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GHENT UNIVERSITY

FACULTY OF PHARMACEUTICAL SCIENCES

ACADEMIC YEAR 2016 - 2017

DEPRESCRIBING OF PSYCHOTROPIC IN PATIENTS ADMITTED TO ORTHOGERIATRIC AND GERIATRIC WARDS

Saïn VANDEPOELE

INTERUNIVERSITY PROGRAMME: MASTER OF SCIENCE IN HOSPITAL PHARMACY

SUPERVISOR

KATY VERHELLE, PharmD

ANNE VERHAEGHE, PharmD

ACADEMIC PROMOTER

PROF. ANNEMIE SOMERS, PharmD, PhD

GHENT UNIVERSITY

FACULTY OF PHARMACEUTICAL SCIENCES

ACADEMIC YEAR 2016 - 2017

DEPRESCRIBING OF PSYCHOTROPIC DRUGS IN PATIENTS ADMITTED TO ORTHOGERIATRIC AND GERIATRIC WARDS

Saïn VANDEPOELE

INTERUNIVERSITY PROGRAMME: MASTER OF SCIENCE IN HOSPITAL PHARMACY

SUPERVISOR

KATY VERHELLE, PharmD

ANNE VERHAEGHE, PharmD

ACADEMIC PROMOTER

PROF. ANNEMIE SOMERS, PharmD, PhD

WORDS OF THANKS ______

Without the support and contribution of many people, this work would not have become what it is today. Therefore I would like to take the opportunity to thank some people for their help and inspiration.

First of all, I am very grateful to Katy, head of pharmacy, and the rest of the hospital pharmacy team for the fascinating internship in the ‘Groeninge’ hospital in which I got excellent guidance and was offered exciting opportunities.

In particular, I would like to thank my internal supervisor Anne for her enthusiastic guidance in which she taught a lot of clinical pharmacy knowledge.

I also want to thank Annemie Somers for the follow-up of my research and the detailed and extensive readings of my study despite her many other work.

I would like to thank my closest colleague Eva who accompanied me during the whole internship, for sharing the moments of happiness and frustration, for her support and help.

A special word of thanks to Tom who always believed in me, who helped me with reasoning questions or layout issues and who gave me advice when I was stuck.

Thanks to my parents and sisters for giving me the opportunity to graduate as a hospital pharmacist and to support this choice in all areas.

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Deze pagina is niet beschikbaar omdat ze persoonsgegevens bevat. Universiteitsbibliotheek Gent, 2021.

This page is not available because it contains personal information. Ghent University, Library, 2021.

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SUMMARY ______

Elderly have a great potential to benefit from their , but are also more vulnerable to adverse reactions. Especially the use of psychotropic can increase the risk on confusion, falls and cognitive impairment. Age related changing pharmacokinetics, polypharmacy and presence of multiple comorbidities, noncompliance and reduced capabilities for safe and appropriate handling of drugs are risk factors for drug related problems with adverse outcomes. Deprescribing may be one way to reduce the number of medicines, to improve appropriate prescriptions and to avoid adverse drug reactions. Deprescribing is the act of tapering, reducing or stopping medication supervised by a health care professional with the goal to improve outcomes. In this study, one of the main objectives was to determine the prevalence of potentially inappropriate prescriptions in a geriatric population. In addition, the acceptation rates of the recommendations, suggested by the pharmacist, were determined and the added value of multidisciplinary communication with healthcare providers was investigated. Patients, aged over 75 with a minimum intake of 5 drugs, were screened at the geriatric and orthogeriatric ward of the ‘Groeninge’ Hospital in Kortrijk for inclusion in this deprescribing study. Different tools are available to support health professionals for deprescribing, including implicit and explicit tools. In this research inappropriate prescriptions were identified by using chapter ‘D’ of the STOPP criteria. In addition, standardized tapering schemes were introduced and applied in practice. These schemes could be adapted according to the needs of the patient. Patients, eligible for a withdrawal scheme, were approached by the clinical pharmacist in training. They were informed about the potential risks and long-term side effects. Afterwards their willingness to reduce psychotropic drugs was questioned. Also geriatricians and general practitioners were involved. Their shared-decision determined if a recommendation could be implemented for a patient. Deprescribing is a process that needs a close follow-up and careful data collection. In this study, a follow-up call after discharge was conducted by the clinical pharmacist to detect problems with withdrawal schemes. In this study, 398 of the 470 screened patients were included. At least one intervention was suggested by the clinical pharmacist in 89.7% of the included patients. The overall acceptation rate of the geriatricians was 80.4%. After counseling by the pharmacist, still 20.9% patients were unwilling to discontinue their psychotropic drugs. Deprescribing was refused because of fear for return of their disease or fear for withdrawal effects. In this study, 145 general practitioners and 104 community pharmacists were contacted to give their approval on the tapering schedule and follow-up. After discharge, 59 patients were called by the pharmacist to detect possible problems with withdrawal schedules. These schedules were interrupted by 31.1% of this patients. Lack of motivation of the patient and insufficient follow-up by the first line caregivers were the main reasons for discontinuation. There is growing evidence that indicates that deprescribing for older people is safe and feasible. Deprescribing can improve optimal and appropriate medication use for elderly patients. However, a frequent medication review should be conducted in the older patient to detect inappropriate prescriptions and to maintain the motivation of the patients. In addition, multidisciplinary cooperation between all healthcare providers is necessary for seamless pharmaceutical care and a proper follow-up after discharge.

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SAMENVATTING ______

Ouderen hebben een groot potentieel om positieve effecten van hun medicijnen te ervaren, maar zijn ook kwetsbaarder voor bijwerkingen. Vooral het gebruik van psychofarmaca kan het risico op verwardheid, valincidenten en cognitieve achteruitgang verhogen. Risicofactoren voor deze slechte gevolgen zijn onder andere leeftijdsgerelateerde veranderingen in de farmacokinetiek, polyfarmacie, de aanwezigheid van comorbiditeiten, therapieontrouw en verminderde vaardigheden om medicatie correct in te nemen. Deprescribing kan het aantal geneesmiddelen doen dalen, het geschikt voorschrijven verbeteren en bijwerkingen voorkomen. Deprescribing is een proces van afbouwen, verminderen of stoppen van geneesmiddelen onder toezicht van een zorgverlener met als doel de eindpunten te verbeteren. In deze studie was een van de hoofddoelstellingen om de prevalentie van potentieel ongeschikt voorschrijven in een geriatrische populatie te bepalen. Daarnaast werd het aanvaardingspercentage van de aanbevelingen, voorgesteld door de apotheker, nagegaan en werd de meerwaarde van de transmurale communicatie met zorgverleners onderzocht. Patiënten ouder dan 75 jaar die minstens 5 geneesmiddelen innamen werden gescreend op geriatrie en orthogeriatrie in AZ Groeninge in Kortrijk voor inclusie in deze afbouwstudie. Verschillende ‘deprescribing’ hulpmiddelen zijn beschikbaar om gezondheidsverstrekkers te helpen, inclusief impliciete en expliciete hulpmiddelen. In dit onderzoek werden ongeschikte voorschriften geïdentificeerd aan de hand van hoofdstuk D van de STOPP criteria. Daarnaast werden standaard afbouwschema's toegepast in de praktijk. Deze schema's kunnen aangepast worden naargelang de noden van de patiënt. Patiënten die in aanmerking komen voor een afbouwschema werden benaderd door de klinisch apotheker in opleiding. Ze werden geïnformeerd over de potentiële risico's en langdurige bijwerkingen en hun bereidheid tot afbouw van psychofarmaca werd bevraagd. Ook de geriaters en huisartsen waren betrokken en hun gezamenlijke beslissing bepaalde of het advies van de apotheker werd opgevolgd. Deprescribing is een proces dat een nauwgezette follow-up en gegevensverzameling vereist. In deze masterproef werd de patiënt opgebeld na ontslag door de klinisch apotheker om mogelijke problemen rond afbouwschema’s op te sporen. In totaal werden 398 van de 470 gescreende patiënten in deze studie geïncludeerd. Bij 89,7% van de geïncludeerde patiënten werd minstens één interventie voorgesteld door de klinisch apotheker. Hiervan werden 80,4% adviezen aanvaard door de geriaters. Toch waren 20,9% van de patiënten niet bereid om hun psychofarmaca af te bouwen na advies door de apotheker. Afbouw werd geweigerd uit angst voor het terugkeren van de aandoening of uit angst voor ontwenningsverschijnselen. In deze studie werden 145 huisartsen en 104 officina- apothekers gecontacteerd met de vraag of ze akkoord gingen met het afbouwschema en of ze wilden instaan voor verdere opvolging. Na ontslag werden 59 patiënten gecontacteerd door de klinisch apotheker om problemen met afbouwschema’s op te sporen. De afbouwschema's werden onderbroken bij 31,1% van de patiënten. Gebrek aan motivatie van de patiënt en onvoldoende follow-up door zorgverstrekkers uit 1e lijn waren redenen voor stopzetting. Er is steeds meer evidentie dat ‘deprescribing’ in de oudere populatie veilig en haalbaar is. ‘Deprescribing’ kan het optimaal en geschikt geneesmiddelengebruik verbeteren. Toch is een nazicht van het medicatieschema op regelmatige basis nodig om ongeschikt voorschrijven te detecteren en de motivatie van de patiënten te behouden. Daarnaast is multidisciplinaire samenwerking tussen alle

VII zorgverleners noodzakelijk voor een duidelijke overdracht van informatie en een goede follow-up na ontslag.

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ABBREVIATIONS ______

ACE Angiotensin Converting

ADME Absorption Distribution Metabolisation Excretion

ADR Adverse Drug Reaction

ACB Anticholinergic Cognitive Burden

ARS Anticholinergic Risk Scale

ATC Anatomical Therapeutic Chemical Classification System

BCFI Belgisch Centrum voor Farmacotherapeutische Informatie

BDZ

CHF Congestive Heart Failure

COPD Chronic Obstructive Pulmonary Disease

CP Community Pharmacist

DDD Defined Daily Dose

DRP Drug Related Problem

EHR Electronic Health Record

EMR Electronic Medical Record

EPR Electronic Patient Record

Etc. Et Cetera

FOD Federale OverheidsDienst (in Belgium)

FPS Federal Public Service

GFR Glomerular Filtration Rate

GP General Practitioner

HARM Hospital Admissions Related to Medication

i.e. id est

INCB International Narcotics Control Board

LOS Length Of Stay

MAI Medication Appropriateness Index

MMSE Mini Mental State Examination

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NHG Nederlandse HuisartsenGenootschap

NIHDI National Institute for Health and Disability Insurance

PIP Potentially Inappropriate Prescribing

PPI Proton Pomp Inhibitor

RCT Randomized Controlled Trial

SD Standard Deviation

START Screening Tool to Alert doctors to the Right Treatment

STOPP Screening Tool of Older Person’s Prescriptions

SIMPATHY Stimulating Innovation Management of Polypharmacy and Adherence in the Elderly SPC Summary of Product Characteristics

SSRI Serotonin Receptor Antagonist

STRIP Systematic Tool to Reduce Inappropriate Prescribing

TCA

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TABLE OF CONTENTS ______

1. INTRODUCTION ...... 1 1.1. Identification of drug related problems (DRP) in the elderly ...... 1 1.2. Deprescribing, a must ? ...... 2 1.3. Medication review ...... 4 1.3.1. Medication reconciliation ...... 4 1.3.2. Identify potentially inappropriate prescribing (PIP) ...... 4 1.4. A step-wise approach to deprescribing ...... 8 1.4.1. Discontinuing medication ...... 8 1.4.2. Monitoring and follow-up ...... 10 1.5. Which drugs to taper? ...... 10 1.6. A clinical pharmacist in geriatrics, an added value? ...... 12 1.7. Barriers to routine deprescribing ...... 13 2. OBJECTIVES ...... 15 3. METHODS ...... 17 3.1. General study description ...... 17 3.2. Workflow ...... 17 3.3. Deprescribing protocol ...... 19 3.3.1. equivalents ...... 19 3.3.2. Deprescribing of hypnosedatives ...... 21 3.3.3. Deprescribing of and ...... 22 3.4. Data collection ...... 23 3.5. Data analysis ...... 23 4. RESULTS ...... 27 4.1. Study group ...... 27 4.2. Patient characteristics ...... 28 4.3. Drug use at admission ...... 28 4.3.1. Number of drugs ...... 28 4.3.2. Use of (psychotropic) drugs ...... 29 4.3.3. Types of drugs ...... 31 4.3.4. Prevalence of PIPs according to STOPP D ...... 32 4.4. Drug use at discharge ...... 34 4.4.1. Number of drugs ...... 34

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4.4.2. Types of drugs ...... 34 4.5. Deprescribing ...... 37 4.6. Follow-up ...... 38 5. DISCUSSION ...... 39 5.1. Drug use...... 39 5.1.1. Number of drugs ...... 39 5.1.2. Use of (psychotropic) drugs ...... 39 5.1.3. Types of drugs ...... 42 5.1.4. Prevalence of PIPs according to STOPP D ...... 44 5.2. Deprescribing ...... 45 5.3. Follow-up ...... 46 5.4. Strengths and limitations of the project and future perspectives ...... 47 6. CONCLUSION ...... 49 7. REFERENCES ...... 51 8. APPENDICES ...... 57 8.1. FARMAKA – REVISED STOPP CRITERIA 2016 ...... 57 8.2. ANTICHOLINERGIC COGNITIVE BURDEN SCORE...... 66 8.3. BENZODIAZEPINE AND Z-DRUG DEPRESCRIBING ALGORITHM ...... 67 8.4. ETHICS COMMITTEE APROVAL ...... 69 8.5. TEMPLATE INFORMED CONSENT ...... 71 8.6. POSTER OF THE ‘DEPRESCRIBING PROJECT’ ...... 72 8.7. PHARMACEUTICAL REPORT ...... 73 8.8. LETTER ...... 75 8.9. EQUIVALENCE TABLE OF DIAZEPAM ...... 76 8.10. STOPP – CRITERIA REVISED DUTCH VERSION (2015) ...... 77

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1. INTRODUCTION ______

1.1. Identification of drug related problems (DRP) in the elderly

Increasing age is associated with a higher incidence of adverse drug reactions (ADR) and a higher prevalence of polypharmacy. Elderly are more sensitive to the development of drug related problems which is based on several contributing factors.

A first factor is the age-related changing pharmacokinetics which comprises four steps i.e. absorption, distribution, and excretion (ADME). These changes may have an impact on drug concentration and therefore on drug activity. Concerning the absorption, the intestinal motility and gastric emptying can be delayed in older patients (1), in comparison with the younger healthy population (2). Assuming that elderly take several drugs, effects of coprescribed drugs should be taken into consideration (1). The absorption of iron decreases in the absence of acidic environment, for example as a result of PPI-use. The second step of ADME is distribution. An increased body fat and decreased total body water have a significant impact on the drug distribution. This changed body composition provides a larger distribution of fat-soluble drugs (such as (BDZ)) resulting in a prolonged drug effect and an increased risk of accumulation. On the other hand, drug concentration of water-soluble drugs (such as digoxin, theofyllin) increases. (2; 1). A dose reduction may be required when these medicines are prescribed for elderly. Also the protein binding has an effect on the distribution. However lower protein levels are usually due to poor nutrition status and chronic illness, rather than increasing age. A clinical significant change in distribution due to this protein binding is only shown in strongly bound drugs such as warfarin, phenytoin for which the drug concentration can be increased. In the third step, the impact of aging on metabolism is mainly on phase 1 reactions or the first pass metabolism due to decreased hepatic flow and reduced mass. For example, an increased bioavailability is seen with drugs such as ACE inhibitors or that are strongly subjected to first- pass metabolism. The last step of ADME is excretion. Renal function and mainly the glomerular filtration rate (GFR) decreases with age. As a result, there is a reduced clearance of drugs that are primarily excreted by the kidney, such as digoxin, , penicillin (3).

