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Deprescribing: A narrative review of the evidence and practical recommendations for recognizing opportunities and taking action

  • Emily Reeve
    Correspondence
    Corresponding author at: Geriatric Medicine Research, Queen Elizabeth II Health Sciences Centre, Nova Scotia Health Authority, Rm. 1315 Camp Hill Veterans' Memorial Building, 5955 Veterans' Memorial Lane, Halifax, NS B3H 2E1, Canada.
    Affiliations
    NHMRC Cognitive Decline Partnership Centre, Kolling Institute of Medical Research, Northern Clinical School, Faculty of Medicine, University of Sydney, NSW, Australia

    Geriatric Medicine Research, Faculty of Medicine, Dalhousie University and Capital Health, Nova Scotia Health Authority, NS, Canada
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  • Wade Thompson
    Affiliations
    Bruyère Research Institute, Ottawa, ON, Canada

    School of Epidemiology, Public Health and Preventive Medicine, University of Ottawa, ON, Canada
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  • Barbara Farrell
    Affiliations
    Bruyère Research Institute, Ottawa, ON, Canada

    Department of Family Medicine, University of Ottawa, Ottawa, ON, Canada

    School of Pharmacy, University of Waterloo, Waterloo, ON, Canada
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Published:January 05, 2017DOI:https://doi.org/10.1016/j.ejim.2016.12.021

      Highlights

      • There needs to be greater integration of regular deprescribing into medical culture.
      • Tools and resources are available to assist clinicians in deprescribing.
      • Available evidence suggests that deprescribing has potential benefits and appears safe.

      Abstract

      Deprescribing can be defined as the process of withdrawal or dose reduction of medications which are considered inappropriate in an individual. The aim of this narrative review is to provide an overview of “deprescribing”; firstly discussing the potential benefits and harms followed by the barriers to and enablers of deprescribing. We also provide practical recommendations to recognise opportunities and strategies for deprescribing in practice.
      Studies focused on minimizing polypharmacy indicate that deprescribing may be associated with potential benefits including resolution of adverse drug reactions, improved quality of life and medication adherence and a reduction in drug costs. While the data on the benefits is inconsistent, deprescribing appears to be safe. There are, however, potential harms including return of medical conditions or symptoms and adverse drug withdrawal reactions which emphasise the need for the process to be supervised and monitored by a health care professional.
      Taking action on deprescribing can be facilitated by knowledge of potential barriers, implementing a deprescribing process (utilising developed tools and resources) and identifying opportunities for deprescribing through engaging with patients and caregivers and other health care professionals and considering deprescribing in a variety of populations.
      Important areas for future research include the suitability of deprescribing of certain medications in specific populations, how to implement deprescribing processes into clinical care in a feasible and cost effective manner and how to engage consumers throughout the process to achieve positive health and quality of life outcomes.

      Keywords

      1. Introduction

      Advances in the treatment of medical conditions mean more people are living with multiple co-morbidities for longer, contributing to an ageing population in Western societies [
      • Mathers C.D.
      • Stevens G.A.
      • Boerma T.
      • White R.A.
      • Tobias M.I.
      • Wilmoth J.
      • et al.
      Causes of international increases in older age life expectancy.
      ]. It is imperative that medications are used appropriately in this population to maximise positive health outcomes, while also ensuring the sustainability of government health care programs and minimizing harms to patients. The aim of this narrative review is to provide an overview of “deprescribing”; firstly discussing the potential benefits and harms followed by the barriers to and enablers of deprescribing. We also provide practical recommendations to recognise opportunities and strategies for deprescribing in practice.
      This narrative review was informed by a literature search conducted in August 2016. Published systematic reviews into different aspects of deprescribing were utilised with citation and reference checking (Google Scholar). Additional searches were conducted in PubMed and Google Scholar to determine if there were recent studies not included in these reviews (searched after the date of systematic review search). Where systematic reviews were not identified, additional searches were conducted using keyword searches (e.g. ‘geriatrician’ and ‘deprescribing’ and appropriate variations). Personal reference libraries were also utilised.

      2. What is “deprescribing”?

      The word “deprescribing” first appeared in the literature in 2003 [
      • Woodward M.C.
      Deprescribing: achieving better health outcomes for older people through reducing medications.
      ,
      • Reeve E.
      • Gnjidic D.
      • Long J.
      • Hilmer S.
      A systematic review of the emerging definition of “deprescribing” with network analysis: implications for future research and clinical practice.
      ]. With growing concern worldwide about the negative effects of overuse of certain medications, increasing attention is being paid to approaches to minimize harm. The focus is shifting from prescribing, which has traditionally been thought of as starting or renewing medications, to that of deprescribing - especially as people age. Deprescribing has been defined as “the process of withdrawal of an inappropriate medication, supervised by a health care professional with the goal of managing polypharmacy and improving outcomes” based on a systematic review of articles using this term between 2003 and 2014 [
      • Reeve E.
      • Gnjidic D.
      • Long J.
      • Hilmer S.
      A systematic review of the emerging definition of “deprescribing” with network analysis: implications for future research and clinical practice.
      ]. Dose reduction and switching to safer medications are also considered deprescribing strategies that maintain effectiveness while minimizing harm. The term “inappropriate medication” encompasses medications where the potential risks outweigh the potential benefits in the individual. This includes both medications which are high risk of harm and those which are unnecessary or ineffective. It may also include those that do not fit with the goals of treatment (for example preventative medications in palliative care patients) or align with patient values and preferences and those which are overly burdensome [
      • Reeve E.
      • Gnjidic D.
      • Long J.
      • Hilmer S.
      A systematic review of the emerging definition of “deprescribing” with network analysis: implications for future research and clinical practice.
      ,
      • Hanlon J.T.
      • Schmader K.E.
      The Medication Appropriateness Index at 20: where it started, where it has been, and where it may be going.
      ]. It is important to note that “deprescribing” is very different from non-adherence or non-compliance with medication because it involves health care professional direction and supervision with the same level of expertise and attention that prescribing entails.

