing strategies depends on

resource personnel available within a given health care setting. No matter how

patients react to withdrawal, the option of going back to BZD use is always available

during the withdrawal process, but that need might be lessened by providing

encouragement (Gilbert 1993).

There was no evidence of emergent depression or anxiety on withdrawing from

BZDs, and indeed the only group to show elevated anxiety ratings during the trial

were the patients who had stayed on BZDs (Curran et al. 2003). Some prescribers

and patients might fear the rebound of anxiety or insomnia by arguing that

withdrawing frail seniors from BZD may be less desirable than leaving them on

drugs. However, the results from Gilbert et al. (1993) suggest that the changes in

negative affect following the BZD withdrawal are not significant. The decision to

withdraw from BZD intake might be hard for some patients, but the probable

cognitive advantages from withdrawal and lack of effectiveness of long-term of

BZDs may help such patients in the decision-making process.

4.3 Characteristics of successful deprescribing interventions

Choosing the appropriate intervention is critical to successful BZD withdrawal.

Some suggestions for successful deprescribing can be drawn from the results of

this review. Prescribers should consider the patient’s clinical characteristics before

44

starting the withdrawal process. Deprescribing BZD in patients with anxiety and

those taking more than 10 mg of diazepam equivalent should be very carefully

planned due to possible relapse (Vicens et al. 2014). However, when conducted

gradually, deprescribing BZD has shown to improve accuracy in speed of

information processing (Curran et al. 2003), working memory (Salzman et al. 1992),

emotional responsiveness (Gilbert et al. 1993), daily functioning (Habraken et al.

1997) without compromising sleep quality (Curran et al. 2003) or with a brief sleep

disturbance and agitation (Hopkins et al. 1982). The BZD withdrawal could be

maximized if patients were provided with a tapered dose regimen and information

about sleep and psychological support (Curran et al. 2003). Prescribers should not

hesitate to initiate BZD withdrawal if the indications for their earlier prescription are

not clear. Hopkins and colleagues (1982), for example, recommended that the

generalized use of psychotropic drugs to suppress a natural grief reaction or

process should be questioned.

4.4 Acceptability of deprescribing interventions

The results of the present review provide some guidance to support prescribers in

their decisions to attempt BZD withdrawal in long term users. In general, many

patients are willing to discontinue BZD intake but they require motivation from their

medical team (physicians, nurses, pharmacists and more). In the survey conducted

by Curran et al. (2003), 57% of the patients interviewed wanted to take part in the

withdrawal programme. Hospitalised elderly patients receiving chronic BZD

treatment were also willing to participate in a short-term withdrawal after being well

informed of the purposes and the advantages of BZD discontinuation (Petrovic et

al. 1999). Scientific evidence supports that the reduction in BZD use is not

associated with detectable negative effects on any health measures (Gilbert et al.

1993).

45

4.5 Limitation and biases

The limitations to this review include small sample sizes of the original studies, not

allowing for comparison of subgroups, and the lack of randomization and unclear

inclusion criteria in some studies.

4.5.1 Selection biases

Deprescribing is a relatively new concept in the medical literature, several older

studies may not have been selected due to differences in terminology used to

describe dose reduction, and studies focussing on health impacts were scarce. This

is the reason why none of the studies included in this review involved pharmacists

for example. The consecutive steps followed to recruit study participants, such as

the requirement to obtain approval from the next of kin for patients with cognitive

impairment, and the loss of subjects due to death or hospitalisation resulting in high

dropout rate (Habraken et al. 1997) could have induced some potential selection

biases. Systematic exclusion of eligible patients and disproportionate distribution of

gender increased the risk of selection biases. Over 70% of participants of this review

were female, and patients with acute physical illness or a history of psychosis were

excluded, as were patients under hospital supervision for psychiatric illness

(Hopkins et al. 1982).

4.5.2 Information biases

Although this review’s strategy was able to identify only a few high quality

deprescribing studies, there is a possibility that patients in deprescribing groups

could have obtained medication from other sources, since none of the studies

actually verified BZD plasma values. The interventions were also heterogeneous:

some studies compared two deprescribing interventions with each other, others

compared a deprescribing intervention with usual care. Studies reported different

tools for measuring health outcomes, for example, different scales for measuring

sleep quality were reported, and the quantitative analysis did not allow the

standardization of these tools. Lack of data comparing the experimental and the

control groups at baseline could have induced some measurements errors (for

46

example, Habraken et al. 1997). A significant number of studies (n=5) had a short

follow-up period (<3 months), therefore increasing the chance of information bias

due to the fact that some subjects could not have developed the outcome of interest

yet. Risk of reporting bias was not assessed due to small sample sizes and

heterogeneity of the studies. Language bias may have also been introduced as we

included only studies in English, French and Germany.

4.5.3 Confounding biases

Extra attention given to intervention groups might have contributed to reduced level

of BZD use (Gilbert et al. 1993) in addition to the intervention itself which might have

brought some confounding biases. The heterogeneity and missing data did not allow

any quantitative meta-analysis. Very few health outcomes were reported with

sufficient frequency to allow reliable meta-analyses and adjustments. Frequently

reported results included sleep quality and cognitive function, but studies reporting

these results were not consistent enough in terms of settings, follow-up duration,

and intervention types. For example, the duration of follow-up was 2 months or less

in some studies (Petrovic et al. (1999) and Tsunoda et al. (2010), while the follow-

up was 12 months or more in other studies (Habraken et al. (1997), Vicens et al.

(2014), Vicens et al. (2016), Petrovic et al. (2002), Salzman et al. (1992) and Curran

et al. (2003)).

4.6 Strengths

This is one of the very few comprehensive systematic reviews of interventions

intended to reduce the doses of BZD and their impacts on health. Different from

other reviews, this study did not include z-drugs, so the health changes observed in

this review are attributable to BZD deprescribing. To help resolve issues of selection

biases observed in previous reviews that only selected articles in English (Page et

al.2016), this review included articles published in three different language (English,

French, and Germany).

47

Conclusion

The overall results of this review demonstrate that BZD deprescribing interventions

are possible without major health impacts in diverse healthcare settings including

hospitals, primary care and nursing homes, and that the adverse impacts on health

are rather negligible and temporary, lasting only during the withdrawal period in most

patients. The odds of discontinuing BZD using a multidisciplinary and educational-

based intervention was up to three times greater in BZD withdrawal group as

compared with usual care at 12 months follow up (Vicens et al.2014) and the result

did not significantly change at 36 months follow up (Vicens et al. 2016). The

comparison of health status between patients who withdrew from BZDs and those

who continued to use BZDs at 6 months, 12 month and 36 months has shown

improvement of the accuracy in speed of information processing (Curran et al.

2003), working memory (Salzman et al. 1992), stability of body, cognitive

performances, language and attention (Tsunoda et al. 2010), emotional

responsiveness (Gilbert et al. 1993), daily functioning (Habraken et al. 1997), total

length and range of trunk motion (Tsunoda et al. 2010) without compromising on

sleep quality (Curran et al. 2003) or with only brief sleep disturbance and agitation

(Hopkins et al. 1982). Further work is necessary to examine the lifespan and trend

of withdrawal benefits over a longer time period. This will help clarify whether or not

a repeat deprescribing intervention might be necessary in certain settings.

Strategies to prevent different forms of dropouts should be developed in future

studies and clinically, more care should be taken to convince doctors of the

importance of BZD withdrawal. The researchers should establish detailed definitions

of the inclusion and exclusion criteria in order to assist general practitioners in the

decision about the eligibility of patients, which will minimize physicians’ subjectivity

in the selection procedure.

48

Annexe A. Description complète des rapports d’études retenues

# Author, year, country

Study design and setting

Number of participants total, or in Intervention Group (IG) or in Control Group (CG); Mean (SD) age; Male or Female proportion (%)

Characteristics of total, or Intervention Group (IG), or Control Group (CG)

Outcome measures

Follow-up duration

Study results

Effect of intervention on discontinuation

Clinical/health outcomes, quality of life outcomes

1

Habraken et al. (1997) Belgium

Double blind-RCT Community

N=55 Age(Mean): 84 years Female, 81% IG (n=17), CG (n=190)

Age, 65 years or older; BZD for at least 1 year.

Daily functioning measured at baseline with Geriatric behaviour Observation scale, Withdrawal symptoms measured weekly during the withdrawal phase, again at 6 months, and 1 year with adjusted BWSQ, Sleep measured weekly during the withdrawal phase, again at 6 months, and 1 year with Groningen scale.