A second contributing factor for drug related problems in elderly patients is the high incidence of comorbidities and the related high drug use. 84% of the patients older than 65 years have 2 or more chronic conditions as compared to 35% of the patients between 45 and 65 years. The most common comorbidities are hypertension, Chronic Obstructive Pulmonary Disease (COPD), mellitus, heart failure, electrolyte disorders, and iron deficiency. Each comorbidity is associated with certain medications which increases the total number of drugs, but also the number of different prescribers (4).

1 | INTRODUCTION

The third factor is the absence of geriatric patients in randomized controlled trials (RCTs) that can contribute to inappropriate prescribing. Due to this underrepresentation there is lacking evidence about the efficacy, safety and doses of several drugs. Involving this population in RCTs is challenging since they are often excluded because of age, concomitant medications and co-morbidities. In addition, the screening takes a lot of time and the risk of drop-outs is high. The number of RCTs of drugs, that are taken frequently by older people, can lead to an increase if more incentives are taken (5).

A fourth important factor that affects the elderly is the compliance, which is poor and can be a potential source of adverse drug reactions and therapeutic failure. Examples of nonadherence in geriatric patients could be overuse, abuse, forgetting, alteration of schedules and doses after a consultation, change in care or discharge from the hospital (6; 3). The underlying factors of nonadherence could be a decreasing mental score and a reduced vision. According to Hughes et al. polypharmacy is the most contributing factor which is proved by the risk of errors that increased a 15-fold when the number of drugs was raised from one to four (1).

1.2. Deprescribing, a must ?

Polypharmacy can be defined as the regular consumption of 5 or more drugs. Excessive polypharmacy is the regular consumption of 10 drugs or more. In a prospective, observational population-based cohort of Belgian community-dwelling patients, it was found that 57,7% was exposed to polypharmacy and even 9,1% to excessive polypharmacy (7). In a study of Wastesson et al., it can be expected that individuals at the age of 65 years spent 8 of the 20 remaining years with polypharmacy. In addition, the question can be asked why patients are given a therapy in which the time required to experience the positive benefits is longer than the life expectancy (8). For patients with a low life expectancy a conservative therapy is justified and medication reduction may be appropriate (9).

Polypharmacy can give rise to adverse drug reactions (ADR), drug-interactions, lower adherence to drug regimens, a higher risk of falls, cognitive impairment, hospital admissions and a higher healthcare cost. These effects are described in detail below.

The first effect is that approximately 30% of community-dwelling older patients taking more than five medications perceived an ADR such as immobility, hypotension, fall accidents, delirium. The risk of an ADR is 38% when taking four drugs and even 82% when taking 7 drugs or more (10). 25% of the adverse drug reactions is estimated preventable (11).

A second result of polypharmacy is that 40% of the patients fail to comply with their treatment often due to misunderstanding, forgetting, incorrectly performing or ignoring the doctor’s recommendation. Depression, a low level of education, lack of confidence in the treating physician and a poor attitude of the patient contributes to lower adherence. There is no single strategy to improve the compliance in every patient. It is the art of the physician and pharmacist to empathize with the situation of the patient so that the patients adherence can be guided in the right direction (12; 13).

2 | INTRODUCTION

A third observation related to polypharmacy are fall incidents. One third of the community-dwelling patients older than 65 years fall at least once a year. The incidence for nursing home patients is even higher and can approach 50%. The most important causes are poor visibility, depression, impaired cognition, aging and syncope but none of these risk factors is as potentially avoidable as medication use (14; 15). Leipzig et al. demonstrated a positive correlation between the use of psychotropic and cardiac drugs and the risk of falling. In patients on psychotropic medication the incidence of fall accidents within 6 months is 58% (15). Counseling of patients by exercising skills and behavior and monitoring medications have found to reduce the risk of fall accidents. For example the withdrawal of psychotropic medications such as benzodiazepines, antidepressants, and neuroleptics can decrease the fall risk in 66% of the cases. However almost half of the intervention group restarted these psychotropic medications within the month (14).

Another consequence of polypharmacy is associated with a decline in cognitive ability. A cognitive impairment was found in 22% of the patients taking 5 drugs, in 33% of the patients taking 6 to 9 medications and even 54% of the patients taking 10 or more (13). Drug classes such as benzodiazepines, opioids and anticholinergics can contribute to the deterioration in cognitive function (16).

The last discussed effect due to polymedication is the higher risk on hospitalization. These admissions can be due to drug related problems (DRPs) or called drug related hospitalized admission (DRHA). In a study of Somers et al., in which the contribution of DRPs to hospital admissions in the elderly is investigated, a distinction is made between adverse drug reactions (ADRs) and drug therapy failure (DTFs). An ADR is defined according to WHO as “a response to a drug that is noxious and unintended and occurs at doses normally used in man for the prophylaxis, diagnosis or therapy of disease, or for modification of physiological function”. An example of an ADR due to unintentional Absence of therapeutic effect due to non-compliance, underdosing or drug-drug interactions is described as drug therapy failure. In this latter study, 23 of 110 patients (or 20.9%) were admitted due to a drug-related problem, in which 14 patients due to an ADR and 9 patients due to DTF. In the literature, the link between DRP and hospitalization is proved by percentages between 4 and 30%. Of these hospitalizations, 50 to 97% was estimated avoidable (17). As a result of these unnecessary hospitalizations and prescribed inappropriate medications the healthcare cost increases. For example in Ireland 9 % of the overall expenses on pharmaceuticals in people older than 70 was related to polypharmacy. In the Netherlands, the cost of hospitalizations due to ADE was 355 million in 2009. It is obvious that polypharmacy increases burden to health economies. Therefore appropriate prescribing should be stimulated by using different tools (3).

Efforts should be done to avoid this negative health outcomes associated with polypharmacy. Deprescribing, the act of tapering, reducing or stopping medications, can be one way to improve the use of medicines in geriatric patients (18; 19). Stopping of some classes of medications such as , antihypertensives and psychotropic medication in older patients has proven to be feasible and does not worsen clinical outcomes such as withdrawal symptoms (20). Moreover, the 12 month mortality has improved and the long-term adverse consequences are reduced (11).

3 | INTRODUCTION

It has been suggested to step out of the traditional quantitative-based polypharmacy, in which the number of drugs being taken into account, but to evolve from inappropriate polypharmacy (inappropriate prescribing) to qualitative-based polypharmacy (appropriate prescribing) (21). Several guidelines to help practitioners with drug deprescribing are discussed further.

1.3. Medication review

1.3.1. Medication reconciliation

We should be able to rely on an accurate and complete patients medication schedule prior to optimize medication use. An extensive medication reconciliation should be performed by a clinical pharmacist or a pharmacist assistant for each older hospitalized patient. The goal of medication reconciliation is to identify an accurate list of all medications that the patient is taking, including name, dosage, frequency, and route, by comparing the medical record to an external list of medications obtained from a patient, hospital, or other provider (22; 10).

In more than half of the elderly admitted to hospital, medication discrepancies are found between the patient’s usual drug therapy and the therapy known in the hospital (23). It is suggested that bringing the medication physically to the hospital gives the best result for the reconciliation (‘brown paper bag’ medication reconciliation) (11).

1.3.2. Identify potentially inappropriate prescribing (PIP)

High drug use frequently leads to prescription of inappropriate drugs. Potentially inappropriate prescribing (PIP) is defined as the use of medicines whose harmful outcomes may outweigh the benefits and contributes to a higher morbidity and mortality (24). S. Cullinan et al. reported a PIP incidence of 20 to 40% in primary care (including GPs, community pharmacists, home care nurses, ..) and 33 to 58% in the 2nd line (i.e. general hospitals). There is an awareness among doctors about the problematic PIPs, however changing the patients prescription is feared because of insufficient geriatric knowledge, a lack of time for medication surveillance or due to a high workload (25). PIPs can be defined by using an indicator, such as a frailty index (25), the STOPP/START or the Beers criteria (24). A positive relationship between the frailty status and the appropriateness of the patient’s medications and the development of ADRs has been shown. By using these indicators health care providers gain insight into the problematic PIPs and can be motivated to review patients medications. Also factors as life expectancy, care goals and comorbidities should be taken into consideration (25). Several tools have been developed to detect inappropriate prescribing. PIP can be classified as underprescribing, misprescribing and overprescribing. Underprescribing is the omission of an indicated drug to treat a specific disease. In 22% of community-dwelling older adults and in 58 to 66% of hospitalized older patients underprescribing, based on the START-criteria, was detected (26). An unfavorable choice of medicine (for example a contra-indication), dose, or duration is called misprescribing. Overprescribing is the presence of a drug which is not indicated for a particular treatment or in the absence of a medical reason. In 21–36% of community-dwelling older adults and in 35–77% of hospitalized older patients inappropriate prescribing, based on the STOPP-criteria, was identified (26).

4 | INTRODUCTION

The appropriateness of prescriptions can be assessed by computerized digital tools or by a patient centred approach. The criteria of these patient centered tools can be based on clinical judgment , also called the implicit criteria or based on standardized guidelines, also known as the explicit criteria (27; 10).

 Computer assisted digital tools

Several hospitals already implemented an Electronic Patient Record (EPR) with computerized decision support. This supportive tools are interaction checkers which can generate alerts for certain drug combinations. There is sufficient evidence that this tool decreases the number of prescribing errors and inappropriate prescriptions with a significant effect on the intermediate endpoints. However, limited information is available on improvements in primary outcomes such as mortality, morbidity, functional and cognitive status and costs. Besides, these computer programs do not reveal every possible drug interaction and take no account of the age related illnesses or complications and other patient-related characteristics (3). Also a lot of inaccurate or unimportant issues are mentioned which leads to frustration and so called ‘alert fatigue’ (ignoring the alerts without reading them carefully) (28).

 Implicit criteria

Implicit criteria focus on all aspects of the patient, including the EPR and the clinical circumstances, rather than drugs or diseases. One of the methods is the Medication Appropriateness Index (MAI) where each prescribed drug is assessed using ten different criteria. Each of the elements including indication, effectiveness, appropriate dosing, contraindications, side-effects, drug-drug interactions, drug-disease interactions, correct directions, lack of duplication, duration and cost is accompanied with a certain weight (a number between 1 and 3). By using the patients antecedents and medication list, a score can be assigned which is multiplied by the weight of this criterion. The higher the score, the less appropriate the prescribed drug. These methods are time consuming, only reliable when the evaluator has substantial clinical knowledge and are not detecting underuse. Although the sensitivity is high, this tool is not frequently used in various settings (10; 3).

 Explicit criteria

Explicit criteria on the other hand are evidence-based, reliable and require little clinical expertise. These tools are more regularly used to detect inappropriate prescribing but also have some disadvantages. The Beers list, the STOPP/START-criteria and the drug burden index are discussed below.

The Beers list is an example of a ‘drugs to avoid’-list and was originally developed in 1991 for use in nursing home residents. This list has been revised 4 times already in 1997, 2003, 2012 and 2015 and can be applied for all patients over 65 years now. The last update added two key areas : drug-drug reactions and drugs in which dosage adjustment is necessary in case of renal insufficiency, but also a summary of drugs with strong anticholinergic properties is included.

5 | INTRODUCTION

The drugs contained in the list are divided into 3 groups: drugs which must always be avoided, drugs that must be avoided in certain diseases and drugs that should be used with caution. However, the application of the Beers list did not reduce the number of hospitalizations, costs, morbidity and mortality (3). In addition, often a drug is indicated as inappropriate while this is less important compared to other inappropriate prescribing such as drug-drug interactions, under- or overuse. Also the evidence grade may be low and the drug related problems may be underestimated since the elderly are underrepresented in studies. The list may be attractive because it is easy to use, is not time-consuming and requires little individualization (29; 30).

The second discussed explicit approach are the STOPP/START (Screening Tool of Older Persons’ Prescriptions/Screening Tool to Alert doctors to Right Treatment) criteria which were developed in 2008 by Gallagher et al. to exceed the limitations of the Beers list. Comparative studies of the STOPP/START criteria and the Beers list described the STOPP/START criteria as more accurate and more sensitive, and drugs listed in the STOPP criteria are more strongly associated with adverse events (31; 3). It has been suggested that screening of the PIP using the STOPP-START criteria should be repeated every six months or systematically during each consultation since a gradual increase in PIP has been observed after this period if not re-evaluated (26).

The aimed objectives of the START/STOPP-criteria are to improve medication appropriateness, to reduce drug costs and to avoid adverse drug reactions (31). The different criteria are classified according to the physiological system and for each STOPP criteria is argued why the drug is considered unsuitable. In 2014 the criteria have been updated by expanding the Delphi panel of United Kingdom and Ireland with experts (i.e. geriatricians, psychiatrists, clinical pharmacologists, hospital pharmacists and primary care physicians) from 12 other European countries. In total, 80 STOPP and 34 START-criteria were defined, an increase of 31% compared to the first version. In 2012 a translation of the STOPP/START criteria, adapted to the Dutch situation, was published to simplify the application in practice .The translated version excluded medicines which are not registered in the Netherlands, used Dutch guidelines (such as the ‘Nederlandse Huisartsen Genootschap’ (NHG) standards) and added or omitted some criteria. The reviewed Dutch version includes 72 STOPP criteria, 8 less compared to the international criteria and 36 START criteria. Although the excluded medicines from the international guidelines are also in Belgium not available, it is not possible to simply apply the Dutch guideline in Belgium. For example, some drugs that were listed in the adapted Dutch guideline, are not on the Belgian market, e.g. carbasalate, oxprenolol, , , etc. (28).

Farmaka, a Belgian organization that focuses on evidence-based medicine and responsible drug use, has also analyzed the STOPP criteria and compared these with the reference ‘Formularium ouderenzorg’. This reference, prepared by Farmaka, gives guidance to all providers in the prescription of drugs to elderly patients and was drafted by general practitioners and pharmacists (see Appendix 8.1).

6 | INTRODUCTION

Farmaka has commented on each criterion of the STOPP criteria using the literature, Belgian guidelines and summaries of product characteristics (SPC). Finally, Farmaka assessed whether the criterion was consistent with good medical practice or should be revised. For example, in Section D, the criterion ‘Neuroleptics used as hypnotics, unless the sleep disorder is due to psychosis or : risk of confusion, hypotension, extrapyramidal adverse effects of falls’ was reviewed by Farmaka. It was concluded that this criterion was invalid and incomplete. Since this indication was not included into guidelines, it was considered that the use of a neuroleptic for sleep- inducing treatment is an off-label use. The focus of this research was on the section D (central and psychotropic drugs) and a part of section F () of the STOPP-criteria.

Another major challenge is to identify the PIPs retrospectively using health administrative data (HAD) to improve quality of prescribing. These data are collected in a standardized way so that computer programs could be developed to assess the criteria appropriateness. It is assumed that data-health administrative-tools will underestimate the prevalence of PIP in a population due to the incomplete clinical information necessary for the determination of the appropriateness. However, no studies of the most promising HAD-based tools are performed yet (26). Also, in a Belgian national report using the NIHDI (National Institute for Health and Disability Insurance) data from 2013 on the Belgian geriatric wards, it appeared that results were underrated (32).