      3. What are the benefits of deprescribing? Are there any risks?

      Polypharmacy and potentially inappropriate medications have been associated in observational studies with a number of negative health outcomes including reduced quality of life, adverse drug reactions (ADRs), falls, non-adherence, hospitalisation and mortality [
      • Hajjar E.R.
      • Cafiero A.C.
      • Hanlon J.T.
      Polypharmacy in elderly patients.
      ,
      • Jyrkkä J.
      • Enlund H.
      • Korhonen M.J.
      • Sulkava R.
      • Hartikainen S.
      Polypharmacy status as an indicator of mortality in an elderly population.
      ,
      • Olsson I.N.
      • Runnamo R.
      • Engfeldt P.
      Medication quality and quality of life in the elderly, a cohort study.
      ,
      • Wallace E.
      • McDowell R.
      • Bennett K.
      • Fahey T.
      • Smith S.M.
      Impact of potentially inappropriate prescribing on adverse drug events, health related quality of life and emergency hospital attendance in older people attending general practice: a prospective cohort study.
      ,
      • Maher R.L.
      • Hanlon J.
      • Hajjar E.R.
      Clinical consequences of polypharmacy in elderly.
      ]. For example, Passarelli et al. [
      • Passarelli M.C.G.
      • Jacob-Filho W.
      • Figueras A.
      Adverse drug reactions in an elderly hospitalised population: inappropriate prescription is a leading cause.
      ] found that an older adult prescribed a potentially inappropriate medication had double the chance of experiencing an ADR compared to an older adult not taking a potentially inappropriate medication. In turn, it is assumed that if we reduce doses of or stop inappropriate medications and minimize the number of medications taken then this will amount to reduced harms and/or benefits. However, potential benefit needs to be balanced against any risks that may arise from medication deprescribing.
      Recently, Huizer-Pajkos and colleagues developed a mouse model of polypharmacy to try and clarify whether there is harm due to polypharmacy in itself [
      • Huizer-Pajkos A.
      • Kane A.E.
      • Howlett S.E.
      • Mach J.
      • Mitchell S.J.
      • De Cabo R.
      • et al.
      Adverse geriatric outcomes secondary to polypharmacy in a mouse model: the influence of aging.
      ]. Both young and old mice were administered a ‘polypharmacy diet’ which consisted of therapeutic doses of five commonly prescribed medications: simvastatin, metoprolol, omeprazole, acetaminophen and citalopram. They found significant declines in mobility, balance and strength in the older polypharmacy diet group (compared to an older group fed a control diet), but no differences in the younger groups. While further studies are needed to confirm these results, the polypharmacy mouse model provides an opportunity to explore the outcomes and reversibility of polypharmacy and inappropriate medication use in a controlled setting.

      3.1 Deprescribing studies

      When reviewing the literature on the benefits and harms of deprescribing, the types of studies can be broadly classified into two groups.
      The first type are studies which focus on whether or not an intervention (e.g. educational intervention, medication review) is effective, with the main outcome the number of medications or number of inappropriate medications used across the population. They generally target older adults, polypharmacy or specific medication classes. The measurement of the effect on health outcomes of deprescribing in these studies is highly dependent on whether or not the intervention works.
      The second type of study targets a specific medication or class of medications in a specific population where use of this medication is considered inappropriate. The target medication is stopped and health outcomes are measured. These types of studies are essential for the development of drug-specific deprescribing guidelines [
      • Farrell B.
      • Pottie K.
      • Rojas-Fernandez C.
      • Bjerre L.
      Methodology for developing deprescribing guidelines: using evidence and GRADE to guide recommendations for deprescribing.
      ] to provide guidance on when it is suitable to withdraw medications. They also have the benefit of measuring drug-specific outcomes including resolution of adverse effects or reduction of risk (e.g. reduced falls and improved cognition following withdrawal of psychotropic medications) [
      • Iyer S.
      • Naganathan V.
      • McLachlan A.J.
      • Le Couteur D.G.
      Medication withdrawal trials in people aged 65 years and older: a systematic review.
      ]. The limitation of this type of study is that only a single medication class can be studied in a specific sub-population at a time which may not cover all situations in which it would be inappropriate.

      3.2 Systematic reviews of the health-related outcomes of deprescribing

      Several systematic reviews have aimed to synthesise the evidence of the feasibility and outcomes of deprescribing [
      • Iyer S.
      • Naganathan V.
      • McLachlan A.J.
      • Le Couteur D.G.
      Medication withdrawal trials in people aged 65 years and older: a systematic review.
      ,
      • Gnjidic D.
      • Le Couteur D.G.
      • Kouladjian L.
      • Hilmer S.N.
      Deprescribing trials: methods to reduce polypharmacy and the impact on prescribing and clinical outcomes.
      ,
      • Page A.
      • Clifford R.
      • Potter K.
      The feasibility and the effect of deprescribing in older adults on mortality and health: a systematic review.
      ,
      • Johansson T.
      • Abuzahra M.E.
      • Keller S.
      • Mann E.
      • Faller B.
      • Sommerauer C.
      • et al.
      Impact of strategies to reduce polypharmacy on clinically relevant endpoints - a systematic review and meta-analysis.
      ,
      • Cooper J.A.
      • Cadogan C.A.
      • Patterson S.M.
      • Kerse N.
      • Bradley M.C.
      • Ryan C.
      • et al.
      Interventions to improve the appropriate use of polypharmacy in older people: a Cochrane systematic review.
      ].

      3.2.1 Intervention studies

      Gnjidic et al. [
      • Gnjidic D.
      • Le Couteur D.G.
      • Kouladjian L.
      • Hilmer S.N.
      Deprescribing trials: methods to reduce polypharmacy and the impact on prescribing and clinical outcomes.
      ], identified that a variety of interventions successfully reduced the number of medications taken by participants. There was, however, minimal and conflicting data on clinical outcomes. Out of the 30 studies identified, only half measured any type of clinical outcome. Six studies reported some benefit on clinical outcomes (e.g. reduction in serious ADRs), however the remaining nine found no positive effect of the intervention [
      • Gnjidic D.
      • Le Couteur D.G.
      • Kouladjian L.
      • Hilmer S.N.
      Deprescribing trials: methods to reduce polypharmacy and the impact on prescribing and clinical outcomes.
      ]. Similarly, Johansson et al. [
      • Johansson T.
      • Abuzahra M.E.
      • Keller S.
      • Mann E.
      • Faller B.
      • Sommerauer C.
      • et al.
      Impact of strategies to reduce polypharmacy on clinically relevant endpoints - a systematic review and meta-analysis.
      ] and Cooper et al. [
      • Cooper J.A.
      • Cadogan C.A.
      • Patterson S.M.
      • Kerse N.
      • Bradley M.C.
      • Ryan C.
      • et al.
      Interventions to improve the appropriate use of polypharmacy in older people: a Cochrane systematic review.
      ] found that interventions to reduce polypharmacy generally lead to a reduction in inappropriate medication use, however, were unable to confirm that this leads to clinically important end-points such as improved mortality or reduced hospital admissions.