12 months

Gradual withdrawal from BZD is possible. Baseline, IG (n=27) At 12 months IG(n=15) Baseline, CG(n=29) At 12 months CG(n=18)

-Decrease in sleep quality during the withdrawal -No major withdrawal symptoms -Positive effect on daily functioning 1. Daily functioning Improvement IG, 4 points (95% IC, -1.3, 9.3) at 6 months Improvement IG, 1.6 points (95% IC, -3.8, 7.0) at 1 year. Deterioration CG, 4.2 points (95% IC, -8.9, 0.4) at 6 months Deterioration in CG, 6 points (95% IC, -10.9, -1.2) 3. Subjective sleep quality The subjective sleep quality decreased in both intervention group.

49





Outcome measures

Follow-up duration

Study results



2 Vicens et al. (2014) Spain

Multi center 3 arms cluster- RCT. Primary care centres

N=532 Female, 72% IG/SIF: 24 GP (n=168) IG/SIW: 25 GP (n=173) CG: 25 GP (n=173)

Anxiety and depression symptoms measured with HADS. Sleep satisfaction measured with Subscale of Oviedo Sleep Questionnaire, Insomnia measured with a list of frequent symptoms, BZD Dependence measured with Severity of Dependence Scale.

12 months

At 12 months, 76 of 168 (45%) patients in the SIW group and 86 of 191 (45%) in the SIF group had discontinued BZD use compared with 26 of 173 (15%) in the Control.

-No increase in HADS scores, sleep dissatisfaction with baseline, with all groups improving slightly in these parameters over time. -sleep satisfaction was significantly higher in the SIF than in SIW.


Multi center 3 arms

N=532 Age, 64. Female, 72% IG/SIF:

Anxiety and depression symptoms

36 months

CG: 45/173 (26.0) SIW: 66/168 (39.2),

Median difference of anxiety CG versus SIW: 0 (-1 to 1) Median difference of depression

50





Outcome measures

Follow-up duration

Study results



Spain cluster- RCT

24 GP (n=168) IG/SIW: 25 GP (n=173) CG: 25 GP (n=173)

measured with HADS. Sleep satisfaction measured with Subscale of Oviedo Sleep Questionnaire, Insomnia measured with a list of frequent symptoms. BZD Dependence measured with Severity of Dependence Scale

RR=1.51 (1.10-2.05) SIF: 79/191(41.3), RR=1.59(1.15-2.19)

CG versus SIW: 0 (-1 to 0) Median difference of sleep satisfaction CG versus SIW: 0 (-1 to 0) Median difference of anxiety CG versus SIF: 0 (-1 to 1) Mean difference of depression CG versus SIF: 0 (0 to 0) Median difference of sleep satisfaction CG versus SIF: 0 (0 to 0) Mean difference of anxiety SIW versus SIF: 0 (-1 to 1) Mean difference of depression SIW versus SIF: 0 (0 to 1) Mean difference of sleep satisfaction SIW versus SIF: 0 (0 to 1)

4 Tsunoda et al. (2010) Japan

Before and after,

Age, 60 or older, on BZD at least 2 months.

2 months

Completers (n=26)

-Discontinuation of BZD leads to an improvement in the stability of body and a -

51





Outcome measures

Follow-up duration

Study results



open label Nursing Home

Female, 43% N= 30

Recovery in cognitive functions during the daytime. -Significant improvements were observed in the CFF and RBANS immediate memory, language, and attention index scores -Range and length of the trunk motion significantly reduced by 20 to 30% with closed eyes. -Cognitive functions significantly improved in the RBANS immediate memory, language, and attention index scores.

5 Tham et al. (1989) UK

RCT Double blind Hospital

N= 31 Mean age, 81 Female, 83% IG/AW ( n=15) IG/GW (n=16)

Elderly, mainly confused patients in geriatric unit On temazepam for more than one month

Hours of sleep were recorded during a 7 day the baseline period while patients were taking temazepam 10 mg nocte.

17 nights

26 patients completed the withdrawal programme

-5 patients in the GW had between 2 and 5 restless nigh with poor sleep. -No anxiety, convulsions, tremor or hallucination occurred. -No difference in hours of sleep between the baseline and period of gradual withdrawal and abrupt withdrawal. Change in mean hours of sleep in abrupt and gradual group (95% CI):

52





Outcome measures

Follow-up duration

Study results



-Baseline Nights Abrupt: 5.9 (5.3 – 6.5) Gradual: 5.8 (5.2-6.4) -Total withdrawal nights Abrupt: 5.6 (5.0 – 6.3) Gradual: 5.6 (5.1-6.1)

6

Gilbert et al. (1993) Australia

RCT Nursing Home

N= 69 Mean age, 86.9 Female, 97% IG (n=30) CG, (n=39)

Residents living in 2 supervised age-care facilities, belonging to same organization. One received intervention and the other was a non-intervention

Sleep, memory, cognitive performance measured with MMSE. Emotional responsiveness measured with PANAS, subjective health.

4 months

Control Pre-test: 76% Post-test: 73% Follow up: 72% Intervention Pre-test: 70% Post-test: 48% Follow up: 35%

-There were no significant differences between the mean MMSE scores, subjective health scores or sleep satisfaction scores over time. - The PANAS data indicated an increase in both the PA and NA scores for intervention setting over comparison setting. (F(1,34) PA=5.59, NA=5.58, p< 0.05)

7 Petrovic et al. (2002) Belgium

RCT Hospital

N=64 Placebo (n=20) Lormetazepam (n= 20) Mean age, 81 Female, 67%

Patient taking BZD for more than 3 months and admitted

Withdrawal symptoms was measured with BZD Withdrawal Symptoms Questionnaire.

12 months

BZD discontinuation success rate was significantly higher in Lormetazepam substitution group than in placebo

-Both subjective sleep quality and withdrawal symptoms were significantly Improvement in Lormetazepam group. -Initial replacement therapy with a low-dose BZD is

53





Outcome measures

Follow-up duration

Study results



to geriatric ward.

Sleep quality was measured with Pittsburgh Sleep Quality Index.

(80% vs 50% ) p<0.05

preferred over placebo, since the latter alternative is associated with worse sleep quality and lower success rate

8 Petrovic et al. (1999) Belgium

Before and after Hospital

N= 56 Intervention on (n= 49) Female, 41 Mean age, 81

Geriatric patients admitted to inpatient ward and taking BZD for at least 3 months.

Subjective estimations of sleep quality were evaluated four times during a period of 6 weeks with Groningen Sleep Quality

1.5 months

Lormetazepam Success (n=18, 75%) Non-success, (n=6, 25%) Trazodone Success (n=20, 80%) Non-success, (n= 5, 20%) Not statistically significant

No differences in subjective sleep quality between lormetazepam and trazodone,

54





Outcome measures

Follow-up duration

Study results



9 Salzman1992 USA

Controlled before and after study, single blind Nursing Home

N=25 Mean age, 81 Female, 80% IG (n= 13) CG, (n=12)

Residents of a nursing home whose physicians (and them) agreed to discontinue BZD formed the intervention group and those physicians (and them) disagreed formed control.

The cognitive testing battery of secondary memory function consisted of WAIS-R digit span and the vigilance test paradigm. Changes in sleep and affect was measured using Dementia Mood Assessment Scale.

12 months

13/13 stopped BZD. 6/10 remained out BZD 1 year later.

-Measures of memory and cognitive Function showed a significant improvement following BZD discontinuance. -No increase in anxiety, agitation, or sleeplessness was noted. 1. Effects on memory Subjects who discontinued BZD, as compared with non-discontinuing controls, showed a significant improvement in total memory (p < 0.004), immediate recall (p < 0.03) and total digits, p < 0.05 (digits forward plus backward). -A trend in improvement in Delayed recall (p < 0.07). - Clinically, patients appeared more alert and less forgetful. - Improvement in cognitive function was noticeable to

55





Outcome measures

Follow-up duration

Study results



nursing staff and family members.

10 Curran et al, 2003 UK

RCT General practices

N=138 Group A (n= 55) Group B (n= 49) Group C (n= 34) Mean age, 76 Female, 71%

25 GP recruited in inner city and suburban London and in rural areas. Patients, at least 65 years old and taking BZD on daily basis for at least 6 months.

Withdrawal symptoms was measured using BWSQ. Sleep with sleep diary. Memory and cognitive function with Spot the Word task, Digit span, Speed of information processing task.

13 months

Of the 104 patients who entered the trial, 80% Successfully withdrew from their BZDs

-There was little difference between groups A and B, but these groups differed from continuers (C) in that the performance of the withdrawers on several cognitive/psychomotor tasks showed relative improvements at 24 or 52 weeks - Withdrawers and continuers did not differ in sleep or BZD withdrawal symptoms.

11 Hopkins et al. (1982) N/A

Before and after Primary care centres

N=78 Female, 56 Mean age, 60

On BZDs for at least 3.

Mood measure with Visual analogue scales rating subjective feeling.

5 months

45 patients (58 %) had discontinued BZD and a further 13 (17%) were taking less than half their original dose.