Another discussed explicit criterion is the drug burden index. A lot of drugs listed in explicit lists are anticholinergic and and are individually identified in other tools. The cumulative effect of several anticholinergics is called anticholinergic burden and can be calculated using an anticholinergic risk scale. There are several risk scales to calculate anticholinergic burden. The Anticholinergic Cognitive Burden (ACB) scale by Boustani et al. (see Appendix 8.2) is one of the most frequently used and validated scale on adverse outcomes. Anticholinergics have been correlated with a decline in cognition, a higher risk of fall accidents and mortality. However, these risk scales tend to simplify the complex pharmacological mechanisms and take no account of dose dependency, possible development of tolerances and the eventual synergistic or antagonistic properties of the drugs (33).

Finally, also combinations of explicit and implicit criteria were designed. A systematic tool to reduce inappropriate prescribing (STRIP) is a Dutch guideline that combines an implicit assessment method with the modified Dutch method of the explicit STOPP-START criteria. The tool is a stepwise process to deal with polypharmacy in the elderly. The five steps include a pharmacotherapeutic anamnesis, a pharmacological analysis, a consultation between doctor and pharmacist (drafting of a pharmacotherapeutic treatment), a consultation with the patient (determining the pharmacotherapeutic treatment) and follow-up and monitoring. The main obstacles in the Dutch implementation research are the large investment of time and the need for further digitization and automatization of certain steps in the process.

In addition, the application of this guideline in the Belgian practice is complicated by the absent consultative culture between GPs and pharmacists and the inadequate compatibility of computer systems of general practitioners and pharmacists (28).

7 | INTRODUCTION

1.4. A step-wise approach to deprescribing

1.4.1. Discontinuing medication

Benzodiazepines, antidepressants, antipsychotics, PPI, and opioids are examples of drugs that have to be tapered off gradually to minimize the risk of withdrawal symptoms. Some practical reduction tools for certain drug classes were developed and are discussed below.

The first example is Psychiatrienet.nl, a website which contains switching tables and reduction schedules of antidepressants and antipsychotics. The withdrawal scheme of until stop is illustrated in Figure 1.

In each case two reduction methods are suggested. In the slow reduction method the dose is decreased with 25% every 4 to 6 weeks. Another more risky reduction method makes use of the commercially available doses with every week another reduction step.

Figure 1 : Withdrawal scheme of amitriptyline according to psychiatrienet.nl (34)

Another practical tool is the deprescribing.org website in which deprescribing algorithms for PPIs, benzodiazepines, antipsychotics and antihyperglycemics can be found. An example of the benzodiazepine and Z-drug deprescribing algorithm is illustrated in Appendix 8.3.

Medstopper.com is a third example. It is a website where the medication list of the patient can be added. For each drug, the treated condition has to be filled in using several options. This webpage contains approximately 400 medications, divided into 80 medication categories (e.g. , diuretics, antipsychotics,..). These medication categories are extended to 125 potential indications (blood pressure, heart failure, depression) and were evaluated by a team of experts in gerontology, polypharmacy, , pharmacy. After analysis of the medication list by Medstopper.com (Figure 2), the drugs are ranked from more likely to stop (colored red and to the top) down to less likely to stop (colored yellow/orange and closer to the bottom). This ranking is based on 3 criteria : 1) the potential of the drug to improve symptoms, 2) the potential of the drug to induce future illness, 3) the risk of HARM. Advices for how to taper the drugs and possible consequences are mentioned. This website provides a visual representation of opinions in

8 | INTRODUCTION which the doctor can decide which action can be taken, the tool is easy to use and is proved to be time- saving (35).

Figure 2 : Analysis of medication list on Medstopper.com (36)

Deprescribing is a popular changing topic in the pharmacotherapy and knowledge should be shared. An example of these committed projects is the SIMPATHY (‘Stimulating Innovation Management of Polypharmacy and Adherence in the Elderly’) project, which runs from the beginning of June 2015 till the end of May 2017. The SIMPATHY consortium is funded by the European Commission and the review of appropriate polypharmacy in hospitals is carried out in 10 institutions from 8 European countries in which Scotland plays the key role.

The aim is to support innovation in the management of polypharmacy and adherence in elderly patients in Europe and to help different groups (caregivers, patients’ associations, policymakers) to implement the best practices. Series of activities will be performed such as publishing case studies on the evolution of polypharmacy and compliance in different European countries of the consortium, comparing current healthcare models, developing networks to share information between health providers and identifying the potential difficulties (21).

9 | INTRODUCTION

1.4.2. Monitoring and follow-up

Only 10% of the patients are discharged with the same medications as at admission. 60% of patients have three or more drug changes during hospitalization. 28 to 40% of medicines are stopped within the hospital and 45% of the drugs were initiated (37). These medication changes make the situation very complicated for an older patient who was just discharged from the hospital with a lot of information about follow-up appointments, post-discharge information and medication management.

It has been described that a multidisciplinary discharge planning team can improve the communication with the patient about his most important interest including major diagnoses, medication changes, follow- up appointments, self-care instructions and who to contact if problems would arise. This multidisciplinary team can include a nurse, a social worker, a physical therapist, a pharmacist (38). In a systematic review of Nazar et al., it can be concluded that the community pharmacist (CP) can play an important role for the patient in identifying drug errors when transiting between care providers. But the contribution of the CP to the medication adherence of the patient is rather limited (37). However a discharge counseling session by a hospital pharmacist was found effective and helped patients with tools for compliance, with an overview of the discharge medication and with an explanation of the new started drugs. A few days after discharge, the patient was called by a study coordinator with pharmacist follow-up if needed. Nevertheless, there was no decrease in medication errors demonstrated after the pharmacist intervention. This makes clear that improving medication safety when changing care is not evident. Involvement of the 1st line caregivers is recommended. In practice, CPs receive information through a discharge letter or medication scheme at discharge or through a telephone call by the hospital pharmacist (37; 39; 40).

A fully digital platform for exchanging medical information is one of the biggest opportunities to improve the communication between healthcare providers and to reduce medication errors. However, this digitization is still in progress in Belgium. A digital platform in Belgium, called ‘Vitalink’, allows exchanging medication information between medicinal professionals. Currently, second line care only has read permission (41).

1.5. Which drugs to taper?

A Delphi expert panel, composed of experts from medicine, pharmacy and nursing, rated 29 drug classes using four criteria with the aim to identify priority drug classes for which evidence-based deprescribing guidelines would be beneficial. These four criteria included the benefit versus harms of the drug therapy, certainty of the estimated effects, patient preference and feasibility and costs. In addition, the need for a guideline to stop the drug and the impact of stopping was questioned. The five priority drug classes for which experts claimed that a guideline for deprescribing is required were benzodiazepines, atypical antipsychotics, statins, tricyclic antidepressants and proton pump inhibitors. It is remarkable that 3 of the 5 priorities have to do with mental health (19).

Reasons why experts find benzodiazepines a priority for deprescribing is because of the risk for withdrawal symptoms, the difficulty to convince the patient to reduce the use of these drugs and the risk 10 | INTRODUCTION of adverse drug reactions such as falls and reduced cognition. In a meta-analysis of 40 studies, it was found that each of the studied psychotropic drug classes contributed to falling, without dependency on other fall risk factors (19). Benzodiazepines are primarily used to treat anxiety and sleep disorders. Use in the elderly is not appropriate and is only recommended for short-terms. Gradually reducing the dose is therefore recommended. Minimal interventions such as a personalized letter, a psychotherapeutic intervention or a conversation with the doctor or pharmacist seemed effective. In a follow-up study of patients with an average age of 70 years, the majority of patients sustained the discontinuation of the benzodiazepine after 10 years (42). In addition, the chronic use of antidepressants in the elderly is high and is therefore one of the priorities to reduce. This drug class can have a great potential to interact with other drugs, can affect the QT interval, can have anticholinergic side effects or side effects such as increased bleeding risk and hyponatremia. The limited effectiveness of these drugs has always been weighed against the side effects. Furthermore, the PHEBE-study showed that 11% of the elderly in residential care took antipsychotics. These drugs can also effect the QT-interval and can have strong anticholinergic properties. This low effectiveness of antipsychotics for neuropsychiatric symptoms in dementia and the adverse effects can explain the high need for deprescribing of antipsychotics (43).

Another important class to focus on are drugs with anticholinergic properties. These drugs can give rise to a higher rate of ADR in older people. In particular, these ADRs are impaired physical function, decline in cognition and function and moreover this drug class has been associated with falls and frailty. In a study of Best et al., the drug burden index (DBI) which measured the total exposure to medicines with anticholinergic and sedative effects, was used. It was concluded that 49% (n=163) of the patients were exposed to DBI-contributing drugs of which antidepressants, opioids and antipsychotics were the most contributing medicines. A higher DBI was associated with a delirium related admission (44) and in a study of Wilson et al. with a higher risk of falls (45).

It was also decided to include the proton pump inhibitors (PPI) having regard to the high current consumption and the often irresponsible chronic intake. This choice is not immediately linked with the previous psychotropic medication at first sight, but can be supported by means of literature research in the past. PPI are very effective in certain gastrointestinal disorders. Overconsumption is frequent due to inappropriate indications for an indefinite period. Long-term PPI can sometimes be required for prevention of reflux esophagitis, Barrett esophagitis or for prevention of ulcer due to long-term NSAID use. However, in most indications such as ulcer, reflux, eradication a therapy of longer than 8 weeks in maximal dose is not necessary. Chronic PPI use on the other hand can even increase the risk of Clostridium difficile , pneumonia, malabsorption of iron, B12, and calcium.

In addition, in a meta-analysis of 11 studies an increased risk of hip fracture was found under PPI users compared to non-users. One possible explanation is the blocking mechanism of the PPI on the H+-K+

11 | INTRODUCTION

ATPase pump in the parietal cells that affects the osteoclasts resulting in an inhibition of the resorption. Another mechanism can be explained by the pH-dependent absorption of calcium. The absorption and dissolution of calcium decreases as a result of a rising pH with the use of PPI (46). Prevention actions seem necessary due to the high prevalence of hip fractures (up to 1 in 3 women), the functional consequences and the costs of these osteoporotic fractures. One possible prevention strategy can be the intake of calcium vitamin D which is low in cost and well tolerated. In a meta-analysis of 12 studies, the effectiveness of vitamin D supplementation in preventing hip and nonvertebral fractures in older persons was investigated. It was concluded that an oral vitamin D supplementation of 800 units cholecalciferol reduced the risk of hip and any nonvertebral fractures in the elderly (47). However, vitamin D supplementation should be restricted to older patients or those at risk of deficiency. Most people can achieve adequate levels of vitamin D through sufficient exposure to the sun and besides, unnecessary vitamin D supplementation increases the risk of renal tract stones (48). The added value of the association with calcium could not be distracted. However a calcium intake of more than 700 mg/day should be necessary for the prevention of non-vertebral fractures (47).

1.6. A clinical pharmacist in geriatrics, an added value?

Whether a clinical pharmacist has an added value depends on the proposed outcomes and the corresponding conclusions. A frequently used surrogate or intermediate outcome is for example the number of medicines. Although, this number is an inappropriate result since it reflects the quantity and not the quality of the prescription and the need for clinical indications. However, the interventions of clinical pharmacists in patients who are at high risk of harm due to polypharmacy has been proven effective in reducing number of (inappropriate) prescriptions and medication costs. In addition, the decrease in number of drugs improves the long-term adherence. In a prospective study on the Dutch intensive care unit, the impact on prescribing errors of a clinical pharmacist in an ICU team was evaluated. Preventable ADEs were reduced from 4 per 1000 monitored patient-days during the baseline period to 1 per 1000 during the intervention period (49). This study reflects a decrease in prescription errors and ADRs and this with an acceptable cost per occupied day by the clinical pharmacist.

Secondly, the outcome can be a hard end point such as hospitalizations, fall accidents and mortality. Several RCTs, reviewed by Gnjidic et al., involving medication reviews by pharmacists could not demonstrate a significant difference in GP visits, hospital readmissions and mortality. However interventions through safety assessment and adjustment of medication, could reduce the risk of falling.

It can be concluded that the impact of clinical pharmacist-based interventions on clinical outcome has mainly proven to affect intermediate outcomes, e.g. the decrease of the number of drugs and the costs and the increase in appropriateness of prescribing (20; 26).

12 | INTRODUCTION

1.7. Barriers to routine deprescribing

A lot of barriers can prevent routine deprescribing. The decision for deprescribing is complicated by pharmaceutical companies who put pressure on doctors on the one hand and make patients believe that every ailment needs a cure and drug.

In the first place, patients who believe they are taking too many drugs, are afraid of the reaction of the doctor when asking for deprescribing. They fear for relapse and fear that there is no possibility to restart the medication.

Secondly, it is not surprising that when a doctor proposes to stop or reduce drugs in the patients therapy, many of them are unwilling to stop. Doctors fear the reactions of family or patient by stopping a drug that was initiated by a specialist. They fear an increased workload and are often not certain why a drug is prescribed for a patient.

The lack of practical, applicable and successful guidelines to reduce polypharmacy and the little awareness of the prevalence of HARMs brings routine deprescribing at a low level (10). Unfortunately, the impact on health outcomes and health care costs has not been evaluated thoroughly. Finally, two important concerns should be mentioned. First, not only inappropriate drugs must be avoided, but also the appropriate and beneficial drugs should be motivated. Second, the responsibility for appropriate prescribing should not only be given to the physician but this should be shared with every other care provider and the family. Two reviews showed that the lack of consultation time is a major obstacle for as well the patient and the physician. This confirms the necessity and the importance of communication with health care providers and the follow-up at regular intervals (43).

13 | INTRODUCTION

14 | INTRODUCTION

2. OBJECTIVES ______

This study focused on hospitalized patients at the geriatric and orthogeriatric wards in the ‘Groeninge’ hospital in Kortrijk. Patients with polypharmacy taking psychotropic drugs were approached for deprescribing, during two similar periods of four months.

The main objectives of this study research were : - To determine the prevalence of potentially inappropriate prescribing (PIPs) based on the STOPP-criteria for the central nervous system (category D) and for high PPI dose both at admission and discharge; - To measure the vitamin D content and to estimate the underuse of vitamin D supplements; - To compare the number and type of drugs at admission and at discharge; - To identify the number and type of drug related problems (DRP); - To give recommendations for deprescribing of psychotropic medication to health care providers such as geriatricians, general practitioners (GPs), community pharmacists (CPs) and to analyze the number of accepted recommendations by the geriatrician and the patient; - To determine the success rate of withdrawal schemes and the importance of post- hospitalization follow-up.

15 | OBJECTIVES

16 | OBJECTIVES

3. METHODS ______

3.1. General study description

This was a single center pharmacist driven intervention study for deprescribing of hypnosedatives, antidepressants and antipsychotics for older (> 75) hospitalized patients.

Approval was obtained from the medical ethics committee at the general hospital Groeninge in Kortrijk (study number AZG2016140). This approval can be found in appendix 8.4. Informed consent was submitted to all participants. The consent template is added to appendix 8.5.