      3.2.2 Medication-specific studies

      Iyer et al. conducted a systematic review of studies examining deprescribing of specific medication classes. They found studies on withdrawal of diuretics, antihypertensives, psychotropics, digoxin and nitrates [
      • Iyer S.
      • Naganathan V.
      • McLachlan A.J.
      • Le Couteur D.G.
      Medication withdrawal trials in people aged 65 years and older: a systematic review.
      ]. Several of the studies on psychotropics indicated a benefit to withdrawal and overall the authors concluded that withdrawal of certain medication classes appeared to be safe, but that there were limitations to the study and their review (including poorly described search strategy, single author screening and no formal quality assessment) [
      • Iyer S.
      • Naganathan V.
      • McLachlan A.J.
      • Le Couteur D.G.
      Medication withdrawal trials in people aged 65 years and older: a systematic review.
      ]. Withdrawal of non-psychotropic drugs could also result in benefits including reduced ankle oedema (nitrates) and nausea and vomiting (digoxin) [
      • Iyer S.
      • Naganathan V.
      • McLachlan A.J.
      • Le Couteur D.G.
      Medication withdrawal trials in people aged 65 years and older: a systematic review.
      ]. Declercq et al. conducted a Cochrane review (9 RCTs, 606 patients) into the withdrawal of antipsychotics in people with dementia [
      • Declercq T.
      • Petrovic M.
      • Azermai M.
      • Vander Stichele R.
      • De Sutter A.I.
      • van Driel M.L.
      • et al.
      Withdrawal versus continuation of chronic antipsychotic drugs for behavioural and psychological symptoms in older people with dementia.
      ]. They found that withdrawal does not appear to have a detrimental effect on behavioural symptoms for the majority of participants [
      • Declercq T.
      • Petrovic M.
      • Azermai M.
      • Vander Stichele R.
      • De Sutter A.I.
      • van Driel M.L.
      • et al.
      Withdrawal versus continuation of chronic antipsychotic drugs for behavioural and psychological symptoms in older people with dementia.
      ].
      Page et al. summarized both types of studies in their systematic review conducted in 2015 [
      • Page A.
      • Clifford R.
      • Potter K.
      The feasibility and the effect of deprescribing in older adults on mortality and health: a systematic review.
      ]. They identified 21 studies which aimed to minimize polypharmacy (i.e. non-medication specific) and a further 111 studies which looked at deprescribing of one or two specific medications, medication classes or therapeutic groups. In their meta-analysis of non-randomised studies, minimizing polypharmacy was associated with a significant reduction in mortality (OR 0.32, 95% CI:0.17–0.60), this effect, however, was not found in the meta-analysis of randomised studies (OR 0.82, 95% CI: 0.61–1.11). This difference may be due to bias in the non-controlled studies (n = 2) or large variability in the type of interventions of the randomised studies (n = 10). Deprescribing of specific medications was not associated with a significant difference in mortality [
      • Page A.
      • Clifford R.
      • Potter K.
      The feasibility and the effect of deprescribing in older adults on mortality and health: a systematic review.
      ].

      3.3 Limitations of deprescribing studies

      There are several explanations for the minimal evidence of benefit on clinical outcomes such as mortality or falls [
      • Hajjar E.R.
      • Cafiero A.C.
      • Hanlon J.T.
      Polypharmacy in elderly patients.
      ,
      • Gnjidic D.
      • Le Couteur D.G.
      • Kouladjian L.
      • Hilmer S.N.
      Deprescribing trials: methods to reduce polypharmacy and the impact on prescribing and clinical outcomes.
      ,
      • Johansson T.
      • Abuzahra M.E.
      • Keller S.
      • Mann E.
      • Faller B.
      • Sommerauer C.
      • et al.
      Impact of strategies to reduce polypharmacy on clinically relevant endpoints - a systematic review and meta-analysis.
      ]. The sample size and follow-up periods in many studies are too small/short to detect a difference. As previously mentioned, the effect on clinical outcomes is likely dependent on the success of the intervention (i.e. how many medications are withdrawn/dose reduced). However, many studies aimed at reducing polypharmacy only have a small average affect across the population. For example, a difference of 0.4 mean drugs per person between intervention (−0.2) and control (+0.2) was found in a meta-analysis of twenty-five studies [
      • Johansson T.
      • Abuzahra M.E.
      • Keller S.
      • Mann E.
      • Faller B.
      • Sommerauer C.
      • et al.
      Impact of strategies to reduce polypharmacy on clinically relevant endpoints - a systematic review and meta-analysis.
      ]. Additionally, there has been question as to whether the harm caused by inappropriate medications and polypharmacy is reversible. Polypharmacy and potentially inappropriate medications may not be directly responsible for the associated harm, and instead may be a surrogate marker for another variable which is not accounted for in the analysis, for example severity of co-morbidities [
      • Jyrkkä J.
      • Enlund H.
      • Korhonen M.J.
      • Sulkava R.
      • Hartikainen S.
      Polypharmacy status as an indicator of mortality in an elderly population.
      ,
      • Gómez C.
      • Vega-Quiroga S.
      • Bermejo-Pareja F.
      • Medrano M.J.
      • Louis E.D.
      • Benito-León J.
      Polypharmacy in the elderly: a marker of increased risk of mortality in a population-based prospective study (NEDICES).
      ]. It could be argued that establishing a solid benefit (e.g. reduction in mortality) of deprescribing is not necessary. If an intervention enables identification and withdrawal or dose reduction of medications deemed to be inappropriate in the individual, without a worsening in outcomes, then this should be seen as a benefit in itself. Patient-important outcomes such as quality of life or patient satisfaction may also be particularly important to explore. In many older adults (and patients at end-of-life), quality of life and decreased burden of care are valued over risk reduction or prolonging life [
      • Hardy J.E.
      • Hilmer S.N.
      Deprescribing in the last year of life.
      ]. The scepticism surrounding the outcomes of deprescribing appears to centre on the determination of which medications are suitable for deprescribing. An example of this debate surrounds the medication class of statins which are prescribed for both primary and secondary prevention of cardiovascular disease. A recent randomised controlled trial (n = 381) established that there was no mortality difference between statin continuers and discontinuers at 60 days in patients with a life expectancy of less than 12 months (quality of life was significantly better in the discontinuation group) [
      • Kutner J.S.
      • Blatchford P.J.
      • Taylor Jr., D.H.
      • et al.
      Safety and benefit of discontinuing statin therapy in the setting of advanced, life-limiting illness: a randomized clinical trial.
      ]. Outside of the end of life context, the evidence is less clear. Some authors argue based on the scarcity of evidence in primary prevention in certain populations (e.g. those over 75 years old with multimorbidity and/or frailty) and potential for harm, that statins deprescribing may be suitable in this population [
      • Gnjidic D.
      • Fastbom J.
      • Fratiglioni L.
      • Rizzuto D.
      • Angleman S.
      • Johnell K.
      Statin therapy and dementia in older adults: role of disease severity and multimorbidity.
      ,
      • Rich M.W.
      Cost-effectiveness of statins in older adults: further evidence that less is more.
      ]. Yet other authors highlight that the older population, has greater potential to benefit based on their greater risk of cardiovascular disease (although many cardiovascular risk calculators are only validated in patients less than 75 years old) and that the evidence on harms has been overstated [
      • Strandberg T.
      Deprescribing statins—is it ethical?.
      ].