56





Outcome measures

Follow-up duration

Study results



Abbreviations: N/A : not available; NH : nursing home; RTC : Randomized clinical trials; SAEs : serious adverse events; IG: intervention group; CG: control group; Standard Deviation (SD); Benzodiazepine (BZD); Gradual withdrawal (GW); Abrupt Withdrawal (AW); General Practitioner (GP)

57

Annexe B. Outils d’évaluation des biais pour chaque étude incluse (critères RTI et SIGN).

RTI Item Bank : études non randomisées

Article à analyser (Auteur, année) : Hopkins 1982

Critère Évaluation Commentaires

1. Is the study design prospective, retrospective, or mixed? Prospective study Pre-post study without control group

2. Are critical inclusion/exclusion criteria clearly stated

(does not require the reader to infer)?

Yes Taking benzodiazepines for at least three

months. Those with acute physical illness

or a history of psychosis were excluded,

as were patients under hospital

supervision for psychiatric illness.

3. Are the inclusion/exclusion criteria measured using valid

and reliable measures?

Yes Patient’s record and interviews

4. Did the study apply inclusion/exclusion criteria uniformly

to all comparison groups/arms of the study?

Not applicable See line 1.

5. Was the strategy for recruiting participants into the study

the same across study groups/arms of the study?

Not applicable See line 1

6. Was the sample size sufficiently large to detect a

clinically significant difference of 5% or more between

groups in at least one primary outcome measure?

Cannot tell 103 patients were taking BZD for more

than 3 months

7. What is the level of detail in describing the intervention

or exposure?

Medium

8. Are the important outcomes pre-specified by the

researchers? Do not consider harms in answering this

question unless they should have been pre-specified.

Yes Sleep and mood

9. Is the selection of the comparison group appropriate,

after taking into account feasibility and ethical

considerations?

Not applicable

10. Any attempt to balance the allocation between the

groups (e.g., through stratification, matching, propensity

scores).

Not applicable

58

11. Did researchers isolate the impact from a concurrent

intervention or an unintended exposure that might bias

results, e.g., through multivariate analysis, stratification, or

subgroup analysis?

Partially Information about alcohol used was

obtained, but authors could not exclude

tablets supply from relatives.

12. Did execution of the study vary from the intervention

protocol proposed by the investigators and therefore

compromise the conclusions of the study?

Can’t tell

13. Were the outcome assessors blinded to the

intervention or exposure status of participants?

No

14. Are interventions/exposures assessed using valid and

reliable measures, implemented consistently across all

study participants?

No

15. Are outcomes assessed using valid and reliable

measures, implemented consistently across all study

participants?

Partly Partly for mood (Bond 1974)

16. Is the length of follow-up the same for all groups? Not applicable

17. Is the length of time following the intervention/exposure

sufficient to support the evaluation of primary outcomes

and harms?

Yes

18. Did attrition from any group exceed 20 percent? No Attrition: 2.5%. Table 6 : at the end of the

study, n=76 (n=78 at the beginning of the

study)

19. Did attrition differ between groups by more than 20

percent?

Not applicable See line 18

20. Does the analysis control for baseline differences

between groups?

Not applicable

21. Are confounding and/or effect modifying variables

assessed using valid and reliable measures across all

study participants?

No No assessment or adjustment for

confounders

22. Were the important confounding and effect modifying

variables taken into account in the design and/or analysis

No No statistical analyses, no adjustment

59

(e.g., through matching, stratification, interaction terms,

multivariate analysis, or other statistical adjustment)?

23. In cases of high loss to follow-up (or differential loss to

follow-up), is the impact assessed (e.g., through sensitivity

analysis or other adjustment method)?

Not applicable

24. Are any important primary outcomes missing from the

results?

No

25. Are the statistical methods used to assess the primary

benefit outcomes appropriate to the data?

No No statistical test used, only frequencies

reported

26. Are any important harms or adverse events that may

be a consequence of the intervention/exposure missing

from the results?

No

27. Are the statistical methods used to assess the main

harm or adverse event outcomes appropriate to the data?

N/A

28. Are results believable taking study limitations into

consideration?

Low N small, Authors recognized further

supplies of tablets might be obtained from

hoarded stocks or from relatives and

friends, and this was impossible to

prevent.

29. Is the source of funding identified? Not reported

SIGN methodology checklist: Randomized controlled trials

Article à analyser (Auteur, année) : Habraken 1997


1. The study addresses an appropriate and clearly

focused question.

Yes

The assignment of subjects to treatment groups is randomised.

Yes

2. An adequate concealment method is used. Yes The authors say that it is a double-blind

study: They used placebo and they say

that outcome assessment was blinded.

60

However, they do not explain in details

how blinding of outcome evaluators has

been performed. Nor did the authors

explain how randomization was performed.

3. The design keeps subjects and investigators ‘blind’ about treatment allocation.

Yes The authors say that it is a double-blind

study: They used placebo and they say

that outcome assessment was blinded.

However, they do not explain in details

how blinding of outcome evaluators has

been performed.

4. The treatment and control groups are similar at the start of the trial.

Can’t say Patients’ characteristics at baseline not

shown, therefore it is difficult to say if

randomization has worked. Important

information to know, as n=55 (total

population)

5. The only difference between groups is the treatment under investigation.

Can’t say See comment 1.5.

6. All relevant outcomes are measured in a standard, valid and reliable way.

Yes Used methods are valid, but they do not

explain how measurements have been

performed (experienced research nurse,

repeated measurements)

7. What percentage of the individuals or clusters recruited into each treatment arm of the study dropped out before the study was completed?

Around 30% in

each arm study

Experimental group : 37% (10/27); Control

group : 32% (9/28)

8. All the subjects are analysed in the groups to which they were randomly allocated (often referred to as intention to treat analysis).

Cannot say Information not given

9. Where the study is carried out at more than one site, results are comparable for all sites.

Cannot say Information not given

How well was the study done to minimise bias? Low quality We do not know whether the experimental

and control groups were comparable at

61

baseline. There is a possibility of

measurement errors

10. Taking into account clinical considerations, your

evaluation of the methodology used, and the statistical

power of the study, are you certain that the overall effect is

due to the study intervention?

Study population

very low.

Confidence level :

low

Sample size calculation: it was estimated

that 63 subjects were needed in each

group to detect a clinically relevant

difference between the experimental and

the control group. The planned sample

size was not achieved due to recruitment

and follow-up problems.

11. Are the results of this study directly applicable to the

patient group targeted by this guideline?

Elderly people >

65 years old,

using BZD for at

least 1 year, with

no serious

dementia

12. Notes. Summarise the authors’ conclusions. Add any

comments on your own assessment of the study, and the

extent to which it answers your question and mention any

areas of uncertainty raised above.

The results in this small study suggest that

gradual withdrawal from BZD is possible in

NHs elderly residents, and that it can have

a positive effect on their daily functioning.

No major withdrawal symptoms were

observed, although there was a decrease

in sleep quality during withdrawal.

SIGN methodology checklist: Randomised controlled trials

Article à analyser (Auteur, année) : Curran 2003


1. The study addresses an appropriate and clearly focused question.

Yes

2. The assignment of subjects to treatment groups is randomized.

Yes The authors say the participants in group A

and B were randomized, not those in C.

62

The methods of randomization was not

provided

3. An adequate concealment method is used. Yes For patients in groups A and B, all drugs

were formulated in identical opaque

capsules and packed with lactose placebo

to appear the same throughout the trial.


Yes The authors say that it is a double-blind

study.


Yes See table 3, 4 and 5


Yes Except the participants in the group C were

not randomized.


Yes Valid methods were used to measure

different outcomes both at baseline and

follow up. Urine samples were obtained

from participants for assessments in lab (to

confirm BZD withdrawal).


25 % of all

participants

dropped out at

week 24

Group A: 18 % (10/55); Group B: 22%

(11/49), Group C: 38% (13/34).

9. All the subjects are analyzed in the groups to which they were randomly allocated (often referred to as intention to treat analysis).

Yes They authors say an intention to treat

analysis was used.


No Twenty-five general practices were

recruited in inner city and suburban

London and in rural areas, but data for

specific practice were not presented.

11. How well was the study done to minimize bias? acceptable

12. Taking into account clinical considerations, your

evaluation of the methodology used, and the statistical p

63

power of the study, are you certain that the overall effect is

due to the study intervention?

13. Are the results of this study directly applicable to the

patient group targeted by this guideline?

Yes

14. Notes. Summarize the authors’ conclusions. Add any

comments on your own assessment of the study, and the

extent to which it answers your question and mention any

areas of uncertainty raised above.

The authors concluded that improvements

in some cognitive aspects such as working

memory, reaction to time, information

processing are possible 6 months after

withdrawal, but the improvement in

episodic memory requires more research.