3.2. Workflow

3.2.1. Selection of patients

Patients hospitalized at the orthogeriatric ward and at one geriatric ward (approximately 30 beds per ward) were considered for inclusion in the study according to the availability of a clinical pharmacist. Patients on the other geriatric wards were screened if the geriatrician requested an electronic consultation. It was decided to include only one of the three geriatric wards in our hospital, due to time constraints. Orthogeriatrics focuses on patients with a fracture, which involves a close cooperation between geriatrics and orthopedics. The other ward is a typical geriatric ward with different pathologies. About 5 geriatricians are switching between all the acute geriatric wards every 3 months. The clinical pharmacist attended the wards approximately 3 days per week during the period April to July 2016 and January to April 2017.

The workflow was described by means of different stages (Appendix 8.6) and is a continuation of a project started in 2015 by a colleague-pharmacist in training.

During the first step the patients were screened and enrolled if they met all of the following requirements: 1) length of stay (LOS) of at least 3 days, 2) age of 75 years or older, 3) minimum intake of 5 drugs and one of the following inclusion criteria: (1) a contra-indication for benzodiazepines (myasthenia gravis, sleep apnea syndrome or severe respiratory insufficiency such as COPD or asthma), (2) a pharmacodynamic synergistic interaction (antidepressants, antipsychotics, anticholinergics, sedative and opioids) or (3) a minimal dose equivalent of 20 mg diazepam. The calculation of the diazepam equivalence is explained in section 3.3.1.

Psychiatric or palliative patients were excluded from the project and were not eligible for a withdrawal scheme.

17 | METHODS

3.2.2. Counseling of patients

The patients eligible for a tapering scheme of one or more psychotropic drugs were approached by the clinical pharmacist in training. In case the electronic medical record revealed that the patient was cognitively weak (mini-mental state examination (MMSE) < 24), the conversation was performed with the family when present or only with the geriatrician. The clinical pharmacist took along an informed consent, the medication schedule at admission and a leaflet about fall prevention when visiting the patient. Before counseling started, the patient or caregiver was asked to sign the informed consent. The patient was informed about the potential risks and long-term side effects and was encouraged to reduce these psychotropic drugs. If the patient agreed, the patients therapy was discussed with the geriatrician and the pharmacist. If the patient did not agree, cessation was not attempted. The clinical pharmacist reviewed the therapy, focusing on the psychotropic medication, and made recommendations in an electronic pharmaceutical report in the EMR (Appendix 8.7), including the dose changes, withdrawal schemes and expected cessation date. This report can be read by the geriatrician in the EMR and was sent electronically via e-health to the GP.

If the geriatrician had accepted one or more recommendations, the withdrawal scheme or another recommendation was implemented (in hospital setting or at home). In addition, the 1st line caregivers were involved if it concerned a withdrawal scheme. The clinical pharmacist informed the GP and the CP by a telephone call. If it appeared that the 1st line had not accepted the advice, the withdrawal scheme was not started. This also happened when the patient refused a tapering schedule. In addition this refusal was reported to the geriatrician. At discharge, the pharmaceutical discharge letter and the medication schedule was printed from the EMR (after validation of the geriatrician). If a psychotropic drug was tapered in the patients therapy, a leaflet with the reduction steps was added. Figure 3 shows an example of the leaflet with the withdrawal scheme of .

Figure 3 : Leaflet of the withdrawal schemee of zolpidem

Three copies of the medication scheme at discharge (plus corresponding leaflet) were provided to the patient. One copy was for the patient /nursing/family, one copy for the general practitioner and one copy for the community pharmacist.

18 | METHODS

A pharmaceutical discharge letter was added for the GP and CP. If the patient was discharged to a nursing home an accompanying letter was added. This letter highlighted the importance of the follow-up of the reduction of psychotropic medication. An example of this letter is shown in Appendix 8.8.

3.2.3. Follow-up

Patients who were discharged with a tapering scheme of psychotropic drugs were contacted by phone by the clinical pharmacist in training about 10 days after discharge If the patient could not be reached, one of the family members was interviewed. For nursing home residents, the responsible nurse was contacted by phone about one week after discharge . The patient or the responsible caregiver was asked if she/he managed to apply the tapering scheme and in case of failure the possible causes were asked for. The pharmacist searched for solutions in case of difficulties and if necessary the GP was contacted.

3.3. Deprescribing protocol

3.3.1. Diazepam equivalents Before tapering these benzodiazepines and Z-drugs, we should have an idea of the strength of the(se) benzodiazepine(s) which the patient is taking. This strength can be determined by converting the benzo (type and strength) in an equivalent dose of diazepam. Therefore a diazepam dose equivalence table for benzodiazepines is used (Table 1 or appendix 8.9) This table is composed based on the book published by the Belgian Center of Pharmacotherapeutic Information (BCFI) (50). As is clear from the table, a dose of a certain benzodiazepine cannot be linked to a fixed dose of diazepam; there is a range of doses between a minimum and maximum limit. This large range is attributable to interindividual variability. In this project, a team of geriatricians and hospital pharmacists decided to apply the minimum limit for the conversion, which is also the most stringent limit. For example: when handling the lower limit, 4.5 mg is equivalent to 10 mg of diazepam or in practice: Lexotan® 3 mg corresponds to 7 mg of diazepam. But when using the upper limit, 9 mg of bromazepam is equivalent to 10 mg of diazepam or in practice: Lexotan® 3 mg corresponds to 3.5 mg of diazepam. Thus, the use of the minimum limit is a more strict measure.

Table 1: Diazepam equivalence of the commercialized benzodiazepines

Diazepam Limit values on Duration of action Generic name Brand name Dose(mg) equivalence(1) equivalence of 10 mg (mg) diazepam Short-acting 0.125 5 Halcion® 0.25 – 0.5 mg 0.25 10

( 1 ) corresponding to the lower limit value on diazepam equivalenc e

19 | METHODS

Continuation Table 1: Diazepam equivalence of the commercialized benzodiazepines

Diazepam Limit values on Duration of action Generic name Brand name Dose(mg) equivalence(1) equivalence of 10 mg (mg) diazepam Intermediate-acting Alpratop® 0.25 5

Alprazolam Alpraz® 0.5 10 0.5 - 1 mg Xanax® 1 20 2 40 Bromatop® 3 7 Bromazepam Lexotan® 6 14 4.5 - 9 mg 12 28 Lendormin® 0.25 10 0.25 – 0.5 mg 5 10 Clozan® 5 - 10 mg 10 20 Dormonoct® 1 20 0.5 - 2 mg 2 40 Lorazetop® 1.0 5 Temesta® 2.5 12.5 2 - 8 mg Serenase® Loramet® 1 10 Loranka® 2 20 Metatop® 1 - 2 mg Noctamid® Stilaze® Oxazepam EG® 15 10 15 - 100 mg Long-acting 10 10 Frisium® 10 - 30 mg 20 20 0.5 5.0 Rivotril® 1 - 4 mg 2 20.0 Tranxene® 5 5.0 10 10.0 Clorazepaat 10 - 30 mg 50 50.0 Uni-Tranxene® 15 15.0 1 Akton® 10 1 - 2 mg 2 20 2 2 Diazepam Valium® 5 5 10 mg 10 10 Ethylloflazepaat Victan® 2 20 1 - 3 mg Flunitrazepam EG® 1 20 0.5 - 2 mg Staurodorm® 27 18 15 - 60 mg Mogadon® 5 10 5 - 10 mg Calmday® 5 20 2.5 - 10 mg 10 Lysanxia® 3 30 - 60 mg 20 6 Z-drugs Zolpeduar® 5 2.5 Zolpidem Stilnoct® 10 5.0 20 mg Zolpitop® Zoplicone Imovane® 7.5 5 15 mg

20 | METHODS

3.3.2. Deprescribing of hypnosedatives

The discontinuation of chronic intake of hypnosedatives including benzodiazepines and Z-products have to be done step by step and in every step the dose should be gradually decreased. In the literature, a reduction of 10 to 20% of the initial dose for one to two weeks is described (51; 52; 50). In this study, the commercialized doses of drugs available in the pharmaceutical sector are used, without having to rely on individually compounded preparations. These preparations are often expensive and would bring an additional workload especially in hospitals and besides not all doctors are familiar with the prescription of these pharmaceutical compoundings.

For deprescription, a distinction between short- and intermediate-acting benzodiazepines and long- acting benzodiazepines was made. At first, short- and intermediate-acting benzodiazepines were reduced in steps corresponding to (half of) the lowest available commercial dose. Each step was held 2 weeks giving the body the time to adapt to the revised dose. Examples of withdrawal schemes are shown in Table 2.

Table 2: Withdrawal schemes of short-and intermediate-acting benzodiazepines

Benzodiazepine Withdrawal scheme 2mg Step 1 2 weeks 1.5 mg Step 2 2 weeks 1 mg Step 3 2 weeks 0.5 mg

Step 4 2 weeks 0.25 mg Step 5 2 weeks 0.125 mg Step 6 2 weeks 0.125 mg every 2 days

Step 7 Stop Benzodiazepine Withdrawal scheme

Bromazepam 12mg Step 1 2 weeks 9 mg

Step 2 2 weeks 6 mg

Step 3 2 weeks 4.5mg

Step 4 2 weeks 3 mg

Step 5 2 weeks 1.5 mg

Step 6 2 weeks 1.5 mg every 2 days Step 7 Stop

Benzodiazepine Withdrawal scheme

Lorazepam 2.5 mg Step 1 2 weeks lorazepam 2 mg Step 2 2 weeks lorazepam 1.5 mg Step 3 2 weeks lorazepam 1 mg Step 4 2 weeks lorazepam 0.5 mg

Step 5 2 weeks lorazepam 0.5 mg every 2 days

Step 6 Stop

21 | METHODS

Secondly, long-acting benzodiazepines for which commercially low doses were available, were reduced using the withdrawal scheme as described above. The other long-acting molecules (clobazam, , flurazepam, nitrazepam and nordazepam) with only a few commercially doses available were recommended to switch to diazepam in order to enable gradually tapering. A general rule used was to initiate the first step with a dose of diazepam 25% lower than the equivalent dose. Alternatively, such as in patients with very high doses of benzodiazepines, it may be recommended to reduce first the originally benzodiazepine to an equivalent dose of 20 mg of diazepam before switching to diazepam. Examples are shown in Table 3.

Table 3: Withdrawal scheme of long-acting benzodiazepines

Benzodiazepine Withdrawal scheme Step 1 2 weeks switch to diazepam 15 mg flunitrazepam 1 mg Step 2 2 weeks diazepam 10 mg (= 20 mg diazepam) or Step 3 2 weeks diazepam 7.5 mg flurazepam 27 mg Step 4 2 weeks diazepam 5 mg (= 18 mg diazepam) Step 5 2 weeks diazepam 2.5 mg Step 6 2 weeks diazepam 2.5 mg every 2 days

Step 7 Stop

If the patient indicated that the reduction steps were going too fast and he would not sustain it, the schedule was adjusted according to the profile of the patient and their compliance. If necessary, a reduction step was maintained longer in agreement with the GP. This was mentioned in the discharge letter and on the sticker with the withdrawal scheme. Given the risk of relapse and withdrawal symptoms, it is essential to monitor the patient in order to encourage them and help them with any misunderstandings. The hospital pharmacist and the community pharmacist can play an important role in this follow-up (see section 1.4.2).

It is clear that a withdrawal schedule is not a strict protocol, but a guideline that has to be adapted to the needs of the patient. This means that in our study, the dosage tapering was individualized by discussion with the geriatrician, doctor and the community pharmacist.

3.3.3. Deprescribing of antidepressants and antipsychotics

For the discontinuation of antidepressants and antipsychotics, the withdrawal schedules on the website of ‘Psychiatrienet’ were adopted. These withdrawal schedules are described more in detail in section 1.4.1. Assuming a geriatric study population, it is not surprising that the dosages of most tricyclic antidepressants and SSRIs are usually low so that in many cases these drugs can be stopped immediately. Exceptions include , nortriptyline and , the dosage of these molecules are reduced to a lower dose than the lowest commercially available dose before being stopped.

22 | METHODS

3.4. Data collection

Patient characteristics such as sex, age, admission at geriatric or orthogeriatric ward and the number of drugs taken were collected for all patients. For all included patients also following patient characteristics were collected at admission: reason for PPI intake, natrium blood level, reason for admission, drug related problems (DRPs), diazepam- equivalence, anticholinergic burden score, vitamin D blood level, intake of vitamin D supplement, MMSE-score and social living situation. The reason for admission was considered as dominantly, partly or not contributing to drug related problems1. The determination of DRPs was assessed by the clinical pharmacist and was not discussed with other healthcare providers. Considerations were taken based on the emergency report written by the emergency doctor. No causality of DRPs was evaluated. The ACB-score was calculated using the anticholinergic burden scale tool which can be found in Appendix 8.2. The number and type of drugs taken at admission and discharge were registered. Drug use at admission was found in the medication module of the EMR and drug use at discharge was registered based on medication schedules at discharge or on discharge letters. The follow-up calls with patients discharged on a withdrawal scheme were performed by the hospital pharmacist about 10 days after discharge. These findings were documented and marked as either a problem or no problem. No standard questionnaire was used. Reasons of failed withdrawal attempts and types of actions that were taken, were documented.

3.5. Data analysis

For the processing of the data, Microsoft Excel 2013 was used. All drugs at admission and at discharge were coded according to the Anatomical Therapeutic Chemical (ATC) classification system. The statistical significance difference in the number of drugs at admission and at discharge was subjected to a paired t-test using SPSS version 24. A p-value of less than 0.05 was considered statistically significant. In addition, all drugs of included patients were subjected to a quality assessment to identify potentially inappropriate prescriptions. This assessment was performed using selected STOPP criteria of the revised Dutch version (2015) (Appendix 8.10). This selection included section D (central nervous system and psychotropic drugs) and a part of section F (gastrointestinal system) which is illustrated in Table 4.

1 ‘dominant’: drug-related symptoms are the main reason for admission and no other symptoms contribute significantly

‘partly contributing’: drug-related symptoms are a substantial reason for admission, but other factors are also present ‘not contributing’: symptoms other than the drug-related symptoms are the main reasons for admission (17)

23 | METHODS

Table 4: Summary of selected STOPP-criteria

STOPP Description criterion D1 Tricyclic antidepressants (TCAs) with dementia, narrow angle glaucoma, cardiac conduction abnormalities, prostatism, or prior history of urinary retention D2 Initiation of tricyclic antidepressants (TCAs) as first-line antidepressant treatment D3 Neuroleptics with moderate-marked antimuscarinic/anticholinergic effect (chlorpromazine, , flupenthixol, fluphenzine, pipothiazine, , ) with a history of prostatism or previous urinary retention D4 Selective serotonin re-uptake inhibitors (SSRI’s) with current or recent significant hyponatremia i.e. serum Na+ < 130 mmol/l D5 Benzodiazepines for ≥ 4 weeks D6 Antipsychotics (i.e. other than or clozapine) in those with parkinsonism or Lewy Body Disease D7 Anticholinergics/antimuscarinics to treat extra-pyramidal side-effects of neuroleptic medications D8 Anticholinergics/antimuscarinics in patients with delirium or dementia D9 Neuroleptic in patients with behavioral and psychological symptoms of dementia (BPSD) unless symptoms are severe and other non- pharmacological treatments have failed D10 Neuroleptics as hypnotics, unless sleep disorder is due to psychosis or dementia D11 Acetylcholinesterase inhibitors with a known history of persistent bradycardia (< 60 beats/min.), heart block or recurrent unexplained syncope or concurrent treatment with drugs that reduce heart rate such as beta-blockers, digoxin, diltiazem, verapamil D12 as first-line treatment, since safer and more efficacious alternatives exist, with the exception of for nausea/vomiting/vertigo, chlorpromazine for relief of persistent hiccoughs and as an anti-emetic in palliative care. D13 Levodopa or dopamine for benign essential tremor D14 First-generation antihistamines F2 PPI for uncomplicated or erosive peptic esophagitis at full therapeutic dosage for > 8 weeks

When at least one drug in the medication scheme of the patient met the STOPP criterion, this criterion was documented. A STOPP criterion was not documented if the drug was stopped or tapered. The difference in prevalence at admission and discharge of each STOPP criterion was assessed using a Mc Nemar test in SPSS version 24. The START criterion ‘vitamin D deficiency in patients with a fracture or osteoporosis’ was not assessed in this study. Not all fall incidents and diagnoses of osteoporosis have been documented. Conclusions were taken based on the documentation of the intake of vitamin D supplements and vitamin D blood levels.