      3.4 Pharmacoeconomic evidence on deprescribing

      In addition to clinical outcomes, deprescribing may also lead to reduced drug costs. Given the ageing population and associated polypharmacy, the government cost of subsidisation of pharmaceuticals is increasing [
      • Kemp A.
      • Preen D.B.
      • Glover J.
      • Semmens J.
      • Roughead E.E.
      How much do we spend on prescription medicines? Out-of-pocket costs for patients in Australia and other OECD countries.
      ]. Cessation of medications can release funds to be spent on other, higher utility interventions, as well as having cost benefits for the consumer. A number of deprescribing interventions have established a decrease in drug costs [
      • Kutner J.S.
      • Blatchford P.J.
      • Taylor Jr., D.H.
      • et al.
      Safety and benefit of discontinuing statin therapy in the setting of advanced, life-limiting illness: a randomized clinical trial.
      ,
      • Garfinkel D.
      • Zur-Gil S.
      • Ben-Israel J.
      The war against polypharmacy: a new cost-effective geriatric-palliative approach for improving drug therapy in disabled elderly people.
      ,
      • Williams M.E.
      • Pulliam C.C.
      • Hunter R.
      • Johnson T.M.
      • Owens J.E.
      • Kincaid J.
      • et al.
      The short-term effect of interdisciplinary medication review on function and cost in ambulatory elderly people.
      ]. Kutner estimated a mean saving of their intervention of US$716.46 per participant based on the cost of the generic brand of statin and the period of follow-up which the participants remained off the statin [
      • Kutner J.S.
      • Blatchford P.J.
      • Taylor Jr., D.H.
      • et al.
      Safety and benefit of discontinuing statin therapy in the setting of advanced, life-limiting illness: a randomized clinical trial.
      ]. Potentially, additional cost benefits may occur through reduced utilisation of services due to reduced ADRs. Eveleigh et al. conducted a cost-utility analysis of treatment advice to discontinue inappropriate anti-depressant use [
      • Eveleigh R.
      • Grutters J.
      • Muskens E.
      • Oude Voshaar R.
      • van Weel C.
      • Speckens A.
      • et al.
      Cost-utility analysis of a treatment advice to discontinue inappropriate long-term antidepressant use in primary care.
      ]. They found that participants in the intervention group had lower loss of productivity costs (i.e. less time taken off work) which they hypothesised was due to patient empowerment and loss of stigma conferred through treatment advice. Overall, however, their intervention did not result in a significant reduction in the number of participants who stopped their antidepressant. Comprehensive drug-specific pharmacoeconomic analyses and models are required to determine whether deprescribing is cost-effective. These models should take into account various inputs such as drug cost, clinician time, cost of adverse drug withdrawal events and money saved avoiding ADRs, among others.

      3.5 Adherence

      Deprescribing has the potential to improve patient adherence through several mechanisms, although the evidence to support this is unclear [
      • Reeve E.
      • Wiese M.D.
      Benefits of deprescribing on patients' adherence to medications.
      ]. An increasing number of medications are associated with reduced adherence [
      • Hajjar E.R.
      • Cafiero A.C.
      • Hanlon J.T.
      Polypharmacy in elderly patients.
      ,
      • Chapman R.H.
      • Benner J.S.
      • Petrilla A.A.
      • Tierce J.C.
      • Collins R.
      • Battleman D.S.
      • et al.
      Predictors of adherence with antihypertensive and lipid-lowering therapy.
      ] with some evidence showing that a reduced number of daily administrations lead to better adherence [
      • Haynes R.B.
      • Ackloo E.
      • Sahota N.
      • McDonald H.P.
      • Yao X.
      Interventions for enhancing medication adherence.
      ]. It has also been proposed that deprescribing may also lead to improved adherence through reduced out-of-pocket costs, increasing the patient's medication knowledge and engagement and resolution of ADRs [
      • Reeve E.
      • Wiese M.D.
      Benefits of deprescribing on patients' adherence to medications.
      ].