There was no variation in sleep quality and

withdrawal symptoms between

withdrawers and continuers.


Article à analyser (Auteur, année) : Salzman 1992


1. Is the study design prospective, retrospective, or mixed? Prospective study Groups were formed before the intervention

2. Are critical inclusion/exclusion criteria clearly stated (does not require the reader to infer)?

Yes All residents of a particular nursing home and taking BZDs were eligible if willing to cooperate with the testing.

3. Are the inclusion/exclusion criteria measured using valid and reliable measures?

Yes

4. Did the study apply inclusion/exclusion criteria uniformly to all comparison groups/arms of the study?

Yes

5. Was the strategy for recruiting participants into the study the same across study groups/arms of the study?

Yes Residents taking BZDs were contacted via their physicians. The physician decided which patients should be allocated to deprescribing group, and the remaining patients were allocated to the control group.

64

6. Was the sample size sufficiently large to detect a clinically significant difference of 5% or more between groups in at least one primary outcome measure?

No N= 25 (Experimental group: n = 13 and control group n =12). Authors say the sample size was exceedingly small.

7. What is the level of detail in describing the intervention or exposure?

High

8. Are the important outcomes pre-specified by the researchers? Do not consider harms in answering this question unless they should have been pre-specified.

Yes Effect of discontinuation on memory and on affect, anxiety, irritability, and sleep

9. Is the selection of the comparison group appropriate, after taking into account feasibility and ethical considerations?

Yes Patients’ physicians selected the control group based on their clinical judgments

10. Any attempt to balance the allocation between the groups (e.g., through stratification, matching, propensity scores).

No

11. Did researchers isolate the impact from a concurrent intervention or an unintended exposure that might bias results, e.g., through multivariate analysis, stratification, or subgroup analysis?

No

12. Did execution of the study vary from the intervention protocol proposed by the investigators and therefore compromise the conclusions of the study?

Cannot say In the introduction, the authors affirm that they aim to evaluate the effect of BZD discontinuation on elderly people who had been taking BZD on a regular daily or monthly basis for more than five months. However, they describe that one participant took clonazepam for only one month.

13. Were the outcome assessors blinded to the intervention or exposure status of participants?

Yes Although the testers were ‘blind’ to the experimental status of each subject, they often knew whether or not a patient had discontinued BZDs because either the patient told them directly or made other comments that suggested that drugs had been discontinued. Participants were not blinded.

65

14. Are interventions/exposures assessed using valid and reliable measures, implemented consistently across all study participants?

No Authors did not effectuate blood levels of BZD to confirm BZD discontinuation.

15. Are outcomes assessed using valid and reliable measures, implemented consistently across all study participants?

Yes However, effect of discontinuation on affect, anxiety, irritability, and sleep were assessed only in a subset of participants (Experimental group: 11/13; Controls: 5/12)

16. Is the length of follow-up the same for all groups? Yes

One-year follow-up evaluated only in the discontinuation group

17. Is the length of time following the intervention/exposure sufficient to support the evaluation of primary outcomes and harms?

Yes Experimental subjects were tested a second time 2-3 weeks after drug discontinuation was completed. A one-year follow-up of BZD use was also conducted.

18. Did attrition from any group exceed 20 percent? No All subjects participated up to the end (results on memory test).

19. Did attrition differ between groups by more than 20 percent?

No

20. Does the analysis control for baseline differences between groups?

No See tables 1 and 3.

21. Are confounding and/or effect modifying variables assessed using valid and reliable measures across all study participants?

Cannot say

22. Were the important confounding and effect modifying variables taken into account in the design and/or analysis (e.g., through matching, stratification, interaction terms, multivariate analysis, or other statistical adjustment)?

No

23. In cases of high loss to follow-up (or differential loss to follow-up), is the impact assessed (e.g., through sensitivity analysis or other adjustment method)?

N/A

24. Are any important primary outcomes missing from the results?

No

25. Are the statistical methods used to assess the primary benefit outcomes appropriate to the data?

Yes

66

26. Are any important harms or adverse events that may be a consequence of the intervention/exposure missing from the results?

No

27. Are the statistical methods used to assess the main harm or adverse event outcomes appropriate to the data?

No Participants of this study should have been blinded. Placebo should have been used ethically, since the physicians already allocated participants to groups based on clinical judgment.

28. Are results believable taking study limitations into consideration?

Low Small sample study, lack of randomization and poor blinding are serious limitations to take into consideration. No multivariate analysis, effect of discontinuation on affect, anxiety, irritability and sleep assessed only in a subgroup of pts. Moreover, physicians decided which patients belonged to the experimental group. It is possible that patients that performed better (were “fitter”) were allocated to the experimental group.

29. Is the source of funding identified? No


Article à analyser (Auteur, année) : Vicens 2014



Yes Compares the efficacy of two interventions to discontinue long-term BZD use.


Yes The assignment of subjects (GP) to treatment groups was randomized at cluster level

3. An adequate concealment method is used. Yes GPs in each of the three regions were randomized 1:1:1 to one of the three study arms using a computer-generated block randomization in blocks of 6 GPs.

67

Randomization and concealment was centralized through a single coordinating centre and the sequence was concealed from both patients and GPs until interventions were assigned.


Yes Owing to study procedures, patients and GPs could not be masked to their random allocation. However main outcome was externally evaluated through personal interviews by psychologists not involved in the study and masked to patient allocation. The statistician and data-entry staff were also unaware of patient allocation.


No The GPs (Table 1) differed in the three study groups; those in the control group were more likely to be male and tended to be slightly older and with less experience in BZD withdrawal than those in the intervention groups. Patients’ characteristics at baseline, however, were very similar (Table 2).


No See line 1.5


Yes Anxiety and depression symptoms were measured using the validated Hospital Anxiety and Depression Scale (HADS), The sleep satisfaction subscale is measured with a seven-point Likert scale ranging from 1 (not satisfied) to 7 (very satisfied). BZD dependence was rated with the Severity of Dependence Scale (SDS), a five-item questionnaire. Changes in alcohol intake during follow-up were self-reported and measured in standard alcohol units per

68

week (1 unit equals 10 g alcohol). Patients were also asked about adverse withdrawal effects.


Very few 3% were lost in group SIF, 2% in group SIW, and 3 % in Group Control. In total, 35 of 532 (6.6%) patients missing the final evaluation. Prescription data were available from the clinical records for 26 out of 35. Intention to treat was used for remaining 9 patients.


Yes Authors says primary and secondary outcomes were analyzed at patient level on an intention-to-treat basis adjusted for data clustering.


Can’t say Authors did not present data per site

11. How well was the study done to minimize bias? High

12. Taking into account clinical considerations, your evaluation of the methodology used, and the statistical p power of the study, are you certain that the overall effect is due to the study intervention?

Yes This study’s methodology and sample size support the hypothesis that the overall effect observed in participants are due to the study intervention, although the randomization at patient’s level could have been better alternative.

13.Are the results of this study directly applicable to the Patient group targeted by this guideline?

Yes Elderly patients (65 years+) and taking BZDs on regular basis. Patients in primary care with no major depressive or anxiety disorder, not currently receiving psychiatric treatment and free from severe medical conditions.

14. Notes. Summarize the authors’ conclusions. Add any comments on your own assessment of the study, and the extent to which it answers your question and mention any areas of uncertainty raised above.

The authors concluded that there was no statistically significant difference in efficacy withdrawing between the SIF and SIW groups). Withdrawal at 12 months did not differ by gender, age, short or long half-life

69

BZD use depression, insomnia or degree of dependence. They observed statistically significant differences in the interaction term and treatment efficacy for BZD dosage and anxiety. The discontinuation rate at 12 months was significantly greater for patients taking less than 10 mg v. more than 10 mg diazepam equivalent in each of the Study groups.


Article à analyser (Auteur, année) : Vicens 2016



Yes Compares the efficacy of two interventions to discontinue long-term BZD use.


Yes The assignment of subjects (GP) to treatment groups was randomized at cluster level

3. An adequate concealment method is used. Yes GPs in each of the three regions were randomized 1:1:1 to one of the three study arms using a computer-generated block randomization in blocks of 6 GPs. Randomization and concealment was centralised through a single coordinating centre and the sequence was concealed from both patients and GPs until interventions were assigned.


Yes Owing to study procedures, patients and GPs could not be masked to their random allocation. However main outcome was externally evaluated through personal interviews by psychologists not involved in

70

the study and masked to patient allocation. The statistician and data-entry staff were also unaware of patient allocation.


No The GPs (Table 1) differed in the three study groups; those in the control group were more likely to be male and tended to be slightly older and with less experience in BZD withdrawal than those in the intervention groups.