24 | METHODS

Associations were investigated by dividing patients into different groups. At first, patients were classified into 2 groups in which patients took benzodiazepines or not. The Pearson chi squared test was performed to determine differences between variables such as sex, residence in nursing home and fall incidents. Differences in number of drugs between both groups were tested by using the Mann-Whitney U-test. On the other hand, patients were divided into groups depending on whether the admission was due to a drug-related problem (dominant or partially contributing) or not. Different variables in these groups were statistically tested to detect risk factors for hospitalized admissions related to medications. The Pearson chi squared test was used for assessing differences in sex and residence in nursing home. Furthermore, the Mann-Whitney U-test was conducted to detect differences in age between the study groups.

25 | METHODS

26 | METHODS

4. RESULTS ______4.1. Study group

In total 470 patients were approached, namely 270 patients during the first period (April - July 2016) and 200 patients during the second period (January - April 2017).

In total 398 of the 470 patients were included in the study (Figure 4). For 72 patients the inclusion criteria were not met. At first, the age of the patients and number of drugs was considered in which 9.7% was younger than 75 years and 40.3% patients had an intake of less than 5 drugs. Furthermore, in 45.8% of patients a pharmacodynamic synergistic interaction was absent and 4.2% patients were excluded due to a LOS less than 3 days. In total 203 (51%) patients were admitted to geriatric wards and 195 (49%) patients to orthogeriatrics. Since 18 patients died during the hospitalization, 380 of 398 included patients were discharged from the hospital.

Figure 4: Summary of study group

All results are discussed for the patients included in the two study periods (n = 398), except for the distribution of drugs at admission and discharge (section 4.3.3 and 4.4.2) and the follow-up of withdrawal schedules after hospitalization (section 4.6). These data were documented only for patients included in the second study period.

27 | RESULTS

4.2. Patient characteristics

The population (n=398) consisted of 309 (77.6%) women and 89 (22.4%) men. The mean age was 84.7 (75-98) ± 5.5 years. For women and men the age was respectively 85.0 ± 5.4 and 83.6 ± 5.8 years (Table 5). Table 5: Age characteristics by sex (n=398)

Female (n=309) Male (n=89) Total (n=398) Mean age (years ± SD) 85.0 ± 5.4 83.6 ± 5.8 84.7 ± 5.5 Maximum age (years) 98 98 98

Regarding the patient origin, 75.9% of the included patients lived at home, 17.6% lived at a nursing home, 5% in a service flat and 1.5% lived with family. The MMSE-score was determined during hospitalization for 264 patients. 63 patients achieved a score equal or more than 24 and 201 patients had a score less than 24. A score less than 24 was defined as cognitive impairment (45). The mean MMSE-score was 20.3 ± 5.5 (Table 6).

Table 6: Origin and MMSE-scores (n=398)

Patient origin N (n = 398) Total (%)

Community 302 75.9 Service flat 20 5 Nursing home 70 17.6 With family 6 1.5 MMSE N (n = 398) Total (%) Mean MMSE-score 20.3 ± 5.5 MMSE-score ≥ 24 63 15.8 MMSE-score < 24 201 50.5 No data 134 33.7

4.3. Drug use at admission

4.3.1. Number of drugs

The mean number of drugs was calculated for all patients (n=398) and was 10.7(5-22) ± 3.8 at admission. For women and men respectively the number of drugs was 10.9 ± 3.9 and 10.2 ± 3.3. Excessive polypharmacy was present (≥ 10 drugs) in 232 patients or in 58.3% of the total study population (Table 7).

28 | RESULTS

Table 7: Number of drugs by sex at admission (n=398)

Women (n= 309) Men (n= 89) Total (n= 398) Mean number of drugs (±SD) 10.9 ± 3.9 10.2 ± 3.3 10.7 ± 3.8 Excessive polypharmacy 185 47 232 (58.3%) (≥ 10 drugs) Maximum number of drugs 22 21 22

4.3.2. Use of (psychotropic) drugs

The average ACB-score was 1.3 per patient (n = 398) and 107 (26.9%) patients had an ACB-score higher than 3. The vitamin D level was determined for 265 patients in which 217 patients (81.9%) had inadequate vitamin D levels (<30 µg/L) and 18.1% had sufficient levels (>30 µg/L). In the 217 patients with inadequate vitamin D levels, 167 patients had a vitamin D deficiency (< 20 µg/L) and 50 patients had an insufficiency (20-30 µg/L). 72.8% of them did not take a vitamin D supplement at admission despite their deficit. In total, 33.2% of the included patients (n=398) took a vitamin D supplement at admission.

80.4% of the included patients (n=398) were benzodiazepine(BDZ) users. The mean diazepam equivalence of the BDZ users was 13.5 mg. 38 patients of the BDZ users (n=320) had a contraindication for benzodiazepines in which COPD was the most frequent indication (n=28) (Table 8).

Table 8: Drugs characteristics of th e BDZ users

N % BDZ users (n=398) 320 80.4 Mean diazepam equivalence (mg) (n=320) 13.5 Contra-indication for benzo-use (n=320) 38 11.9 COPD as contra-indication (n=38) 28 73.7

A distribution of the diazepam equivalence of the benzodiazepine users (n=320) is shown in Figure 5. A large part of the benzodiazepine users (n = 77) had a diazepam equivalent between 0 and 5mg, the second largest group had a diazepam equivalent between 15 and 20 mg (n = 71).

29 | RESULTS

90

80 77 71 70 63 58 60

50

users (n=320)users 40 -

30 Benzo 20 16 14

10 5 4 4 5 0 2 1 0 0-5 6-10 11-15 15-20 21-25 26-30 15-20 21-25 26-30 46-50 51-55 56-60 60-65 Diazepam equivalence (mg)

Figure 5 : Distribution of diazepam equivalen ce (mg) of the benzo users (n=320)

In this study, the most common benzodiazepines used were lorazepam (32.5%), lormetazepam (29.1%) and the benzodiazepine related z-drug zolpidem (15.9%) (Table 9).

Table 9: Summary of most common benzodiazepines among BDZ users (n=320 )

ATC-code Benzodiazepine N % (n=320) N05BA06 lorazepam 104 32.5 N05BA08 bromazepam 35 10.9 N05BA12 alprazolam 29 9.1 N05CD06 lormetazepam 93 29.1 N05CF02 zolpidem 51 15.9

The differences between the variables fall incidents, sex, residence in nursing home and number of drugs between benzodiazepine users and non-users were determined and are shown in Table 10. As can concluded from the table, female patients were more likely to take benzodiazepines than males (p-value = < 0.001). In addition, BDZ users took a significantly higher number of drugs at admission compared to non-benzo users (p-value= 0.013). However no relationship between the intake of benzodiazepines and fall incidents (p-value = 0.411) or coming from a nursing home (p-value = 0.643) was found.

30 | RESULTS

Table 10: Benzodiazepine use in relation to fall incidents and sex and origin .

N (n=398) BDZ user Non BDZ user p-value (n=320) (n=78) Fall incidents 168 138 30 0.411 Female 310 262 48 < 0.001 Coming from a nursing home 70 57 13 0.643 Number of drugs (±SD) 10.7 ± 3.8 11.0 ± 3.8 9.8 ± 3.6 0.013

Hospital admission was dominantly or partly drug related for 164 patients (41.2%). In 11 of the 164 patients (2.8 %), a drug was considered to be the dominant reason for hospital admission and in 153 of the patients (38.4 %), a drug was found to partly contribute to admission. These considerations were assessed by the clinical pharmacist and were not discussed with a panel of healthcare providers. Drugs which attributed to hospital admissions concerned central nervous system drugs, drugs for the musculoskeletal system medication and cardiovascular drugs. The differences between the variables age, sex and residence in nursing home between patients admitted due to a DRP and due to no DRP were determined and are shown in Table 11. Female patients were more frequently admitted because of a drug related problem compared to males (p-value = 0.003). However, no relationship was found between drug related hospitalization and age (p- value = 0.880) or coming from a nursing home (p-value= 0.226).

Table 11: Drug related problems in relation to age, sex and origin.

DRP (n=164) No DRP (n=234) p-value Mean age (years) 84.8 84.9 0.880 Female (# patients) 140 169 0.003 Coming from a nursing home (# patients) 36 54 0.226

4.3.3. Types of drugs

Types of drugs at admission were assessed for all patients (n=200) of the second study period and are shown in Figure 6. This distribution is a representation of all (both included and excluded) patients. Three major drug classes dominated the distribution. Of all documented drugs 27.5% were drugs that acted on the nervous system (N), 26.7% were drugs of the cardiovascular system (C) and 21.1% were drugs of the alimentary tract and metabolism (A).

31 | RESULTS

30.0 27.5 26.7

25.0 21.1 20.0

15.0 10.4

10.0 Numberofdrugs (%) 4.5 5.0 2.9 3.2 1.5 0.2 0.7 0.5 0.1 0.6 0.0 0.0 A B C D G H J L M N P R S V Drug classes

Figure 6 : Distribution of drug classes at admission

The drug classes according to the ATC classification system are drugs for (A) Alimentary tract and metabolism, (B) Blood and blood forming organs, (C) Cardiovascular system, (D) Dermatological drugs, (G) Genitourinary system and reproductive hormones, (H) Systemic hormonal preparations, excluding reproductive hormones and insulins, (J) Antiinfectives for systemic use, (L) Antineoplastic and immunomodulating agents, (M) Musculoskeletal system, (N) Nervous system, (P) products, insecticides and repellents, (R) Respiratory system, (S) Sensory organs, (V) Various ATC structures.

4.3.4. Prevalence of PIPs according to STOPP D

The frequency of potentially inappropriate prescriptions at admission and discharge (n=398) as determined by the STOPP criteria is shown in Table 12. The prevalence of PIPs, reported as the percentage of prescriptions with at least one PIP, was 94.0% at admission and 66.8% at discharge. 698 PIPs were registered at admission and 359 PIPs at discharge. The number of PIPs decreased with 48.6%, however still in 66.8% patients, at least 1 PIP was present at discharge. In general, it can be considered that for each PIP criterion the prevalence was decreased when comparing admission and discharge. Except for patients with parkinsonism or Lewy Body Disease that took antipsychotics (D6) and patients that took levodopa or dopamine agonists for benign essential tremor (D13), the number of PIPs did not change at discharge. The most frequently involved drugs in PIPs at admission were long term use of antidepressants (7%), long term use of benzodiazepines (80.4%), anticholinergics (11.8%) and high dose of PPIs (49.2%). The Mc Nemar test found a significant difference in prevalence of the STOPP indicators D1, D2, D5, D8, D14 and F2 between admission and discharge. The prevalence of the STOPP indicators D2, D5 and F2 was almost halved at discharge.

32 | RESULTS

Table 12: Number of PIPs per patient at admission and discharge

STOPP indicator At admission At discharge p- value

N (n=398) % N (n=380) % D1 19 4.8 8 2.1 < 0.001 Tricyclic antidepressants (TCAs) with dementia, narrow angle glaucoma, cardiac conduction abnormalities, prostatism, or prior history of urinary retention D2 21 5.3 13 3.4 0.008 Initiation of tricyclic antidepressants (TCAs) as first-line antidepressant treatment D3 8 2.0 4 1.1 0.125 Neuroleptics with moderate-marked antimuscarinic/anticholinergic effect (chlorpromazine, clozapine, flupenthixol, fluphenzine, pipothiazine, promazine, zuclopenthixol) with a history of prostatism or previous urinary retention D4 6 1.5 5 1.3 1.0 Selective serotonin re-uptake inhibitors (SSRI’s) with current or recent significant hyponatremia i.e. serum Na+ < 130 mmol/l D5 320 80.4 163 42.9 < 0.001 Benzodiazepines for ≥ 4 weeks D6 6 1.5 6 1.5 1.0 Antipsychotics (i.e. other than quetiapine or clozapine) in those with parkinsonism or Lewy Body Disease D7 2 0.5 1 0.3 1.0 Anticholinergics/antimuscarinics to treat extra-pyramidal side-effects of neuroleptic medications D8 46 11.6 25 6.6 < 0.001 Anticholinergics/antimuscarinics in patients with delirium or dementia D9 14 3.5 9 2.4 0.125 Neuroleptic antipsychotic in patients with behavioral and psychological symptoms of dementia (BPSD) unless symptoms are severe and other non-pharmacological treatments have failed D10 15 3.8 10 2.6 0.063 Neuroleptics as hypnotics, unless sleep disorder is due to psychosis or dementia D11 11 2.8 8 2.0 0.250 Acetylcholinesterase inhibitors with a known history of persistent bradycardia (< 60 beats/min.), heart block or recurrent unexplained syncope or concurrent treatment with drugs that reduce heart rate such as beta-blockers, digoxin, diltiazem, verapamil D12 5 1.3 1 0.3 0.125 Phenothiazines as first-line treatment, since safer and more efficacious alternatives exist, with the exception of prochlorperazine for nausea/vomiting/vertigo, chlorpromazine for relief of persistent hiccoughs and levomepromazine as an anti-emetic in palliative care. D13 1 0.3 1 0.3 1.0 Levodopa or dopamine agonists for benign essential tremor D14 22 5.5 8 2.1 < 0.001 First-generation antihistamines F2 196 49.2 97 25.5 < 0.001 PPI for uncomplicated peptic ulcer disease or erosive peptic esophagitis at full therapeutic dosage for > 8 weeks

33 | RESULTS

4.4. Drug use at discharge

4.4.1. Number of drugs

The mean number of drugs was calculated for 380 patients. 18 patients died during the hospitalization, including 10 women and 8 men. At discharge the mean number of drugs was 11.5 ± 3.6. The number of drugs was higher than at admission and was found to be statistically significant (p-value = < 0.001). The number of drugs for women and men was respectively 11.7 ± 3.6 and 10.9 ± 3.4 (Table 13).

Table 13: Number of drugs by sex at discharge

Drug characteristic Women (n= 299) Men (n= 81) Total (n= 380)

Mean number of drugs (±SD) 11.7 ± 3.6 10.9 ± 3.4 11.5 ± 3.6 Excessive polypharmacy 221 55 276 (72.6%) (≥ 10 drugs) Maximum number of drugs 24 19 24

4.4.2. Types of drugs

The distribution of drug classes at discharge was calculated for all patients (n=188) of the second study period. 12 (included or excluded) patients died during this hospitalization period. The percentage change on discharge per drug class in relation to the distribution at admission is shown in Figure 7. The largest change was seen in drugs of the alimentary tract and metabolism. This drug class increased from 21.1% to 28.1%. In addition, a decrease of 4.8% was found in the cardiovascular drugs. The proportion of the nervous system drugs, on the other hand, was slightly reduced (1.1%) compared to admission. The shift of these drug classes at discharge is discussed in more detail below.