      3.6 Safety of deprescribing

      The systematic review conducted by Page et al. in 2015 concluded that based on the studies conducted to date, deprescribing is safe. It is, however, important to consider that return of medical condition can occur upon medication withdrawal. The evidence on the prevalence of return of condition is limited and varies by drug class [
      • Iyer S.
      • Naganathan V.
      • McLachlan A.J.
      • Le Couteur D.G.
      Medication withdrawal trials in people aged 65 years and older: a systematic review.
      ,
      • Page A.
      • Clifford R.
      • Potter K.
      The feasibility and the effect of deprescribing in older adults on mortality and health: a systematic review.
      ]. In studies which focus on individualised withdrawal of inappropriate medications, only a small proportion of participants (2–18%) have needed to restart the medication due to re-occurrence of the condition/symptoms [
      • Garfinkel D.
      • Zur-Gil S.
      • Ben-Israel J.
      The war against polypharmacy: a new cost-effective geriatric-palliative approach for improving drug therapy in disabled elderly people.
      ,
      • Garfinkel D.
      • Mangin D.
      Feasibility study of a systematic approach for discontinuation of multiple medications in older adults: addressing polypharmacy.
      ]. A systematic review of deprescribing proton pump inhibitors (PPI, 6 studies) reported that between14 and 64% of patients could successfully discontinue their PPI [
      • Haastrup P.
      • Paulsen M.S.
      • Begtrup L.M.
      • Hansen J.M.
      • Jarbøl D.E.
      Strategies for discontinuation of proton pump inhibitors: a systematic review.
      ], while a systematic review of deprescribing benzodiazepines (28 studies) found success rates ranging from 25 to 85% [
      • Paquin A.M.
      • Zimmerman K.
      • Rudolph J.L.
      Risk versus risk: a review of benzodiazepine reduction in older adults.
      ]. The systematic review by Iyer found that between 15 and 80% of participants in antihypertensive withdrawal studies restarted the medication before the end of the study. This large variation may reflect differences in study types and cardiovascular risk of the populations. For symptomatic conditions and diseases which can be objectively measured through surrogate outcomes (e.g. hypertension, diabetes) the condition, sign or symptom appears to resolve quickly upon re-initiation of the medication [
      • Iyer S.
      • Naganathan V.
      • McLachlan A.J.
      • Le Couteur D.G.
      Medication withdrawal trials in people aged 65 years and older: a systematic review.
      ]. However, for preventative medications with no acutely measurable effect, determining whether the condition has returned, or will occur in the future is difficult to determine. It is currently unknown whether breaks in therapy (i.e. through a deprescribing trial) will have long term effects on the overall management of a disease, nor how long it takes for the benefits to be recovered. This is likely to be highly dependent on the disease and medication in question. For example, investigation into the effect of breaks of therapy (6 weeks) with cholinesterase inhibitors is inconclusive, with some indicating no overall worsening in outcomes [
      • Pariente A.
      • Fourrier-Réglat A.
      • Bazin F.
      • Ducruet T.
      • Dartigues J.F.
      • Dragomir A.
      • et al.
      Effect of treatment gaps in elderly patients with dementia treated with cholinesterase inhibitors.
      ], and others reporting worsening of symptoms which is not recovered on restarting therapy [
      • Doody R.S.
      • Geldmacher D.S.
      • Gordon B.
      • Perdomo C.A.
      • Pratt R.D.
      Open-label, multicenter, phase 3 extension study of the safety and efficacy of donepezil in patients with Alzheimer disease.
      ].
      It is also possible for adverse drug withdrawal events (ADWEs) to occur upon medication withdrawal (for example, insomnia when deprescribing benzodiazepines or rebound heartburn when stopping a PPI). However, the potential for serious harm due to ADWEs appears to be rare [
      • Paquin A.M.
      • Zimmerman K.
      • Rudolph J.L.
      Risk versus risk: a review of benzodiazepine reduction in older adults.
      ,
      • Graves T.
      • Hanlon J.T.
      • Schmader K.E.
      • Landsman P.B.
      • Samsa G.P.
      • Pieper C.F.
      • et al.
      Adverse events after discontinuing medications in elderly outpatients.
      ,
      • Marcum Z.A.
      • Pugh M.J.V.
      • Amuan M.E.
      • Aspinall S.L.
      • Handler S.M.
      • Ruby C.M.
      • et al.
      Prevalence of potentially preventable unplanned hospitalizations caused by therapeutic failures and adverse drug withdrawal events among older veterans.
      ] and several drug class specific deprescribing interventions have found no difference in the rate of ADWEs between intervention and control groups [
      • Page A.
      • Clifford R.
      • Potter K.
      The feasibility and the effect of deprescribing in older adults on mortality and health: a systematic review.
      ]. Medications commonly implicated in ADWEs include cardiovascular, central nervous system and gastrointestinal medications among others [
      • Graves T.
      • Hanlon J.T.
      • Schmader K.E.
      • Landsman P.B.
      • Samsa G.P.
      • Pieper C.F.
      • et al.
      Adverse events after discontinuing medications in elderly outpatients.
      ,
      • Gerety M.B.
      • Cornell J.E.
      • Plichta D.T.
      • Eimer M.
      Adverse events related to drugs and drug withdrawal in nursing home residents.
      ]. It is recommended that these medications be tapered prior to discontinuation to minimize the likelihood of ADWEs [
      • Scott I.A.
      • Hilmer S.N.
      • Reeve E.
      • Potter K.
      • Le Couteur D.
      • Rigby D.
      • et al.
      Reducing inappropriate polypharmacy: the process of deprescribing.
      ] (see ‘The process of deprescribing’ section).
      Other potential harms of deprescribing include reversal of drug-drug interactions and harm to the doctor-patient relationship [
      • Reeve E.
      • Shakib S.
      • Hendrix I.
      • Roberts M.S.
      • Wiese M.D.
      The benefits and harms of deprescribing.
      ,
      • Uijtendaal E.V.
      • Zwart-van Rijkom J.E.F.
      • van Solinge W.W.
      • Egberts T.C.G.
      Serum potassium influencing interacting drugs: risk-modifying strategies also needed at discontinuation.
      ,
      • Anderson K.
      • Freeman C.
      • Stowasser D.
      • Scott I.
      Prescriber barriers and enablers to minimising potentially inappropriate medications in adults: a systematic review and thematic synthesis.
      ,
      • Bokhof B.
      • Junius-Walker U.
      Reducing polypharmacy from the perspectives of general practitioners and older patients: a synthesis of qualitative studies.
      ]. There is little research into these, however, the possibility of these harms emphasises the need for appropriate monitoring following withdrawal and a patient-centred approach [
      • Reeve E.
      • Shakib S.
      • Hendrix I.
      • Roberts M.S.
      • Wiese M.D.
      Review of deprescribing processes and development of an evidence based, patient-centred deprescribing process.
      ].

      4. Taking action on deprescribing

      Integrating deprescribing into medical culture must begin when a medication is prescribed. The term ‘life-long medication’ should be removed from health care professionals' vocabularies and replaced with ‘time-to-review’ expiry dates [
      • Currow D.
      • Abernethy A.P.
      A framework for managing comorbid conditions in palliative care.
      ]. The expected duration of therapy should be included with instructions for medications. Taking action on deprescribing can be facilitated by knowledge of potential barriers, implementing a deprescribing process (utilising developed tools and resources) and identifying opportunities for deprescribing through engaging with patients and caregivers and other health care professionals and considering deprescribing in a variety of populations.