No See line 1.5


Yes Anxiety and depression symptoms were measured using the validated HADS The sleep satisfaction subscale is measured with a seven-point Likert scale ranging from 1 (not satisfied) to 7 (very satisfied). BZD dependence was rated with the Severity of Dependence Scale (SDS), a five-item questionnaire. Changes in alcohol intake during follow-up were self-reported and measured in standard alcohol units per week (1 unit equals 10 g alcohol). Patients were also asked about adverse withdrawal effects.


Few 86 patients (16.2%) were lost at 36 months (33 in the SIF group, 27 in the SIW group, and 26 in the control group).


Yes Authors says primary and secondary outcomes were analyzed at patient level on an intention-to-treat basis adjusted for data clustering.


Can’t say Authors did not present data per site

71

11. How well was the study done to minimize bias? High

12. Taking into account clinical considerations, your evaluation of the methodology used, and the statistical power of the study, are you certain that the overall effect is due to the study intervention?

Yes This study’s methodology, large sample size, and long follow up period support the hypothesis that the overall effect observed in participants are due to the study intervention, although the randomization at patient’s level could have been better alternative. The criteria used to define deprescribing in this study is much broader, previous studies have used different definitions for cessation of BZD use.

13. Are the results of this study directly applicable to the Patient group targeted by this guideline?

Yes Elderly patients (65 years+) and taking BZDs on regular basis. This study excluded patients with severe comorbidities, and this limits the generalizability of results to more-difficult-to-treat patients, such as those with severe medical or psychiatric disease and those under psychiatric care.


SIW and SIF interventions, accompanied by a tailored stepped-dose reduction, are up to 1.5 times more effective than routine care in discontinuing long-term BZD use. A between-group analysis at 36 months indicated that the three groups had no significant differences in HADS anxiety score, HADS depression score, and sleep satisfaction. However, within-group analysis indicated a significantly lower HADS anxiety score in the SIF group at 36 months relative to baseline. The interventions used in the present study can be considered safe as they did not increase anxiety, depression, or sleep dissatisfaction compared with the control group at 12 and 36 months

72


Article à analyser (Auteur, année) : Tsunoda 2010


1. Is the study design prospective, retrospective, or

mixed?

Prospective

study,

Groups were formed before the

intervention



Yes 60 years and older, leaving in a particular

nursing home in Japan, and being on BZDs

for at least 2 months. Participants were

excluded if they had critical condition, had

history of medication abuse within 6

months and physician judged important to

exclude.

3. Are the inclusion/exclusion criteria measured using

valid and reliable measures?

Cannot say Authors do not report how

inclusion/exclusion criteria were measured.



N/A There was only one group

5. Was the strategy for recruiting participants into the

study the same across study groups/arms of the study?

N/A See line 4




No N=30, Authors agree sample was small


or exposure?

High Authors stated BZD-derivative hypnotic

drug was discontinued over 3 weeks by a

weekly 25% reduction, and the subjects

were observed for the following 5 weeks.

The intervention was fully explained with

enough details on page 1260.




Yes Authors pre-specified they will assess the

postural sway and cognitive function

following BZD discontinuation.

73



considerations?

N/A There was no comparison group in this

study.



scores).

N/A See line 4




subgroup

analysis?

No No multivariate analysis, no subgroup

analysis




No



No This was an open label study, the

investigators were not blinded.



study participants?

Yes



participants?

Yes Clinical Stabilometric Platform (CSP), the

Critical Flicker Fusion Test (CFF), the

Repeatable Battery for the Assessment of

Neuropsychological

Status (RBANS), and the Leeds Sleep

Evaluation Questionnaire (LSEQ) were

used to measure clinical outcomes.

16. Is the length of follow-up the same for all groups? N/A See line 4.

17. Is the length of time following the

intervention/exposure sufficient to support the evaluation

of primary outcomes and harms?

Probably not 5 weeks follow up may be short.

18. Did attrition from any group exceed 20 percent? NO 4/30 (13%)

74


percent?

N/A See line 4.


between groups?

N/A See line 4.



study participants?

No





No




N/A


results?

No



Yes .



from the results?

No



N/A


consideration?

Low Small sample size, open label procedure

and a lack of any control group. The

absence of blind measure by the assessor

might also have confounded the results. No

multivariate analysis, follow-up short (5

weeks)

29. Is the source of funding identified? Yes Some authors received fees or grants from

the Japanese Society of Clinical Neuro

75

psychopharmacology, Pfizer Health

Research Foundation, Mochida Memorial

Foundation, GlaxoSmithKline, Otsuka,

Dainippon Sumitomo Pharma, Janssen

Pharmaceutical, and Pfizer.


Article à analyser (Auteur, année) : Gilbert 1993


1. Is the study design prospective, retrospective, or mixed? Prospective study, Groups were formed before the

intervention. Controlled before and after

study



Medium All residents at each age-care setting were

invited to participate. Critically ill patients

and the demented were excluded, but

criteria of critical illness not provided.

3. Are the inclusion/exclusion criteria measured using valid

and reliable measures?

Can’t tell Criteria of critical illness was not provided.

Not sure if patients were assessed by one

physician or more.



Yes All residents at each setting were invited to

participate. Residents who were acutely ill,

restricted to bed or diagnosed as

dementing were excluded from the study.

5. Was the strategy for recruiting participants into the study

the same across study groups/arms of the study?

Cannot tell Although the two NHs seem similar (the 2

groups were geographically separated

aged-care settings from the same

organization and similar in respect to

philosophy of care, staffing levels and

qualifications, staff-residents ratio, resident

selection criteria and medication

administration procedures), the authors

76

provide no details on the strategy for

recruiting participants in the comparison

group




Can’t tell 60 participants agreed to participants in

the study, and only 44 were using BZD.


or exposure?

Medium Physicians of intervention group were

encouraged to reduce BZD use, but the

process of reduction and duration not

reported.




Yes, but Proportion of BZD use, total prescription

drugs, cognitive function and emotional

responsiveness, subjective health and

sleep ratings. Outcomes described in the

abstract, but not in the method section.



considerations?

Yes, but The 2 groups were similar in respect to

philosophy of care, staffing levels and

qualifications, staff-residents ratio, resident

selection criteria and medication

administration procedures. Baseline

characteristics of participants in both

groups were quite similar, with the

exception of sex and pension status (%

receiving free medication) (Table 1)



scores).

No




subgroup analysis?

No

77




Can’t tell Their methodology poorly described in the

method section. Therefore, this point is

difficult to assess.



Can’t tell Medical practitioners were told which of

their patients had been involved, and were

asked to encourage a reduction in BZD

consumption. Authors did not report

exactly who assessed the participants and

whether they were blinded or not.



study participants?

Probably yes Participants lived in supervised units, BZD

used was verified through their medical

records (not clearly described in text).



participants?

Yes All participants were interviewed on three

occasions using a standard questionnaire,

with MMSE and PANAS


All participants from both groups were

reassessed by questionnaire on

enrolment, at four weeks and 12 weeks

later.

17. Is the length of time following the intervention/exposure

sufficient to support the evaluation of primary outcomes

and harms?

Yes 3 months follow up was enough, given the

short life expectancy in this population

group.

18. Did attrition from any group exceed 20 percent? No Twenty-two (81 %) residents at the

intervention setting regularly attended the

relaxation classes.


percent?

No 19 %


between groups?

No

78



study participants?

No Age and number of prescribed

medications are possible confounding

variables.





No See line 21




No


results?

Yes Data for MMSE post-test are missing.



Yes Pre-test and post-test assessments were

conducted with validated tools.



from the results?

Yes Seven (12%) residents died during the

study, but data about which group they

belonged are not provided.



Yes Differences between the intervention and

comparison at baseline were analyzed

using t-tests, and over time using repeated

measures analysis of covariance, with pre-

test measures as the covariates. Changes

in BZD use over time were examined

using the Cochran Q nonparametric rest.


consideration?

Low Methodology very poorly described in the

method section. Inclusion criteria poorly

described. Sample size small. No

multivariate analysis. No information on

how deprescribing was effectuated.

29. Is the source of funding identified? Yes Section 16 grant from South Australian

Health Commission

79


Article à analyser (Auteur, année) : Petrovic 1999


1. Is the study design prospective, retrospective, or mixed?

Prospective study Groups were formed before the intervention

2. Are critical inclusion/exclusion criteria clearly stated (does not require the reader to infer)?

Yes Patients who had been taking BZD for at least 3 months were invited to participate in the study upon admission to the geriatric ward

3. Are the inclusion/exclusion criteria measured using valid and reliable measures?

Yes

4. Did the study apply inclusion/exclusion criteria uniformly to all comparison groups/arms of the study?

Yes

5. Was the strategy for recruiting participants into the study the same across study groups/arms of the study?

Yes

6. Was the sample size sufficiently large to detect a clinically significant difference of 5% or more between groups in at least one primary outcome measure?