30.0

25.0 +7.0 20.0 21.1 15.0 26.7 27.5 10.0 +0.7

5.0 10.4 4.5

Numberofdrugs (%) 0.0 -1.1 -1.5 A B C-4.8D G H J L M N P R S V -5.0

-10.0 Drug classes Drug classes at admission % change on discharge

Figure 7 : Distribution of drug classes at discharge

The drug classes according to the ATC classification system are drugs for (A) Alimentary tract and metabolism, (B) Blood and blood forming organs, (C) Cardiovascular system, (D) Dermatological drugs, (G) Genitourinary 34 | RESULTS

system and reproductive hormones, (H) Systemic hormonal preparations, excluding reproductive hormones and insulins, (J) Anti-infectives for systemic use, (L) Antineoplastic and immunomodulating agents, (M) Musculoskeletal system, (N) Nervous system, (P) Antiparasitic products, insecticides and repellents, (R) Respiratory system, (S) Sensory organs, (V) Various ATC structures.

The distribution of the subclasses of the ATC class A at admission and discharge is shown in Figure 8. The increase of drug class A with 7% could be attributed to the increase of drugs for constipation (A06), (A11) in which mainly vitamin D and minerals (A12) in which mainly calcium.

160 152 140 120 113 99 95 96 100 75 80 60 41

Numberofdrugs 40 31 20 0 A01 A02 A03 A04 A05 A06 A07 A08 A09 A10 A11 A12 A14 A15 A16 Subclassification of drug class A Admission Discharge

Figure 8 : Number of drugs at admission and discharge pe r subclass of A

Drug class A is subdivided into following subclasses ( A01) : Stomatological preparations, (A02) : Drugs for acid related disorders, (A03) Drugs for functional gastrointestinal disorders , (A04) and antinauseants, (A05) and liver therapy, (A06) Drugs for constipation, (A07) Antidiarrheals, intestinal anti-inflammatory/anti-infective agents, (A08) Antiobesity preparations, (A09) Digestives, including , (A10) : Drugs used in diabetes, (A11) Vitamins, (A12) : supplements, (A14) Anabolic agents for systemic use, (A15) Appetite , (A16) : Other alimentary tract and metabolism products

The proportion of cardiovascular drugs decreased from 26.7 to 21.9% at discharge. This change was due to a decrease of lipid modifying agents(C10) from 92 drugs at admission to 77 at discharge. In addition, there was a decrease of agents acting on the renin angiotensin system (C09) from 65 drugs to 52 and a reduction of cardiac drugs (C01) (i.e. antiarrhythmic drugs, cardiac glycosides,..) from 46 drugs to 29. The distribution of the subclasses of ATC class C at admission and discharge is shown in Figure 9.

35 | RESULTS

140 124 119 120

100 92 77 80 65 60 52 46 40 Numberofdrugs 29

20

0 C01 C02 C03 C04 C05 C06 C07 C08 C09 C10 Subclassification of drug class C Admission Discharge

Figure 9 : Number of drugs at admission and discharge per subclass of C

Drug class C is subdivided into following subcla sses : (C01) Cardiac therapy, (C02) Antihypertensive drugs, (C03) drugs, (C04) Peripheral vasodilators, (C05) Vasoprotective drugs, (C07) Beta blocking agents, (C08) Calcium channel blockers, (C09) Agents acting on the renin -angiotensin system, (C10)Lipid modifying agents

Although only a small decrease (1.1%) was reported in drug class N, still a major shift took place between the subclasses. The proportion of subclass N02 ( drugs) increased from 126 drugs at admission to 184 drugs at discharge. The proportion of subclasses N05 ( drugs) and N06 (psychoanaleptics) decreased from 191 drugs to 162 and from 108 drugs to 96 respectively. The distribution of subclasses N at admission and discharge is shown in Figure 10 .

250

200 184 191 162 150 126 108 96

100 Numberofdrugs 50

0 N01 N02 N03 N04 N05 N06 N07 Subclassification of drug class N Admission Discharge

Figure 10 : Number of drugs at admission and discharge per subclass of N

Drug class N is subdivided into following subclasses : (N01) drugs, (N02) Analgesic drugs, (N03) Antiepileptic drugs, (N04) Antiparkinson drugs, (N05) Psycholeptic drugs, (N06) Psychoanaleptics and (N07) Other nervous system drugs

36 | RESULTS

4.5. Deprescribing

The clinical pharmacist in training made 357 different reports in the EMR of the patients which contained 847 recommendations. For 89.7% of the included patients (n=398) at least one intervention was suggested. Minimum 1 recommendation was accepted in 80.4% of the reports and in 75.6% minimum 1 recommendation was implemented. A total of 4298 drugs were taken at admission. The clinical pharmacist in training proposed to reduce 656 drugs in which 379 drugs were deprescribed effectively. Overall, 15.3% of all drugs at admission were reduced. At first, 228 withdrawal schemes for benzodiazepines were proposed. The geriatrician accepted 209 schemes (91.7%) but unfortunately only 134 schemes (58.8%) were implemented by the geriatrician due to negligence, forgetting or reviewed opinion. For the 209 accepted withdrawal schemes, a counseling was considered by the pharmacist. 148 patients were questioned about their willingness to withdraw these drugs. 79.1 % of the interviewed patients were motivated for cessation and 20.9% were unwilling. Although 61 of 209 patients were eligible for a tapering scheme, they were not approached for an interview due to time shortage or because of weak mental status of the patient. However, in some of these patients a withdrawal scheme was initiated when discussed with the geriatrician and GP. Apart from the BDZ, for 59 patients the reduction of antidepressants was suggested. Dose reduction or complete stopping was implemented in 35 patients. For 18 patients deprescribing of antipsychotics was suggested and in 8 patients the reduction was started. In addition, in 12 patients the reduction of antihistamines was suggested and in 9 patients the reduction was accepted and implemented. Also reduction of anticholinergics was accepted in 9 patients. Dose reduction or stopping of PPI use was suggested in 322 patients. 59.3% of the recommended reductions was accepted by the geriatrician. Prescribing of vitamin D was suggested for 120 patients and was accepted in 63.3% of the patients. A summary of the suggested, accepted and implemented recommendations can be found in Table 14.

Table 14: Summary of the suggested, accepted and implemented interventions

Number of suggested Number of accepted Number of implemented interventions (%) interventions (%) interventions (%)

Total interventions 357 287 (80.4) 270 (75.6)

(De)prescribing of

benzodiazepines 228 209 (91.7) 134 (58.8) antidepressants 59 38 (64.4) 35 (59.3) antipsychotics 18 10 (55.6) 8 (44.4) antihistamines 12 9 (75.0) 9 (75.0) anticholinergics 13 10 (76.9) 9 (69.2) PPI 322 191 (59.3) 181 (56.2) vitamin D 120 76 (63.3) 70 (58.3)

37 | RESULTS

In addition, the first line caregivers were contacted as part of the follow-up. In this study, 145 general practitioners and 104 community pharmacists were informed about withdrawal schemes. Communication with the first line occurred through a discharge letter and medication scheme, either by a telephone call or both. A summary of the communication with the first line caregivers is shown in Table 15.

Table 15: Communication with the first line caregivers

Number of contacts Number of contacts with with GP (%) (n=145) CP (%) (n=104) discharge letter + medication scheme 26 (17.9) 13 (12.5) (written) Telephone call (orally) 16 (11.0) 15 (14.4) Written and orally 103 (71.0) 76 (73.1)

4.6. Follow-up

A follow-up call was performed after discharge by the hospital pharmacist for patients included in the second study period. During this period, 59 patients were eligible to be called after hospitalization regarding the implemented withdrawal schemes. 45 (76.3%) of them could be reached. 8 patients were still on the ward and had not been discharged yet and 6 patients were lost of follow-up. 45 persons were contacted from which 12 patients, 14 family members, 16 nursing home nurses and 3 GPs. For 68.9% of the patients (n=45) no problems were observed and the withdrawal scheme was maintained. However, in 14 (31.1%) of the contacted patients problems were detected. 7 patients were no longer motivated and so the withdrawal attempt failed. But in 3 of the patients sensitization was successful and the withdrawal scheme would be reconsidered with the GP. In 3 patients the withdrawal scheme was stopped due to insufficient follow-up by the first line caregivers. Another explanation of the failure, which occurred in 2 patients, was due to discharge with the wrong medication schedule in which the withdrawal was not clear. And finally for 2 patients the drug was discontinued but another drug was restarted.

38 | RESULTS

5. DISCUSSION ______

5.1. Drug use

5.1.1. Number of drugs

In this research, the mean number of drugs taken at admission was 10.7± 3.8. The number of drugs in community dwelling persons with an age over 80 years, reported in a Belgian study of Wauters et al., was 5.4 (7) and the presence of polypharmacy and excessive polypharmacy was 57.7% and 9.1% respectively. Our observation was that 58.3% of the patients took 10 drugs or more which is higher compared to findings of Wauters et al. A retrospective analysis of patients at geriatric wards in Sydney observed polypharmacy for 60% of the patients and excessive polypharmacy for 11% of the patients (44). Another study of Somers et al. which was performed at the geriatric wards of the Ghent university hospital found an average of 5.9 drugs at admission (17). It is clear that the number of drugs at admission, revealed in this study, was higher compared to findings in the literature. This can be explained by several reasons. First, one of the requirements for inclusion was the minimum intake of 5 drugs. In fact, the complete population of this research was dealing with ‘polypharmacy’ (intake of ≥ 5 drugs). Further, not only regular or chronic medications were taken into account but also acute and temporary drugs (topical, dermatological, ophthalmological, supplements). However, some studies reported higher number of drugs. In a study of Page et al., residents of residential age care facilities were taking an average of 9.3 medicines (18) and in a RCT of Potter et al. an average of 9.6 regular medicines per patient was found. This may be due to the origin of the patient (nursing home resident) and the fact that the majority of the patients lived with dementia which can contribute to a higher number of drugs. In a study of Perehudoff et al. 80% of the patients took 5 medicines or more which is a similar result compared to the findings in this study. The high presence of polypharmacy could be due to the selection method of the patients. Patients for whom a consultation with the geriatric liaison team was requested, were included (53). From our study it can be concluded that the mean number of drugs was higher in women than men. This result was confirmed by a study in the US in which the number of medications increased with age and female gender (54). The mean number of drugs taken at discharge was 11.5 ± 3.6. There was an increase in medicines of 0.8 from admission to discharge. Similar findings were reported in other studies. A study in the US found an increase of 2.9 drugs on an acute medical service. An increase of 6.0 to 6.2 was reported in an older population of a Slovakian study and an increase of 4.1 to 4.7 in an older Australian population at admission (54).

5.1.2. Use of (psychotropic) drugs

The mean ACB score, calculated by the anticholinergic cognitive burden scale by Boustani et al., was 1.3. 26.7% of the included patients had an ACB-score higher than 3. A Belgian health survey of 2013 reported that 7% of the patients, aged over 75 and hospitalized in geriatric departments, had an ACB score higher than 3 (32). Since it is not clear from this latter survey which anticholinergic rating scale was used, comparisons are difficult to make. In a similar research, a prevalence of 17.9% was detected

39 | DISCUSSION when the anticholinergic risk scale (ARS) was used (23). However, it is difficult to extrapolate these results. The ARS listed only 49 medicines compared to 88 medicines listed in the ACB scale and the rating score of certain drugs (i.e. quetiapine) was different between the rating scales. In our study, medicines contributing to anticholinergic burden were not registered. According to Best et al. patients are most exposed to SSRIs, antipsychotics, receptor agonists, (44). Wilson et al. reported similar drug classes which attributed to anticholinergic burden (45). It was shown that a higher anticholinergic burden was associated with cognitive impairment in older people (33), with delirium related hospital admission (44) and fall incidents (45). However, is it useful to calculate anticholinergic burden knowing that risk scales seem to simplify pharmacological mechanisms and do not take into account dose-dependency of anticholinergic adverse effects and possible synergic and antagonistic effects of medicines (33)?

This study showed a mean vitamin D level in serum of 18.4 µg/L. In a research of Broe et al., the effect of vitamin D supplement doses in elderly nursing home residents on fall risk was determined. The mean vitamin D level was similar for this population: 19.5 µg/L. A higher dose of vitamin D was not associated with a lower risk of falls. However, it was shown that patients taking 800IU cholecalciferol per day had fewer fall incidents compared to the placebo group. Similar findings were reported in a Swiss and Australian randomized trial (55). In a meta-analysis of RCTs, it was concluded that a supplementation of 800 IU vitamin D per day reduced the risk of hip and nonvertebral fractures both for ambulatory and institutionalized elderly persons. The importance of vitamin D in elderly with bone loss, was attributed to the beneficial effect on muscle strength and balance (47). Nevertheless, a British clinical trial found no association between the vitamin D level and the risk on falls. The explanation was that serum concentrations of vitamin D were higher in healthy patients, which resulted in fewer falls (55). In this study, the prevalence of the START criterion ‘vitamin D deficiency in patients with a fracture or osteoporosis’ had not been documented. Knowing that 72.8% of the patients with inadequate vitamin D levels (< 30 µg/l) took no vitamin D supplements at admission, the measurement of the prevalence of this START criterion would be beneficial. In a study of Wauters et al. the absence of vitamin D and calcium supplements in patients with known osteoporosis or fragility fractures was 9.1% (56) and according to Dalleur et al. 13.9% (57). This percentages proved the importance of applying the START- criterion in daily practice. However, for 120 patients prescribing of vitamin D was suggested by the clinical pharmacist in training. The effect of this proposed intervention was clear by the shift of drug class with ATC code A on discharge (Figure 7). The drug distribution at discharge showed an increase of 7% in drugs of the alimentary tract and metabolism, which contained vitamins such as vitamin D supplements. The high level of acceptance by the geriatricians was partly due to results revealed by the Belgian health care report. It was revealed that only 16.2% of geriatric patients in AZ Groeninge stayed with vitamin D during hospitalization. This was a poor result compared to the national mean of this report in which 50% of the patients stayed with vitamin D (32). This has convinced the geriatricians to monitor the vitamin D content closely.