      4.1 Barriers to and enablers of deprescribing

      There has been increasing research interest into why deprescribing does not happen as often in practice as it should (as evidenced by the high rate of inappropriate medication use). These barriers and enablers have been explored from both the health care professional point of view and the consumer perspective.
      In 2014, Andersen et al. conducted a systematic review (21 studies) of prescriber-reported barriers to and enablers of deprescribing [
      • Anderson K.
      • Freeman C.
      • Stowasser D.
      • Scott I.
      Prescriber barriers and enablers to minimising potentially inappropriate medications in adults: a systematic review and thematic synthesis.
      ]. Through thematic analysis, the authors identified four main themes: awareness (the prescriber's insight into the appropriateness of their prescribing), inertia (failure to act despite awareness), self-efficacy (having the skills, knowledge, attitudes and information to deprescribe) and feasibility (including regulatory, patient, resources, time and medical culture influences). They noted that there was limited research outside of general practitioners (GPs) working in primary care. Since this review, several new studies have been conducted with concordant findings. Turner et al. [
      • Turner J.P.
      • Edwards S.
      • Stanners M.
      • Shakib S.
      • Bell J.S.
      What factors are important for deprescribing in Australian long-term care facilities? Perspectives of residents and health professionals.
      ] investigated the perspectives of residents and health care professionals (GPs, nurses and pharmacists) in residential aged care facilities. Across the different stakeholder groups, factors considered important for deprescribing included the resident's goals of care, the health system structure and the evidence for deprescribing. Kouladjian et al. [
      • Kouladjian L.
      • Gnjidic D.
      • Reeve E.
      • Chen T.F.
      • Hilmer S.N.
      Health care practitioners' perspectives on deprescribing anticholinergic and sedative medications in older adults.
      ] also investigated the attitudes of pharmacists as well as specialists and GPs regarding deprescribing anticholinergic and sedative medications. They identified that the most noteworthy barrier to deprescribing was devolving responsibility, that is, the passing of blame and responsibility to other health care professionals. The complex prescribing environment is contributed to by patient complexity (polypharmacy and multimorbidity) and prescriber complexity (multiple providers, poor communication, restricted autonomy). This can make clinical treatment guidelines unsuitable and hinder deprescribing attempts in the time constrained environment of health care provision [
      • Bokhof B.
      • Junius-Walker U.
      Reducing polypharmacy from the perspectives of general practitioners and older patients: a synthesis of qualitative studies.
      ,
      • Clyne B.
      • Cooper J.A.
      • Hughes C.M.
      • Fahey T.
      • Smith S.M.
      • Mangoni A.
      • et al.
      “Potentially inappropriate or specifically appropriate?” Qualitative evaluation of general practitioners views on prescribing, polypharmacy and potentially inappropriate prescribing in older people.
      ,
      • Ailabouni N.J.
      • Nishtala P.S.
      • Mangin D.
      • Tordoff J.M.
      Challenges and enablers of deprescribing: a general practitioner perspective.
      ].
      GPs' perceptions of patients' and their family's (caregiver's) attitudes have also been reported as a hindrance to deprescribing [
      • Anderson K.
      • Freeman C.
      • Stowasser D.
      • Scott I.
      Prescriber barriers and enablers to minimising potentially inappropriate medications in adults: a systematic review and thematic synthesis.
      ,
      • Ailabouni N.J.
      • Nishtala P.S.
      • Mangin D.
      • Tordoff J.M.
      Challenges and enablers of deprescribing: a general practitioner perspective.
      ]. While international studies indicate that the vast majority of patients are hypothetically willing to have a medication deprescribed [
      • Reeve E.
      • Wiese M.D.
      • Hendrix I.
      • Roberts M.
      • Shakib S.
      People's attitudes, beliefs, and experiences regarding polypharmacy and willingness to deprescribe.
      ,
      • Qi K.
      • Reeve E.
      • Hilmer S.
      • Pearson S.-A.
      • Matthews S.
      • Gnjidic D.
      Older peoples' attitudes regarding polypharmacy, statin use and willingness to have statins deprescribed in Australia.
      ,
      • Galazzi A.
      • Lusignani M.
      • Chiarelli M.T.
      • Mannucci P.M.
      • Franchi C.
      • Tettamanti M.
      • et al.
      Attitudes towards polypharmacy and medication withdrawal among older inpatients in Italy.
      ,
      • Sirois C.
      • Ouellet N.
      • Reeve E.
      Community-dwelling older people's attitudes towards deprescribing in Canada.
      ], there are a number of barriers to deprescribing that have been described by patients. These include attitudes surrounding the benefits and lack of harm of their medications (i.e. belief that it is appropriate) and fears or uncertainty as to how they would be without the medication. The recommendation of their GP has been described as a strong influence towards, or against deprescribing [
      • Bokhof B.
      • Junius-Walker U.
      Reducing polypharmacy from the perspectives of general practitioners and older patients: a synthesis of qualitative studies.
      ,
      • Luymes C.H.
      • van der Kleij R.M.
      • Poortvliet R.K.
      • de Ruijter W.
      • Reis R.
      • Numans M.E.
      Deprescribing potentially inappropriate preventive cardiovascular medication: barriers and enablers for patients and general practitioners.
      ,
      • Reeve E.
      • To J.
      • Hendrix I.
      • Shakib S.
      • Roberts M.S.
      • Wiese M.D.
      Patient barriers to and enablers of deprescribing: a systematic review.
      ,
      • Reeve E.
      • Low L.-F.
      • Hilmer S.N.
      Beliefs and attitudes of older adults and carers about deprescribing of medications.
      ,
      • Linsky A.
      • Simon S.R.
      • Bokhour B.
      Patient perceptions of proactive medication discontinuation.
      ]. Other external influences include family members, friends, media and family history of disease [
      • Luymes C.H.
      • van der Kleij R.M.
      • Poortvliet R.K.
      • de Ruijter W.
      • Reis R.
      • Numans M.E.
      Deprescribing potentially inappropriate preventive cardiovascular medication: barriers and enablers for patients and general practitioners.
      ,
      • Reeve E.
      • To J.
      • Hendrix I.
      • Shakib S.
      • Roberts M.S.
      • Wiese M.D.
      Patient barriers to and enablers of deprescribing: a systematic review.
      ,
      • Reeve E.
      • Low L.-F.
      • Hilmer S.N.
      Beliefs and attitudes of older adults and carers about deprescribing of medications.
      ]. These barriers may be counteracted by a belief that the medication is inappropriate (not working, no longer needed or causing side effects), a general dislike of medications, knowing that there is a process for deprescribing and that their medication can be restarted if necessary [
      • Bokhof B.
      • Junius-Walker U.
      Reducing polypharmacy from the perspectives of general practitioners and older patients: a synthesis of qualitative studies.
      ,
      • Luymes C.H.
      • van der Kleij R.M.
      • Poortvliet R.K.
      • de Ruijter W.
      • Reis R.
      • Numans M.E.
      Deprescribing potentially inappropriate preventive cardiovascular medication: barriers and enablers for patients and general practitioners.
      ,
      • Reeve E.
      • To J.
      • Hendrix I.
      • Shakib S.
      • Roberts M.S.
      • Wiese M.D.
      Patient barriers to and enablers of deprescribing: a systematic review.
      ,
      • Reeve E.
      • Low L.-F.
      • Hilmer S.N.
      Beliefs and attitudes of older adults and carers about deprescribing of medications.
      ,
      • Linsky A.
      • Simon S.R.
      • Bokhour B.
      Patient perceptions of proactive medication discontinuation.
      ]. Luymes conducted qualitative analysis of audiotaped consultations of GPs and patients participating in a study of deprescribing potentially inappropriate cardiovascular medications [
      • Luymes C.H.
      • van der Kleij R.M.
      • Poortvliet R.K.
      • de Ruijter W.
      • Reis R.
      • Numans M.E.
      Deprescribing potentially inappropriate preventive cardiovascular medication: barriers and enablers for patients and general practitioners.
      ]. Their analysis echoed these barriers and enablers and found that patients appreciated discussing their doubts about deprescribing with their GP [
      • Luymes C.H.
      • van der Kleij R.M.
      • Poortvliet R.K.
      • de Ruijter W.
      • Reis R.
      • Numans M.E.
      Deprescribing potentially inappropriate preventive cardiovascular medication: barriers and enablers for patients and general practitioners.
      ]. In this study, deprescribing of the cardiovascular medication was agreed upon by both physician and patient in 42 of the 49 consultations [
      • Luymes C.H.
      • van der Kleij R.M.
      • Poortvliet R.K.
      • de Ruijter W.
      • Reis R.
      • Numans M.E.
      Deprescribing potentially inappropriate preventive cardiovascular medication: barriers and enablers for patients and general practitioners.
      ].
      The beliefs of caregivers towards deprescribing have been found to be similar, however, acting as a surrogate decision maker is difficult and feelings of guilt and responsibility if their care recipient's condition worsens have been reported [
      • Reeve E.
      • Low L.-F.
      • Hilmer S.N.
      Beliefs and attitudes of older adults and carers about deprescribing of medications.
      ,
      • Post S.G.
      • Stuckey J.C.
      • Whitehouse P.J.
      • Ollerton S.
      • Durkin C.
      • Robbins D.
      • et al.
      A focus group on cognition-enhancing medications in Alzheimer disease: disparities between professionals and consumers.
      ]. Todd and colleagues explored the attitudes of palliative care patients towards medication withdrawal [
      • Todd A.
      • Holmes H.
      • Pearson S.
      • Hughes C.
      • Andrew I.
      • Baker L.
      • et al.
      ‘I don't think I'd be frightened if the statins went’: a phenomenological qualitative study exploring medicines use in palliative care patients, carers and healthcare professionals.
      ]. When patients were accepting of their illness and disease trajectory, they reported placing less importance on their medications and they no longer had fear surrounding ceasing them.
      While there are a number of reported barriers, there are significant opportunities for deprescribing and strategies to facilitate medication optimisation in practice which are discussed in the following sections.