Cannot tell The authors affirm that the study was powered to detect a statistically significant difference in GSQ score of four points, but they do not provide the number of participants required to detect this difference.

7. What is the level of detail in describing the intervention or exposure?

High

8. Are the important outcomes pre-specified by the researchers? Do not consider harms in answering this question unless they should have been pre-specified.

Yes The primary outcome was the immediate and eventual success rate of BZD cessation and The evolution of the sleep quality before, during and after the intervention.

9. Is the selection of the comparison group appropriate, after taking into account feasibility and ethical considerations?

Cannot tell No information on baseline characteristics of pts in the two groups.

10. Any attempt to balance the allocation between the groups (e.g., through stratification, matching, propensity scores).

No

80

11. Did researchers isolate the impact from a concurrent intervention or an unintended exposure that might bias results, e.g., through multivariate analysis, stratification, or subgroup analysis?

Yes

Logistic regression analysis

12. Did execution of the study vary from the intervention protocol proposed by the investigators and therefore compromise the conclusions of the study?

Can’t tell

13. Were the outcome assessors blinded to the intervention or exposure status of participants?

NO All interviews were carried out by the same Psychologist.

14. Are interventions/exposures assessed using valid and reliable measures, implemented consistently across all study participants?

Yes

15. Are outcomes assessed using valid and reliable measures, implemented consistently across all study participants?

Can’t tell Some of the participants were confused, there’s a risk of selection bias if one group had more confused participants than the other, but this does entirely affect the study because subjects were assessed before and after the intervention.


Yes

17. Is the length of time following the intervention/exposure sufficient to support the evaluation of primary outcomes and harms?

Yes 6 weeks in both arms

18. Did attrition from any group exceed 20 percent? Yes Lormetazepam group: 25%, Trazodone group: 20%

19. Did attrition differ between groups by more than 20 percent?

No

20. Does the analysis control for baseline differences between groups?

No

21. Are confounding and/or effect modifying variables assessed using valid and reliable measures across all study participants?

Yes Authors mentioned using logistic regression to control confounding variables (Age, gender, BZD dose, type of drug substitution and reasons for hospital

81

admission) but results of the analysis not presented in tables.

22. Were the important confounding and effect modifying variables taken into account in the design and/or analysis (e.g., through matching, stratification, interaction terms, multivariate analysis, or other statistical adjustment)?

Yes Age, gender, BZD dose, type of drug substitution and reasons for hospital admission.

23. In cases of high loss to follow-up (or differential loss to follow-up), is the impact assessed (e.g., through sensitivity analysis or other adjustment method)?

No

24. Are any important primary outcomes missing from the results?

No

25. Are the statistical methods used to assess the primary benefit outcomes appropriate to the data?

Yes

26. Are any important harms or adverse events that may be a consequence of the intervention/exposure missing from the results?

No

27. Are the statistical methods used to assess the main harm or adverse event outcomes appropriate to the data?

No Participants of this study should have been blinded. Placebo should have been used.

28. Are results believable taking study limitations into consideration?

Low It is not described how patients have been allocated in the two groups. No information on baseline characteristics of pts in the two groups. Although the authors affirm that their study has enough statistical power to detect a difference in GSQ score of four points. They do not provide the number of participants required to detect this difference. Moreover, they do not describe whether a difference of 4 points in GSQ score is clinically meaningful or not. Sample size is small (n=49), and percentage of loss of follow-up high: (Lormetazepam group: 25%, Trazodone group: 20%).

29. Is the source of funding identified? No

82


Article à analyser (Auteur, année) : Petrovic 2002



Yes Evaluation of withdrawal program in which geriatric inpatients’ regular BZD was replaced by either 1mg Lormetazepam or placebo.


Yes, but Authors affirm that the assignment of subjects to groups was randomized, but they provide no details on how randomization has been performed.

3. An adequate concealment method is used. Yes, but Authors affirm that the study is a double-blind, placebo-controlled trial, but they do not describe whether placebo tablets and lormetazepam tablets were similar. They do not provide much details on the blinding of physicians and GPs who evaluated the follow-up


Yes, but See point 1.3.


Probably yes See table 1


Yes


Yes Sleep measured with the validated PSQI and symptoms with BWSQ.


20 % in Lormetazepam group and 50 % in placebo


Cannot tell Data for dropped out participants were analyzed using the assessments conducted before they left.

83


No

11. How well was the study done to minimize bias? Acceptable

12. Taking into account clinical considerations, your evaluation of the methodology used, and the statistical power of the study, are you certain that the overall effect is due to the study intervention?

Low Small sample size, high dropout rate, no multivariate analysis. Information on how randomization has been performed, and concealment methods (placebo, blinding) is missing.

13. Are the results of this study directly applicable to the Patient group targeted by this guideline?

Yes Elderly hospitalized patients (65 years+) and taking BZDs on regular basis.


Withdrawal success rate was higher in Lormetazepam group vs placebo (80% vs. 50%, p<0.05). Authors noted a parallel rise and a subsequent drop in PSQI and BWSQ, worse score in placebo group, suggesting worse health outcomes.

84

Annexe C. Les stratégies de recherche et les mots-clés.

# MedLine Results comments

1 exp Pharmaceutical Preparations/ or Drug Evaluation/ 101,902

2 exp therapeutic uses/ 367,632

3 exp polypharmacy/ 1,438

4 exp inappropriate prescribing/ 1,210

5 exp medication errors/ 2,819

6 drug therapy.fs. 220,557

7 exp drug therapy/ 133,575

8 "administration & dosage".fs. 132,351

9 (medication* or prescrib* or prescription* or polypharmacy or inappropriate or "drug evaluation").ti,ab,kf,ot.

107,808

10 or/1-9 588,595

11 Withholding Treatment/ 1,177

12 Substance Withdrawal Syndrome/ 927

13 (withdraw* or withhold or withheld or cease or ceased or cessation or discontinu* or taper or tapered or tapering).ti,ab,kf,ot.

48,865

14 or/11-13 49,316

15 10 and 14 19,967

16 ((medication* or prescrib* or prescription* or polypharmacy or inappropriate) adj3 (reduce or reduced or reducing or stop or stopped or stopping)).ti,ab,kf,ot.

2,645

17 15 or 16 22,350 meds withdrawal

18 exp aged/ 376,090

19 exp Nursing Homes/ 3,507

20 homes for the aged/ 1,293

21 exp geriatrics/ 1,234

22 exp aging/ 19,625

23 Veterans/ 2,241

24

(Older or eldest or elder* or senior* or frail* or "old age home*" or "homes for the aged" or "home for the aged" or "nursing home*" or "old age home*" or "homes for the aged" or "home for the aged" or "nursing home*" or geriatric* or geriatry or aging or veteran*).ti,ab,kf,ot.

169,241

85

25 or/18-24 485,335 aged

26 (trial or trials or pilot or prospective or follow-up or cohort or bias).ab,kf,ot,ti.

611,356

27 exp "Quality of Health Care"/ 907,420

28 exp "health care quality, access, and evaluation"/ 950,313

29 exp "study characteristics"/ 449,509

30 exp "Epidemiologic Methods"/ 841,762

31 or/26-30 1,407,404 studies/epidemio

32 25 and 17 and 31 6,713 meds withdrawal & aged &

studies/epidemio

33 exp deprescribing/ or exp Potentially Inappropriate Medication List/

483

34 (deprescrib* or deprescrip* or "beer's criteria" or "beers criteria" or "beer's list" or "beers list" or stopp).ti,ab,kf,ot.