In this research 80.4% of the patients were benzodiazepine users. This high percentage may be due to the predetermined inclusion criteria. Based on the distribution of drug classes by ATC code the proportion of nervous system drugs was 27.5%. This latter percentage represented a part of all

40 | DISCUSSION consumed drugs and did not represent the intake per patient. In addition, this distribution was plotted for all patients during the second study period, including those who did not meet the inclusion criteria. 34% of the patients took psychotropic medications in a retrospective study cohort of patients staying at the day clinic of geriatrics in Utrecht (58). On the other hand, the Belgian health care report 2013 mentioned a national average of BDZ use of 18% (32). This report seems to underestimate the BDZ use in the geriatric population compared to other findings. In this study research, no relationship between the intake of benzodiazepines and fall incidents (p-value = 0.411) was found. This was against all expectations. The absence of statistical significance may be due to the low number of non-BDZ users in the study. Secondly, it may be due to the selection of the patients. 49% was admitted via orthogeriatrics in which the incidence of fall incidents and fractures is high. Better results would be obtained if diazepam equivalents were linked to fall incidents, rather than the use of benzodiazepines. Nevertheless, in a systematic review by Leipzig et al., the relation between fall risk and psychotropic drugs was investigated. Several studies found an association between falls and the intake of psychotropic medication such as antidepressants, neuroleptics and benzodiazepines (15; 59). However, in a study of Van Strien et al. distinction was made between incidental falls and recurrent falls. In this latter study, only an association between the intake of psychotropic medication and multiple falls was found. The reason of a single fall was attributed to an underlying cause, but for patients with recurrent falls the link with psychotropic medication was more obvious. The effect of antipsychotics on falls was attributed to drug effects on gait and stability. Tapering antipsychotic medication was found to improve the mobility of geriatric patients (58). In addition, taking benzodiazepines, including short-and long-acting molecules, would contribute to more fall incidents. However, it had been concluded that only long-acting benzodiazepines had a higher risk on fall incidents. This effect can be explained because half-lives of benzodiazepines may seem longer due to reduced hepatic drug clearance in the elderly (58). Finally, the link of fall incidents with antidepressants, mainly SSRIs, was demonstrated. These drugs were described as having a direct effect on fall incidents through their sedative and orthostatic effects. Next, Strien et al. found significant differences in living situation and sex between psychotropic and non- psychotropic users. The group of psychotropic users had more females and more patients lived in long term care facilities or had professional help. A similar result was confirmed in this study, female patients were more likely to take benzodiazepines (p < 0.001). However the link between benzodiazepine use and residence in a nursing home could not be confirmed. Moreover, Strien et al. found that psychotropic medication users took an average of 8.8 medications compared to 5.1 medicines among non users (58). In this research, the largest group of BDZ users had a diazepam equivalent between 0 and 5 or between 15 and 20 mg. The mean diazepam equivalent was 13.5 mg. No similar study reported consumption data of diazepam equivalents in the elderly. However, in a study of Ray et al. an association between diazepamequivalents and the rate of falls was reported. A higher risk of falls was associated with higher diazepam doses (60). The link between diazepam doses and risk on falls was not investigated in this research. In this study the most common taken benzodiazepines among benzo-users were lorazepam (32.5%), lormetazepam (29.1%) and zolpidem (15.9%). Also Wayne et al. observed that the most frequent intermediate-acting benzodiazepine was lorazepam (64.7% of all benzodiazepine use) (60). The INCB

41 | DISCUSSION reported a high manufacture of alprazolam, diazepam and lorazepam during the period 2006-2015 which followed the overall trend in consumption. According to a report of ‘The Order of Pharmacists’ in France, the most consumed benzodiazepines were alprazolam, zolpidem and bromazepam. In this study 41.2 % of the admissions were attributable to drug related problems, in which 2.8 % were considered to be the dominant reason for hospital admission and 38.4% were found to partly contribute to admission. This percentage was high compared to a study of Somers et al. in which 20.9% of the patients presented with a drug related admission. Additionally, patients admitted due to a DRP took a higher number of drugs compared to patients who were admitted because of other reasons. No relationship between DRPs and residence in nursing home or sex was found according to Somers et al. (17). No association between DRPs and nursing home residents was found (p-value = 0.226) according to our study. However, female patients were found to be more admitted because of drug related problems compared to men (p-value = 0.003). In a review of Beijer et al, the prevalence of HARMs varied from 0.4 to 41.3%. This variation was attributed to a large number of studies which reported a lower percentage of ADR related hospital admissions compared to smaller studies. Moreover, it was shown that the percentage among elderly was 4 times higher than in the younger population: 16.6% compared to 4.1%. And if hospitalizations were prevented, 7 times more elderly could be kept out of hospital than non-elderly. A high amount of money seems to be wasted, thinking of all these preventable hospitalizations (61). In this study, no relationship between the prevalence of DRPs and age was found. However, patients admitted due to a DRP were younger compared to patients admitted for another reason according to Somers et al. Despite the large sample size, the method used to detect DRPs in our study was not well substantiated. Considerations concerning DRPs were not discussed with other healthcare providers and the causality of the DRP was not evaluated. Probably this attributed to a higher prevalence of DRPs and insignificance between the variables.

5.1.3. Types of drugs

The main drug classes at admission were the nervous system drugs (27.5%), cardiovascular drugs (26.7%) and drugs of the alimentary tract and metabolism (21.1%) Compared to a study of Perehudoff et al., in which the relationship between discrepancies and potential clinical outcomes was assessed for patients admitted to non-geriatric wards at the Ghent University Hospital, the 3 main classes were identical. These consisted of 30% cardiovascular drugs, 19% central nervous drugs and 16% alimentary tract drugs (53). In a study of Dalleur et al. at the University Hospital St-Luc in Brussels, the most frequent drugs prescribed in community dwelling older patients were 38.8% of (N05), 24.3% drugs for acid related disorders (ATC code A02), 23.1% of psychoanaleptics (N06) and 20.3% of cardiac therapy (ATC code CO1) (57). In this study, the ATC codes of drugs were not always documented at the time of discharge from the hospital. For example, medication changes conducted on another ward than geriatric wards were not documented when the patient was transferred before discharge. Differences between ATC distribution at admission and discharge are discussed below. In this study the increase of alimentary tract drugs was one of the largest differences between admission and discharge. This increase may be due to prescribing of vitamin D and drugs for constipation during hospitalization. In addition, considering the focus of this project, it is surprising that the subclass A02 only decreased 42 | DISCUSSION from 99 to 95 drugs. This can be explained by the fact that mostly the dose was reduced (i.e. Pantomed® 40 mg to 20 mg) which had no effect on the ATC code. The ATC code is a classification system and does not take into account the assumed average maintenance dose per day. Another remarkable change was the decrease of the proportion of cardiovascular drugs. This reduction was mainly due to a decrease of cardiac drugs (antiarrhythmics and cardiac glycosides) and a decrease of lipid modifying agents. The latter drug class was probably stopped during hospitalization because primary prevention did not benefit from life expectancy. Although the slight decrease (1.1%) of ATC class N compared to admission, the shift of subclasses N was an important observation in this study. The distribution of the subclasses showed that the proportion of analgesic drugs had increased strongly (from 126 to 184 drugs). The increase of pain medication was expected because many patients were recovering from a fall incident and underwent surgery of a knee or hip replacement. In addition, the increase of oral could be attributed to the increased prescription of opioid at discharge. Although, the association of laxatives with the regular use of opioids was absent in 10.7% of the cases according to a study of Wauters et al (56). A measurement of the prevalence of START criteria beyond the scope of this research. The proportion of psycholeptics (N05) and psychoanaleptics (N06), on the other hand, had decreased from 191 at admission to 162 drugs at discharge and from 108 to 96 respectively. It would have been better to distinguish between patients in which only a dose reduction occurred compared to patients in which a tapering schedule was initiated and the medication was ceased. The ATC code remained the same for patients who were discharged with a reduced dose of a drug and the proportion of that drug class did not decrease at discharge. A possibility in the future is to take into account the defined daily dose (DDD). The defined daily dose is the considered average maintenance dose per day for a drug used for its main indication in adults. In a study of Tjagvad et al., benzodiazepine prescriptions and factors associated with increasing amounts of benzodiazepines were studied in patients aged between 18 and 67 years. For each prescription, the numbers of DDD dispensed were measured. In addition, patients were classified into 2 groups depending on whether they took more (high dose) or less (moderate dose) than 584 DDD per year. Tjagvad et al. concluded that 30% of the patients was prescribed more than 365 DDD per year, which indicated a therapeutic amount of benzodiazepine in its main indication per day or in other words 1 DDD per day. This number indicates an inappropriate use of benzodiazepines (62). A DDD measurement can detect dose reductions and provides better insight into drug changes at discharge. The distribution of the ATC drug classes at discharge was similar to findings in the Belgian health report 2013. In this survey, the prevalence of patients, who had been discharged with psychotropic medication and PPIs, was 26% and 21% respectively. These results corresponded to findings reported in the study of Potter et al. in which the most commonly prescribed new medications were laxatives, analgesics and vitamins in addition to eye drops and topical agents (63). Also a study of Somers et al. (2010) showed a decrease in the use of psychotropic medication and an increase in the use of laxatives (17).

43 | DISCUSSION

5.1.4. Prevalence of PIPs according to STOPP D

The PIP prevalence of the STOPP criteria category D, observed in this study, was very high: 94.0% at admission and 66.8% at discharge. A limitation of the registration of PIPs at discharge was that PIPs resolved without requirement of pharmacist involvement, may not have been documented. The Mc Nemar test showed that the STOPP indicators D1, D2, D5, D8, D14 and F2 were significantly different at discharge. The absence of statistical significance in the remaining documented STOPP indicators may be due to the low incidence in patients. In a systematic literature review of Tommelein et al. that aimed to determine the prevalence and type of PIPs for community dwelling patients, the overall PIP prevalence was 22.6% (64). In an investigation of older patients admitted to six European hospitals, the PIP prevalence was determined by using the STOPP criteria and was 51.3% (65). The large difference in PIP prevalence could be attributed to different living situations: community dwelling patients compared to acute sick patients in the hospital. However, a cross sectional study of a cohort of older Belgian patients in primary care found a PIP prevalence of 41% (57). Prevalences may vary depending on the selected STOPP criteria and the way of applying and interpreting the tools by various healthcare providers. Recommendations to improve the validity and applicability of explicit tools are suggested in the study of Dalleur et al. The validity of explicit criteria could be improved by mentioning contraindications for criteria and by avoiding contradictions and overlaps. The applicability of explicit criteria on the other hand, could be improved by clearly describing the conditions, drug categories and diseases, by suggesting tips and possible alternatives (57). The high PIP prevalence of 94% in this study research is probably due to the high number of benzo users (80.4%) at admission. The STOPP criterium D5 (use of benzodiazepines longer than 4 weeks) was met for all benzo users and therefore a high overall prevalence was detected. The most frequently drugs involved in PIPs were , antidepressants and NSAIDs according to a study of Tommelein et al (64). In our study, the most common drugs involved at admission were benzodiazepines (80.4%), PPIs (49.2%), anticholinergics (11.8%) and antidepressants (7%). The prevalence of all these drugclasses was significantly reduced at discharge. A strong decrease of PPI users and BDZ users took place, from 80.4% to 45.5% and from 49.2% to 25.0% respectively. The most common contributing STOPP criteria were benzodiazepines and neuroleptic drugs in older patients with recurrent fall incidents (15.2%) and prolonged prescription of high-dose proton pump inhibitors (8.2%) according to Gallagher et al. (65). In a research of Wauters et al., in which the impact of inappropriate prescribing in people aged over 80 years was studied, the most common criterion for misuse was the intake of benzodiazepines for longer than 4 weeks (35%). In addition, the absence of vitamin D and calcium supplements in patients with known osteoporosis was 9.1% (56). A study of Dalleur et al. reported a PIP prevalence of 4.9% for long-acting benzodiazepines (57). The large difference can be explained by the fact that every intake of a (short or long-acting) benzodiazepine for more than 4 weeks was recorded in our study. The prevalence of benzodiazepines and neuroleptic drugs in older patients with recurrent falls was not measured.

44 | DISCUSSION

5.2. Deprescribing

In this study 656 drugs or 15.2% of all drugs at admission (n= 4298) were suggested to deprescribe. In a study of Page et al. even 271 drugs or 58% of all drugs (n=464) of the residents were targeted to deprescribe (18). Page et al. performed a complete medication review for each resident and thus more drugs were targeted to deprescribe. For 75.6% of the patients in this study at least one recommendation was accepted, which is lower compared to a randomized controlled trial of Potter et al. in which at least 1 drug was tapered in 89% of the participants. Also in a RCT of Gallagher et al. the acceptance rate was high; 91% of STOPP recommendations and 97% of START recommendations were accepted and implemented (26). In a study of Klopotowska et al.in which the participation of a hospital pharmacist in reducing prescribing errors and HARMs was investigated on ICU, 71% of the recommendations were accepted by the ICU physicians. The lower degree of acceptance in our study may be due to the drug classes that were targeted. On the other hand, no complete appropriateness check of the medication scheme at admission was performed and less drugs were proposed to deprescribe. Finally in 31 (20.9%) patients was no cessation attempted since the willingness to cease a medication was absent. In a study of Reeve et al., the patients willingness to stop medications was checked by administering questionnaires and was found to be 89% in older patients. However, the real-life acceptance rate of this withdrawal attempt was expected to be lower (66). In several studies, different acceptances rates are found. For example in a RCT of community-dwelling older patients with polypharmacy, only 1.5 drugs of the 4.5 recommended drugs were stopped (67). In a study of Garfinkel al. in which the Good Palliative-Geriatric Practice algorithm was applied, the success rate for discontinuation was very high (82%) (68). Difference in populations on the one hand (palliative versus community-dwelling patients) and the types of drug classes that were targeted on the other hand, can explain the varied degrees of acceptance. Similar findings were mentioned in a study of Potter et al. in which antidepressants, PPIs and benzodiazepines had a lower withdrawal success rate compared to other classes such as biphosphonates, aspirin and iron supplements. It can be concluded that risk-modifying drugs (statins, aspirin, vitamins) were more successfully tapered than symptom-modifying drugs (analgesics, antidepressant, hypnotics) (63). The focus of this study is on psychotropic medication and PPIs, which can explain the lower withdrawal success rate. In addition, several problems were recurring for certain BDZ users. A first example was the almost impossible reduction of Flunitrazepam®, a long-acting benzodiazepine that was equated to narcotic drugs by the Belgian government. Almost all users, included in this study, refused the withdrawal of this drug. In the past, the addiction to Flunitrazepam®, was already recognized by the International Narcotics Control Board (INCB). The INCB was concerned about the sale of this molecule on the illicit market in frequent diversions (69). In this research, telephone conversations with GPs revealed that this molecule is not frequently prescribed nowadays, only for elderly patients who took it for years. A second common problem is the intake of multiple benzodiazepines in addicts admitted to hospital. When a patient with problematic alcohol use suddenly stops or reduces drinking, withdrawal symptoms may occur. Benzodiazepines appear to be the most appropriate therapy to treat alcohol withdrawal. They act on neurotransmission pathways and have cross-tolerance with . The preference is given to long-acting benzodiazepines (Valium®, Tranxene®) because increased 45 | DISCUSSION compliance and reduced morbidity (due to less pronounced withdrawal symptoms) is expected (70). Kosten et al. referred to a study in which a significant reduction of withdrawal symptoms was found with benzodiazepines compared to the placebo group (71). However, for patients with a problematic benzodiazepine use in combination with a problematic alcohol use, the administration of long-acting benzodiazepines is contraindicated because of risk on oversedation. But when do we speak of a problematic benzodiazepine use? Should we substitute all benzodiazepines to an equivalent dose of diazepam? And if we should add another benzodiazepine, do we run the risk that these patients will get used to this higher dose? (70; 72). The article of Kosten et al. refers to studies in which carbamazepine seemed effective in patients undergoing benzodiazepine withdrawal. One last consideration is the position of alternative medication therapies in the treatment of sleeping disorders. Considering the increase in the number of prescriptions for psychotropic drugs in Belgium, we may ask questions about the adequacy of these prescriptions. A number of patients are prescribed psychotropic drugs while an alternative is possible. Fytotherapy could be one of the possible alternatives. Herbs such as Passiflora, and (pyrones) are often incorporated into plant preparations. The latter is an extract of a pepper plant, but should cause liver failure and it is not permitted in Belgium. Passiflora preparations are commercialized and are known under the brand names Sedinal®, Sedistress® and Valdispert®. Valerian is used in Dormiplant®, Sedistress sleep®, Valdispert®,.. (73) Usually these phytopreparates are not included into the hospital's formularium and thus alternatives are not systematically presented during the counseling of the patient. However, the addition of these preparations to a withdrawal scheme of benzodiazepines could be an option for patients who are convinced they need ‘a sleeping pill’. Another possible alternative is the use of the hormone . In Belgium only 1 drug has been registered, known under the brand name Circadin® at a dose of 2 mg melatonine (73). However, variable ranges of doses are available in herb shops. The use of this agent was investigated for jet lag, but according to the SPC this agent has only indications for short-term primary in people aged over 55 (74). And finally, the use of trazodone in low doses (between 25 and 100 mg) is common in the elderly. Trazodone is used for its sedative side effects, but actually it is indicated for depression in doses between 150 and 300 mg. The addition of Trazolan® to the patients therapy next to the use of benzodiazepines is often seen in patients with complaints of insomnia.