      4.2 Opportunities for deprescribing: working with patients and other health care professionals

      Shared, informed decision making is central to delivering patient-centred care and can be an effective method of reaching agreement in regard to treatment of chronic illnesses [
      • Penge J.
      • Crome P.
      Appropriate prescribing in older people.
      ]. While some patients may still want a recommendation from their doctor, or in fact for their doctor to make the decision [
      • Belcher V.N.
      • Fried T.R.
      • Agostini J.V.
      • Tinetti M.E.
      Views of older adults on patient participation in medication-related decision making.
      ,
      • Levinson W.
      • Kao A.
      • Kuby A.
      • Thisted R.
      Not all patients want to participate in decision making.
      ], shared decision making and respect for patient autonomy can still occur through the discussion of options, benefits and harms and elicitation of patient preferences and values [
      • Reeve E.
      • Denig P.
      • Hilmer S.N.
      • Ter Meulen R.
      The ethics of deprescribing in older adults.
      ]. Patients should ideally have sufficient knowledge of the decision in question, have realistic expectations for outcomes and be confident in their decision [
      • Stacey D.
      • Légaré F.
      • Col N.F.
      • Bennett C.L.
      • Barry M.J.
      • Eden K.B.
      • et al.
      Decision aids for people facing health treatment or screening decisions.
      ]. When faced with unclear evidence as to the suitability for deprescribing, patient values and preferences may be a salient guide for health care professionals [
      • Reeve E.
      • Denig P.
      • Hilmer S.N.
      • Ter Meulen R.
      The ethics of deprescribing in older adults.
      ,
      • Stacey D.
      • Légaré F.
      • Col N.F.
      • Bennett C.L.
      • Barry M.J.
      • Eden K.B.
      • et al.
      Decision aids for people facing health treatment or screening decisions.
      ,
      • Gillick M.R.
      Choosing appropriate medical care for the elderly.
      ].
      A recent study found that patient belief in the importance of medications correlated poorly with their GPs' belief in importance, highlighting the need for continual dialogue between doctors and patients [
      • Sidorkiewicz S.
      • Tran V.-T.
      • Cousyn C.
      • Perrodeau E.
      • Ravaud P.
      Discordance between drug adherence as reported by patients and drug importance as assessed by physicians.
      ]. There are compelling reasons why patients should be involved throughout the deprescribing process (Box 1). Jansen and colleagues drew from the psychology, communication and decision making literature to review how to enhance deprescribing through shared decision making [
      • Jansen J.
      • Naganathan V.
      • Carter S.M.
      • McLachlan A.J.
      • Nickel B.
      • Irwig L.
      • et al.
      Too much medicine in older people? Deprescribing through shared decision making.
      ]. They recommended five steps; creating awareness that options exist, discussing the options and their benefits and harms, exploring patient preferences for the different options and making the decision. By enacting this process, the patient is less likely to be resistant to deprescribing as they will have been provided the information as to why medication withdrawal is being recommended [
      • Reeve E.
      • To J.
      • Hendrix I.
      • Shakib S.
      • Roberts M.S.
      • Wiese M.D.
      Patient barriers to and enablers of deprescribing: a systematic review.
      ]. Patient-directed interventions are among the most effective approaches to medication withdrawal [
      • Ostini R.
      • Jackson C.
      • Hegney D.
      • Tett S.E.
      How is medication prescribing ceased?: a systematic review.
      ]. One difficulty in making informed, shared decisions surrounding continuation of a medication versus deprescribing is the lack of available high quality information and syntheses on benefits and harms of treatment options. Jansen et al. noted that evidence-based tools and resources are necessary to facilitate discussions on continued medication use versus deprescribing [
      • Jansen J.
      • Naganathan V.
      • Carter S.M.
      • McLachlan A.J.
      • Nickel B.
      • Irwig L.
      • et al.
      Too much medicine in older people? Deprescribing through shared decision making.
      ].
      Importance of consumer involvement in deprescribing.
      Tabled 1
      General practitioners (GPs), nurse practitioners, medical specialists and pharmacists may all be involved in leading or contributing to deprescribing efforts. Qualitative studies indicate that patients are likely to be more willing to have a medication deprescribed if it is recommended by their doctor (which may be their GP or another medical practitioner who they have a relationship with) [
      • Reeve E.
      • To J.
      • Hendrix I.
      • Shakib S.
      • Roberts M.S.
      • Wiese M.D.
      Patient barriers to and enablers of deprescribing: a systematic review.
      ,
      • Reeve E.
      • Low L.-F.
      • Hilmer S.N.
      Beliefs and attitudes of older adults and carers about deprescribing of medications.
      ,
      • Linsky A.
      • Simon S.R.
      • Bokhour B.
      Patient perceptions of proactive medication discontinuation.
      ]. Interventions with close involvement of the GP appear to be more successful in achieving deprescribing than those conducted by an external research team [
      • Reeve E.
      • Shakib S.
      • Hendrix I.
      • Roberts M.S.
      • Wiese M.D.
      Review of deprescribing processes and development of an evidence based, patient-centred deprescribing process.
      ,
      • Ostini R.
      • Jackson C.
      • Hegney D.
      • Tett S.E.
      How is medication prescribing ceased?: a systematic review.