757 deprescribing

35 or/32-34 7,459 meds withdrawal & aged &

studies/epidemio OR Deprescribing

36 (Smoker* or cigarette* or smoking).ti. or Smoking Cessation/ 13,893

37 (Alcohol adj3 (withdrawal or consumption)).ti. 1,703

38 exp Alcohol-Related Disorders/ 6,659

39 or/36-38 21,734 alcohol-smoking

40 35 not 39 7,228 38794 ref

except alcohol-smoking

41 limit 40 to (english or french or german) 7,052 anglais-français-allemand

42 41 39509 06/08/2019

86

# EMBASE Results Comments Results

#1 drug'/exp AND [2017-2019]/py 320,634 296,003

#2 drug screening'/exp AND [2017-2019]/py 14,931 7,918

#3 drug therapy'/exp AND [2017-2019]/py 382,646 136,788

#4 polypharmacy'/exp AND [2017-2019]/py 3,177 948

#5 inappropriate prescribing'/exp AND [2017-2019]/py 1,512 494

#6 medication error'/exp AND [2017-2019]/py 2,452 836

#7 drug therapy'/exp AND [2017-2019]/py 382,646 136,788

#8 pharmaceutics'/exp AND [2017-2019]/py 183,200 53,528

#9 administration and dosage'/exp AND [2017-2019]/py 975 2,206

#10

medication*:ti,ab,kw OR prescrib*:ti,ab,kw OR prescription*:ti,ab,kw OR polypharmacy:ti,ab,kw OR

inappropriate:ti,ab,kw OR 'drug evaluation':ti,ab,kw AND [2017-2019]/py

125,705 34,272

#11 #1 OR #2 OR #3 OR #4 OR #5 OR #6 OR #7 OR #8 OR #9

OR #10 833,687 318,363

#12 treatment withdrawal'/exp AND [2017-2019]/py 32,688 1

#13 withdrawal syndrome'/exp AND [2017-2019]/py 2,939 22

#14

withdraw*:ti,ab,kw OR withhold:ti,ab,kw OR withheld:ti,ab,kw OR cease:ti,ab,kw OR ceased:ti,ab,kw OR cessation:ti,ab,kw OR discontinu*:ti,ab,kw OR taper:ti,ab,kw OR tapered:ti,ab,kw

OR tapering:ti,ab,kw AND [2017-2019]/py

59,584 15,996

#15 #12 OR #13 OR #14 76,657

#16

((medication* OR prescrib* OR prescription* OR polypharmacy OR inappropriate) NEAR/3 (reduce OR reduced OR reducing OR stop OR stopped OR stopping)):ti,ab,kw AND

[2017-2019]/py

3,064

#17 (#11 AND #15) OR #16 49,935 Meds withdrawal

#18 aged'/exp AND [2017-2019]/py 334,333

#19 nursing home'/exp AND [2017-2019]/py 3,600

#20 home for the aged'/exp AND [2017-2019]/py 397

87

#21 geriatrics'/exp AND [2017-2019]/py 2,283

#22 aging'/exp AND [2017-2019]/py 26,574

#23 veteran'/exp AND [2017-2019]/py 4,763

#24

older:ti,ab,kw OR eldest:ti,ab,kw OR elder*:ti,ab,kw OR senior*:ti,ab,kw OR frail*:ti,ab,kw OR 'old age home*':ti,ab,kw

OR 'homes for the aged':ti,ab,kw OR 'home for the aged':ti,ab,kw OR 'nursing home*':ti,ab,kw OR

geriatric*:ti,ab,kw OR geriatry:ti,ab,kw OR aging:ti,ab,kw OR veteran*:ti,ab,kw AND [2017-2019]/py

156,410

#25 #18 OR #19 OR #20 OR #21 OR #22 OR #23 OR #24 422,134 Aged

#26 trial:ti,ab,kw OR trials:ti,ab,kw OR pilot:ti,ab,kw OR

prospective:ti,ab,kw OR 'follow up':ti,ab,kw OR cohort:ti,ab,kw OR bias:ti,ab,kw AND [2017-2019]/py

625,537

#27 health care quality'/exp AND [2017-2019]/py 448,714

#28 epidemiology'/exp AND [2017-2019]/py 469,939

#29 #26 OR #27 OR #28 1,144,366 Studies/Epidemio

#30 #17 AND #25 AND #29 8,769 Meds withdrawal AND

Aged AND Studies/Epidemio

#31 deprescribing'/exp AND [2017-2019]/py 8

#32 potentially inappropriate medication'/exp AND [2017-2019]/py 631

#33 beers criteria'/exp AND [2017-2019]/py 13

#34 deprescrib*:ti,ab,kw OR deprescrip*:ti,ab,kw OR 'beers

criteria':ti,ab,kw OR 'beers list':ti,ab,kw OR stopp:ti,ab,kw AND [2017-2019]/py

849

#35 #31 OR #32 OR #33 OR #34 1,175

Deprescribing (concept relativement nouveau -

sans restriction sur l'âge)

#36 #30 OR #35 9,734

[[Meds withdrawal AND Aged AND

Studies/Epidemio] OR Deprescribing]

88

#37 alcoholism'/exp AND [2017-2019]/py 8,560

#38 (alcohol NEAR/3 (withdrawal OR consumption)):ti AND [2017-

2019]/py 1,464

#39 smoker*:ti OR cigarette*:ti OR smoking:ti OR 'smoking

cessation'/exp AND [2017-2019]/py 13,427

#40 #37 OR #38 OR #39 22,927 Alcohol-Smoking

#41 #36 NOT #40 9,459

[[Meds withdrawal AND Aged AND

Studies/Epidemio] OR Deprescribing]

NOT Alcohol-Smoking

#42 #41 AND ([english]/lim OR [french]/lim OR [german]/lim) 9,401 Limits :

English/French/German

# AgeLine Results Comments

S1

DE "Drugs" OR DE "Antibiotics" OR DE "Anticholinergic Drugs" OR DE "Aspirin" OR DE "Cholinergic Drugs" OR DE "Generic Drugs" OR DE "Nonprescription Drugs" OR DE "Nonsteroidal Anti Inflammatory Drugs" OR DE "Prescription Drugs" OR DE "Psychotropic Drugs" OR DE "Antibiotics" OR DE "Anticholinergic Drugs" OR DE "Aspirin" OR DE "Cholinergic Drugs" OR DE "Generic Drugs" OR DE "Nonprescription Drugs" OR DE "Nonsteroidal Anti Inflammatory Drugs" OR DE "Prescription Drugs" OR DE "Psychotropic Drugs" OR DE "Drug Therapy" OR DE "Drug Use" OR DE "Drug Utilization Review" OR DE "Medication Errors" OR DE "Polypharmacy" OR DE "Self Medication"

707

S2 DE "Psychotropic Drugs" OR DE "Antianxiety Drugs" OR DE "Antidepressants" OR DE "Antipsychotic Drugs" OR DE "Narcotics"

253

89

S3 (DE "Drug Interactions") OR (DE "Drug Use") 24

S4 DE "Drug Effects" OR DE "Drug Interactions" 72

S5 DE "Side Effects" OR DE "Adverse Drug Reactions" 85

S6

TI ( medication* or prescrib* or prescription* or polypharmacy or inappropriate or "drug evaluation" ) OR AB ( medication* or prescrib* or prescription* or polypharmacy or inappropriate or "drug evaluation" ) OR SU ( medication* or prescrib* or prescription* or polypharmacy or inappropriate or "drug evaluation" )

874

S7 S1 OR S2 OR S3 OR S4 OR S5 OR S6 1,203

S8

TI ( withdraw* or withhold or withheld or cease or ceased or cessation or discontinu* or taper or tapered or tapering ) OR AB ( withdraw* or withhold or withheld or cease or ceased or cessation or discontinu* or taper or tapered or tapering ) OR SU ( withdraw* or withhold or withheld or cease or ceased or cessation or discontinu* or taper or tapered or tapering )

143

S9 S7 AND S8 51

S10

TI ( (medication* or prescrib* or prescription* or polypharmacy or inappropriate) N3 (reduce or reduced or reducing or stop or stopped or stopping) ) OR AB ( ( (medication* or prescrib* or prescription* or polypharmacy or inappropriate) N3 (reduce or reduced or reducing or stop or stopped or stopping) ) OR SU ( ( (medication* or prescrib* or prescription* or polypharmacy or inappropriate) N3 (reduce or reduced or reducing or stop or stopped or stopping) )

47

S11 S10 OR S9 90 Meds withdrawal

S12

DE "Medical Research" OR DE "Controlled Clinical Trials" OR DE "Epidemiology" OR DE "Gerontological Research" OR DE "Longitudinal Studies" OR DE "Randomized Controlled Trials"

3,115

90

OR DE "Research Techniques" OR DE "Study Participation"

S13 DE "Data Collection" 75

S14 DE "Quality of Care" 8

S15

TI ( trial or trials or pilot or prospective or follow-up or cohort or bias ) OR AB ( trial or trials or pilot or prospective or follow-up or cohort or bias ) OR SU ( trial or trials or pilot or prospective or follow-up or cohort or bias )

2,382

S16 S12 OR S13 OR S14 OR S15 4,267 Studies/Epidemio

S17 S11 AND S16 49 Meds withdrawal AND Studies/Epidemio

S18 TX deprescrib* or deprescrip* or "beer's criteria" or "beers criteria" or "beer's list" or "beers list" or stopp

50 Deprescribing (concept relativement nouveau)

S19 S17 OR S18 87 [[Meds withdrawal AND Studies/Epidemio] OR Deprescribing]

S20 DE "Alcohol Consumption" OR DE "Alcoholism" 71

S21 DE "Smoking" 70

S22 TI alcohol N3 (withdrawal or consumption) 6

S23 TI smoker* OR cigarette* OR smoking 162

S24 S20 OR S21 OR S22 OR S23 220 Alcohol-Smoking

*S25 S19 AND S24 1

[[Meds withdrawal AND Aged AND Studies/Epidemio] OR Deprescribing] AND Alcohol-Smoking

S26 S19 NOT S25 86

[[Meds withdrawal AND Aged AND Studies/Epidemio] OR Deprescribing] NOT Alcohol-Smoking

*S25 la banque AGELINE ne permettait pas de faire la recherche S19 NOT S24 directement. C'est pourquoi cette étape intermédaire a été ajoutée 387 / 392

91

# PsychInfo Results

1 exp polypharmacy/ or exp drug therapy/ or exp "prescribing (drugs)"/ 6,392

2 deprescribing.af. 47

3 beer's criteria.ti. 0

4 beer's criteria.id. 3

5 beer's criteria.af. 141

6 beer's list.af. 0

7 2 or 3 or 4 or 5 or 6 173

8 (deprescrib* or deprescrip* or stopp).af. 104

9 "POTENTIALLY INAPPROPRIATE".af,ti. 268

10 7 or 8 or 9 313

11 DRUG WITHDRAWAL/ 179

12 exp Treatment withholding/ 21

13 (withdraw* or withhold or withheld or cease or ceased or cessation or discontinu* or taper or tapered or tapering).ti,ab,id.