5.3. Follow-up

In this study, the follow-up after hospitalization revealed that for 31.1% of the patients the withdrawal attempt failed. In a review of Reeve et al., some approaches to optimize the patients’ willingness to cease medications are represented. This includes: presenting deprescribing in a way that does not provoke stress or fear and does not affect the relationship with the prescriber, by clarifying that the advice is formulated to achieve therapeutic goals and by making clear the steps of the reduction process. Furthermore, it is important to consider every adult individually for deprescribing and to mention that deprescribing is a trial (75; 66). In a systematic review of 31 studies was found that diuretics, antihypertensives and psychotropic medication could be discontinued without problems. Especially psychotropic medication had a high risk of relapse (63).

46 | DISCUSSION

In several articles, the need for follow-up after discharge was emphasized in which the patients preference was a face-to-face conversation over a telephone call (75). However, in a study of Haynes et al., which objective was to determine the role of a pharmacist in improving care transitions, also follow- up calls were performed. These post-discharge calls were conducted by non-healthcare professionals, making this follow-up less time-consuming and less expensive than when performed by a pharmacist. However, some pharmacists preferred to conduct the follow-up call personally (39). On the other hand, in a study of Gujral et al. the impact of CPs on discussing patients’ belief about their myocard infarct drugs did not improve the medication adherence at 12 months. In this latter study, a face-to-face conversation by the researcher 5 to 6 weeks after discharge preceded the telephone call conducted by the CP 3 months after discharge (76). However according to a review by Nazar et al., in which the contribution of CPs in improving transfer of care was studied, CPs could play a role in the identification of DRPs. The interventions of CPs in the reviewed studies were characterized by home visits within a certain period of time after discharge, reporting discrepancies in the prescribed drugs after comparison with the medication schedule at discharge or by a medical review a few months post- discharge (37). It is clear that in also in our study the follow-up after discharge was an added value. However, the interviewer did not use a standardized questionnaire that determined sleep quality and possible withdrawal symptoms. In a study of Baldwin et al. the association between sleeping disorders and the effect on quality of life (QOL) was investigated by using the short form (SF) – 36 questionnaire. This was a measurement for health-related quality of life including questions about physical and social activities, pain, mental health, emotional problems, vitality and general health perceptions. Another example of a questionnaire which focused specifically on sleep habits was the Sleep Habits Questionnaire (SHQ) which was completed by patients in the study of Baldwin et al (77). There are plenty of ways to measure sleep quality or quality of life, which is also recommended to be used in future research when conducting a follow-up call post discharge.

5.4. Strengths and limitations of the project and future perspectives

This was a single center observational prospective study. In ideal circumstances, a prospective multicenter randomized controlled trial would have been performed. To determine if the results are generalizable, this study should be performed in several care settings including those in primary care and nursing home care. In addition, this study was only performed on geriatrics, while geriatric patients were spread throughout the hospital. It would be an opportunity to extend this project hospital-wide with the focus on non-psychiatric patients with long-term benzodiazepine use. The full potential of interventions would be more appreciated if there was a comparison with a control group rather than comparison with uncontrolled ‘usual care’. According to Thompson and Schoenfeld, the use of a usual care-arm is appropriate in two-armed randomized controlled trials for drug and devices and for non-pharmacological interventions lying well outside usual-care practices (37). Medication reconciliation was found to be the key factor in improving care transitions according to Haynes et al. Benefits that were cited were: clarifying certain drug therapies for the patient and enabling communication with the doctors (39). Also in this study research, discrepancies or recent therapy changes in the medication scheme were often revealed which took extra time when making recommendations in the EMR. Medication reconciliation is certainly an added value but was beyond the scope of this project, considering the amount of time required.

47 | DISCUSSION

Furthermore, factors as potential drug-drug or drug-disease interactions and adherence but also outcome parameters such as life expectancy, future risk of ADRs and quality of life were not assessed in this research and would be beneficial. The addition of a pharmaco economic analysis would be opportune (75). In future studies, deprescribing should be applied for all categories of the STOPP criteria when detecting inappropriate prescriptions. In addition, also the START criteria should be screened because the effect of misuse and underuse is often omitted. According to a study of Wauters et al., it was demonstrated that patients with a high underuse (3 drugs or more) have a 3.3 fold higher risk of mortality and a 2.8 fold higher risk of hospitalization compared to patients without underuse. The effect of misuse was associated with a higher risk for hospitalization, but not for mortality (56). Another future perspective would be the counseling of patients at discharge. This session, led by a clinical pharmacist, can help patients understand their new medication regimen and can anticipate barriers to noncompliance. A teach-back method, which is mostly not performed by nurses due to lack of time, could improve understanding medication related problems (39). Finally, the information exchange should occur between all healthcare actors, with the necessary information security and protection. An electronic platform of healthcare, called eHealth, was established by the Belgian government in 2008. This allows an electronic exchange of health data through different systems. One of the systems is called Vitalink; this platform includes a vaccination platform (Vaccinet), an exchange platform for medication schemes and includes sumEHR (Summarized Electronic Health Record). The latter is an encrypted and structured file which is accessible for GPs, for specialists in the hospital and for the patient but not for (hospital) pharmacists. Nevertheless, these applications are still in development and are faced with problems such as inadequate usability in software packages (41).

48 | DISCUSSION

6. CONCLUSION ______

This study aimed to evaluate the process of deprescribing on geriatric wards. This evaluation could be organized thanks to the collaboration between the clinical pharmacist, the geriatricians, the general practitioners, community pharmacists and the caregivers in nursing homes. The study showed that the clinical pharmacist could provide at least 1 recommendation for 89.7% of the 398 included patients. These recommendations resulted in a decrease of the prevalence of PIPs with 48.6% at discharge. Moreover, 15.3% of all drugs at admission were deprescribed. This decline could be mainly attributed to accepted interventions by the geriatrician for the reduction of benzodiazepines, antidepressants and PPIs. Besides, the effect of deprescribing was clearly visible in the shift of ATC classes at discharge. The proportion of ATC class A (drugs of the alimentary tract and metabolism) increased with 7% mainly due the increased prescription of drugs for constipation, vitamin D and minerals such as calcium. A favorable shift in the subclasses of the nervous system drugs (ATC class N) took place. This trend showed an expected increase of the analgesic drugs, but also a desired decrease of the proportion of psycholeptic and psychoanaleptic drugs. The involvement of first-line healthcare providers seemed necessary to achieve a good follow-up. For example, follow-up calls with discharged patients revealed that in some cases the tapering scheme was interrupted due to incomplete follow-up. Nevertheless, 68.9% of patients completed the schedule properly so we can conclude that the various contacts with the GP and community pharmacists were beneficial. Deprescribing is not easy and the algorithm should always be personalized. It provides guidance for doctors, pharmacists and other healthcare providers on when and how to reduce or stop medications. Moreover, deprescribing requires a centralized patient approach that takes into account the patients preferences, expectations but also their medical history and medicines. Clinical pharmacists may have an important role in counseling and monitoring the patient and in helping physicians to make decisions regarding deprescription.

49 | CONCLUSION

50 | CONCLUSION

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56 | REFERENCES

8. APPENDICES ______

8.1. FARMAKA – REVISED STOPP CRITERIA 2016

57 |

FARMAKA – REVISED STOPP CRITERIA 2016 (2)

58 | APPENDICES

FARMAKA – REVISED STOPP CRITERIA 2016 (3)

59 | APPENDICES

FARMAKA – REVISED STOPP CRITERIA 2016 (4)

60 | APPENDICES

FARMAKA – REVISED STOPP CRITERIA 2016 (5)

61 | APPENDICES

FARMAKA – REVISED STOPP CRITERIA 2016 (6)

62 | APPENDICES

FARMAKA – REVISED STOPP CRITERIA 2016 (7)

63 | APPENDICES

FARMAKA – REVISED STOPP CRITERIA 2016 (8)

64 | APPENDICES

FARMAKA – REVISED STOPP CRITERIA 2016 (9)

65 | APPENDICES

8.2. ANTICHOLINERGIC COGNITIVE BURDEN SCORE

66 | APPENDICES

8.3. BENZODIAZEPINE AND Z-DRUG DEPRESCRIBING ALGORITHM

67 | APPENDICES

BENZODIAZEPINE AND Z-DRUG DEPRESCRIBING ALGORITHM (2)

68 | APPENDICES

8.4. ETHICS COMMITTEE APROVAL

69 | APPENDICES

ETHICS COMMITTEE APROVAL (2)

70 | APPENDICES

8.5. TEMPLATE INFORMED CONSENT

71 | APPENDICES

8.6. POSTER OF THE ‘DEPRESCRIBING PROJECT’

72 | APPENDICES

8.7. PHARMACEUTICAL REPORT

73 | APPENDICES

PHARMACEUTICAL REPORT (2)

74 | APPENDICES

8.8. LETTER

Saïn Vandepoele Ziekenhuisapotheker in opleiding t. 056/634966 [email protected] campus vercruysselaan

Naam rusthuis Dr. Veronique Ghekiere Adres Medisch diensthoofd geriatrie Postcode + stad t. 056/633232 [email protected] campus reepkaai

Anne Verhaeghe Kortrijk, datum Klinisch apotheker t. 056/635080 [email protected] campus vercruysselaan

Betreft : ‘Deprescribing van psychofarmaca bij de geriatrische patiënt’

Beste

Uw patiënt, XXXXX (naam + geboortedatum), neemt al geruime tijd XXXX (GM), een geneesmiddel die behoort tot de groep van de psychofarmaca.

Veel studies benadrukken de verhoogde incidentie van ernstige risico’s veroorzaakt door polymedicatie bij de geriatrische patiënt. Voornamelijk het chronisch gebruik van benzodiazepines en/of de combinatie met andere psychofarmaca verhogen het risico op verwardheid, duizeligheid, cognitieve stoornis, valaccidenten, verstoorde coördinatie,…. Deze geneesmiddelen kunnen verslavend zijn waardoor mensen last krijgen van angst of slapeloosheid als zij hun tabletten niet innemen. Dit zijn tijdelijke symptomen van ontwenning.

Het is daarom aangeraden om dit/deze geneesmiddel(en) geleidelijk aan te verminderen en zo mogelijk te stoppen. De patiënt werd hiervoor geïncludeerd in het project ‘Deprescribing van psychofarmaca’ binnen AZ Groeninge die als doelstelling heeft om het gebruik van psychofarmaca bij de geriatrische patiënt af te bouwen. Hierbij wordt de medicatie bij opname, die mogelijks gerelateerd is aan de ziekenhuisopname, geëvalueerd door een klinisch apotheker. In samenspraak met de geriater en huisarts kunnen één of meerdere geneesmiddelen in het medicatieschema worden gereduceerd of zelfs worden gestopt. De patiënt wordt hierover geïnformeerd en gestimuleerd. Ook de huisapotheker (indien van toepassing) wordt betrokken in dit project.

Het voorstel is om elke 2 weken de dosis met een fractie te verlagen. Mocht blijken dat dit voor de patiënt te snel gaat, kan in samenspraak met de huisarts beslist worden om het afbouwplan over langere termijn aan te houden.

In bijlage kan je het medicatieschema met het afbouwschema van het/de desbetreffend geneesmiddel(en) van deze patiënt terugvinden.

Binnen een periode van 1 à 2 weken zouden wij u graag opnieuw contacteren om de continuïteit van deze afbouw te bekijken en eventuele onduidelijkheden op te helderen.

Alvast bedankt voor jullie opvolging en medewerking.

Met vriendelijke groeten

Saïn Vandepoele Anne Verhaeghe Veronique Ghekiere Ziekenhuisapotheker Klinisch apotheker Medisch diensthoofd geriatrie in opleiding

75 | APPENDICES

8.9. EQUIVALENCE TABLE OF DIAZEPAM

Diazepam Grenzen aan Werkingsduur Benzodiazepine Specialiteit ATC code dosis(mg) equivalentie equivalentie van 10 mg (mg) diazepam Kortwerkend 0,125 5 Triazolam Halcion N05CD05 0,25 - 0,5 mg 0,25 10 Intermediair Alpratop 0,25 5 Alpraz 0,5 10 Alprazolam N05BA12 0,5 - 1 mg Xanax 1 20 2 40 Bromatop 3 7,0 Bromazepam Lexotan N05BA08 6 14,0 4,5 - 9 mg 12 28,0 Brotizolam Lendormin N05CD09 0,25 10,0 0,25 - 0,5 mg 5 10,0 Clotiazepam Clozan N05BA21 5 - 10 mg 10 20,0 Dormonoct 1 20,0 Loprazolam N05CD11 0,5 - 2 mg 2 40,0 Lorazetop 1,0 5,0 Lorazepam Temesta N05BA06 2,5 12,5 2 - 8 mg Serenase Loramet 1 10,0 Loranka 2 20,0 Lormetazepam Metatop N05BA06 1 - 2 mg Noctamid Stilaze Oxazepam N05BA04 15 10 15 - 100 mg Langwerkend 10 10 Clobazam Frisium N05BA09 20 20 10 - 30 mg 0,5 5,0 Clonazepam Rivotril N03AE01 1 - 4 mg 2 20,0 5 5,0 Tranxene 10 10,0 Clorazepaat N05BA05 10 - 30 mg 50 50,0 Uni-Tranxene 15 15,0 1 10 Cloxazolam Akton N05BA22 1 - 2 mg 2 20 2 2 Diazepam Valium N05BA01 5 5 10 mg 10 10 Ethylloflazepaat Victan N05BA18 2 20 1 - 3 mg Flunitrazepam N05CD03 1 20 0,5 - 2 mg Flurazepam Staurodorm 27 18 15 - 60 mg Nitrazepam Mogadon N05CD02 5 10 5 - 10 mg Nordazepam Calmday N05BA16 5 20 2,5 - 10 mg 10 3 Prazepam Lysanxia N05BA11 30 - 60 mg 20 6 Z-drugs Zolpeduar 5 2,5 Zolpidem Stilnoct N05CF02 10 5,0 20 mg Zolpitop Zoplicone Imovane N05CF01 7,5 5 15 mg

76 | APPENDICES

8.10. STOPP – CRITERIA REVISED DUTCH VERSION (2015)

77 | APPENDICES

STOPP – CRITERIA REVISED DUTCH VERSION (2015) (2)

78 | APPENDICES