6,248

14 (medication* or prescrib* or prescription* or polypharmacy or inappropriate or "drug evaluation").ti,ab,id.

11,647

15 exp drugs/ 16,487

16 DRUG THERAPY.mp. or Drug Therapy/ 5,773

17 exp drug dosages/ 485

18 ("drug evaluation" or "pharmaceutical preparations").ti,ab,id. 11

19 1 or 14 or 15 or 16 or 17 or 18 26,835

20 11 or 12 or 13 6,273

21 19 and 20 2,092

22 ((medication* or prescrib* or prescription* or polypharmacy or inappropriate) adj3 (reduce or reduced or reducing or stop or stopped or stopping)).ti,ab,id.

265

23 21 or 22 2,322

24 exp geriatrics/ or exp gerontology/ 1,866

92

25 nursing homes.mp. or exp Nursing Homes/ or exp residential care institutions/ 2,483

26 exp aging/ 5,975

27 (older or eldest or elder* or senior* or frail* or "old age home*" or "homes for the aged" or "home for the aged" or "nursing home*" or "old age home*" or "homes for the aged" or "home for the aged" or "nursing home*" or geriatric* or geriatry or aging or veteran*).ti,ab,id.

26,156

28 24 or 25 or 26 or 27 28,072

29 (trial or trials or pilot or prospective or follow-up or cohort or bias).ti,ab,id. 50,030

30 exp "quality of care"/ 1,056

31 exp health care services/ 9,995

32 exp "Quality of Care"/ 1,056

33 "epidemiologic* method*".ti,ab,id. 20

34 "epidemiologic* method*".ti,ab,id. 20

35 *"Epidemiology"/ 2,115

36 epidemiology.mp. or exp EPIDEMIOLOGY/ 3,885

37 29 or 30 or 31 or 32 or 35 or 36 61,539

38 23 and 28 and 37 85

39 10 or 38 387

40 SMOKING CESSATION/ or ALCOHOL WITHDRAWAL/ or NICOTINE WITHDRAWAL/ 1,076

41 (smoker* or cigarette* or smoking).ti. 2,274

42 (alcohol adj3 (withdrawal or consumption)).ti. 515

43 40 or 41 or 42 3,040

44 39 not 43 372

la limite de langue n'a pas été appliquée pcq certaines références n'affichent pas cette information

45 44

93

# CINAHL Results

S1 (MH "Drug Therapy+") 15,060

S2 MW "Drug Therapy" 39,691

S3 MW "administration and dosage" 24,168

S4 (MH "Drugs+") 8,742

S5 (MH "Polypharmacy") 597

S6 (MH "Inappropriate Prescribing") 626

S7 (MH "Drug Evaluation+") 849

S8 (MH "Medication Errors+") 1,453

S9

TI ( medication* or prescrib* or prescription* or polypharmacy or inappropriate or "drug evaluation" ) OR AB ( medication* or prescrib* or prescription* or polypharmacy or inappropriate or "drug evaluation" ) OR SU ( medication* or prescrib* or prescription* or polypharmacy or inappropriate or "drug evaluation" )

35,298

S10 (S1 OR S2 OR S3 OR S4 OR S5 OR S6 OR S7 OR S8 OR S9) 85,871

S11 (MH "Euthanasia, Passive") 229

S12 (MH "Substance Withdrawal Syndrome") 282

S13

TI ( withdraw* or withhold or withheld or cease or ceased or cessation or discontinu* or taper or tapered or tapering ) OR AB ( withdraw* or withhold or withheld or cease or ceased or cessation or discontinu* or taper or tapered or tapering ) OR SU ( withdraw* or withhold or withheld or cease or ceased or cessation or discontinu* or taper or tapered or tapering )

11,242

S14 S11 OR S12 OR S13 11,331

S15 S10 AND S14 3,880

S16

TI ( ((medication* or prescrib* or prescription* or polypharmacy or inappropriate) N3 (reduce or reduced or reducing or stop or stopped or stopping)) ) OR AB ( ((medication* or prescrib* or prescription* or polypharmacy or inappropriate) N3 (reduce or reduced or reducing or stop or stopped or stopping)) ) OR SU ( ((medication* or prescrib* or prescription* or polypharmacy or inappropriate) N3 (reduce or reduced or reducing or stop or stopped or stopping)) )

1,068

S17 S16 OR S15 4,858

S18 (MH "Aged+") 67,442

94

S19 (MH "Nursing Homes+") 1,956

S20 (MH "Nursing Home Patients") 1,091

S21 (MH "Geriatrics") 527

S22 (MH "Aging+") 4,408

S23 (MH "Veterans+") 1,894

S24

TI ( (older or eldest or elder* or senior* or frail* or "old age home*" or "homes for the aged" or "home for the aged" or "nursing home*" or "old age home*" or "homes for the aged" or "home for the aged" or "nursing home*" or geriatric* or geriatry or aging or veteran*) ) OR AB ( (older or eldest or elder* or senior* or frail* or "old age home*" or "homes for the aged" or "home for the aged" or "nursing home*" or "old age home*" or "homes for the aged" or "home for the aged" or "nursing home*" or geriatric* or geriatry or aging or veteran*) ) OR SU ( (older or eldest or elder* or senior* or frail* or "old age home*" or "homes for the aged" or "home for the aged" or "nursing home*" or "old age home*" or "homes for the aged" or "home for the aged" or "nursing home*" or geriatric* or geriatry or aging or veteran*) )

49,290

S25 (S18 OR S19 OR S20 OR S21 OR S22 OR S23 OR S24) 97,175

S26 (MH "Research Concepts and Principles+") 43,886

S27 (MH "Epidemiological Research+") 1,074

S28 (MH "Epidemiology+") 67,700

S29 (MH "Quality of Health Care") 6,865

S30 (MH "Research+") 264,717

S31 TI ( trial or trials or pilot or prospective or follow-up or cohort or bias ) OR AB ( trial or trials or pilot or prospective or follow-up or cohort or bias ) OR SU ( trial or trials or pilot or prospective or follow-up or cohort or bias )

139,883

S32 S26 OR S27 OR S28 OR S29 OR S30 OR S31 324,368

S33

TI ( deprescrib* or deprescrip* or "beer's criteria" or "beers criteria" or "beer's list" or "beers list" or stopp ) OR AB ( deprescrib* or deprescrip* or "beer's criteria" or "beers criteria" or "beer's list" or "beers list" or stopp ) OR SU ( deprescrib* or deprescrip* or "beer's criteria" or "beers criteria" or "beer's list" or "beers list" or stopp )

268

S34 (MH "Alcohol-Related Disorders+") 3,436

S35 (MH "Smoking Cessation") 1,252

95

S36 TI alcohol N3 (withdrawal or consumption) 590

S37 TI smoker* OR TI cigarette* OR TI smoking 3,717

S38 S34 OR S35 OR S36 OR S37 7,985

S39 (S17 AND S25 AND S32) 1,084

S40 S33 OR S39 1,300

*S41 S38 AND S40 60

S42 S40 NOT S41 1,240

S43

S40 NOT S41 Narrow by Language: - english Narrow by Language: - french Narrow by Language: - german

S43

*S41 la banque CINAHL ne permettait pas de faire la recherche S40 NOT S38 directement. C'est pourquoi cette étape intermédiaire a été ajoutée

*S41

S43

S40 NOT S41 Narrow by Language: - english Narrow by Language: - french Narrow by Language: - german

S43

*S41 la banque CINAHL ne permettait pas de faire la recherche S40 NOT S38 directement. C'est pourquoi cette étape intermédiaire a été ajoutée

*S41

96

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