      ]. However, the majority of studies have been conducted in primary care and so what the involvement of the GP should be when deprescribing is conducted in other settings is not clear. The primary care setting provides access to prescription history and medical records and provides an environment for ongoing monitoring after discontinuation. Conversely, deprescribing by GPs may be hindered by time limitations and professional barriers with specialists (i.e. GPs may not want to alter medications started by a specialist) [
      • Anderson K.
      • Freeman C.
      • Stowasser D.
      • Scott I.
      Prescriber barriers and enablers to minimising potentially inappropriate medications in adults: a systematic review and thematic synthesis.
      ]. Multidisciplinary interventions are generally observed to be the most effective at reducing polypharmacy and inappropriate medication use [
      • Hamdy R.C.
      • Moore S.W.
      • Whalen K.
      • Donnelly J.P.
      • Compton R.
      • Testerman F.
      • et al.
      Reducing polypharmacy in extended care.
      ,
      • Kaur S.
      • Mitchell G.
      • Vitetta L.
      • Roberts M.S.
      Interventions that can reduce inappropriate prescribing in the elderly: a systematic review.
      ], and the involvement of pharmacists and nurses in a deprescribing process appears to be a path to enhancing deprescribing in practice [
      • Steinman M.A.
      Polypharmacy - time to get beyond numbers.
      ]. Many patients are comfortable with the involvement of a pharmacist or nurse in the deprescribing process (with GP involvement) [
      • Reeve E.
      • Wiese M.D.
      • Hendrix I.
      • Roberts M.
      • Shakib S.
      People's attitudes, beliefs, and experiences regarding polypharmacy and willingness to deprescribe.
      ,
      • Sirois C.
      • Ouellet N.
      • Reeve E.
      Community-dwelling older people's attitudes towards deprescribing in Canada.
      ]. Further research is required to determine whether specific health care professionals should lead deprescribing decision-making and monitoring, whether a team approach is more effective and how deprescribing can be integrated into regular care. The optimal functioning of a multidisciplinary approach needs to consider remuneration models and division of responsibilities appropriate to professional competencies. Geriatricians recognise their role in therapeutic management although cite fragmentation of health care as a limiting factor [
      • Kouladjian L.
      • Gnjidic D.
      • Reeve E.
      • Chen T.F.
      • Hilmer S.N.
      Health care practitioners' perspectives on deprescribing anticholinergic and sedative medications in older adults.
      ].
      Hospitalisation provides an opportunity to review medications and conduct deprescribing, however, studies show that levels of polypharmacy and inappropriate medication use do not change during hospitalisation [
      • Hubbard R.E.
      • Peel N.M.
      • Scott I.A.
      • Martin J.H.
      • Smith A.
      • Pillans P.I.
      • et al.
      Polypharmacy among inpatients aged 70 years or older in Australia.
      ,
      • Ní Chróinín D.
      • Neto H.M.
      • Xiao D.
      • Sandhu A.
      • Brazel C.
      • Farnham N.
      • et al.
      Potentially inappropriate medications (PIMs) in older hospital in-patients: prevalence, contribution to hospital admission and documentation of rationale for continuation.
      ]. Setting specific barriers to deprescribing includes the focus on acute medical problems, limited time for follow-up and lack of collaboration with different levels of care [
      • Anderson K.
      • Freeman C.
      • Stowasser D.
      • Scott I.
      Prescriber barriers and enablers to minimising potentially inappropriate medications in adults: a systematic review and thematic synthesis.
      ,
      • Ní Chróinín D.
      • Neto H.M.
      • Xiao D.
      • Sandhu A.
      • Brazel C.
      • Farnham N.
      • et al.
      Potentially inappropriate medications (PIMs) in older hospital in-patients: prevalence, contribution to hospital admission and documentation of rationale for continuation.
      ,
      • Cullinan S.
      • Fleming A.
      • O'Mahony D.
      • Ryan C.
      • O'Sullivan D.
      • Gallagher P.
      • et al.
      Doctors' perspectives on the barriers to appropriate prescribing in older hospitalized patients: a qualitative study.
      ]. Junior doctors are often responsible for the majority of prescribing activities during hospitalisation. In a pilot survey in the UK, junior doctors reported that it was not their responsibility to conduct medication review activities or deprescribing, instead deferring this to pharmacists, consultants or the patient's regular GP [
      • Jubraj B.
      • Marvin V.
      • Poots A.J.
      • Patel S.
      • Bovill I.
      • Barnett N.
      • et al.
      A pilot survey of junior doctors' attitudes and awareness around medication review: time to change our educational approach?.
      ]. In a recent commentary, Scott and Le Couteur called for consult physicians to take the lead in deprescribing to ensure that others in the clinical hierarchy adopt and sustain this practice [
      • Scott I.A.
      • Le Couteur D.G.
      Physicians need to take the lead in deprescribing.
      ]. The feasibility of a deprescribing intervention in hospital was demonstrated by McKean and colleagues [
      • McKean M.
      • Pillans P.I.
      • Scott I.A.
      A medication review and deprescribing method for hospitalised older patients receiving multiple medications.
      ]. Through education and provision of a deprescribing protocol to clinicians and clinical pharmacists on acute medical care wards, 34.3% of regular medications were discontinued during hospital admission. Follow-up was conducted on a proportion of their participants, of which only 1.2% of ceased medications had been restarted due to symptom relapse [
      • McKean M.
      • Pillans P.I.
      • Scott I.A.
      A medication review and deprescribing method for hospitalised older patients receiving multiple medications.
      ]. Outpatient clinics may also be a suitable setting for deprescribing approaches, although access to complete medical records and communication with GPs in fragmented health care systems are barriers that need to be considered [
      • Mudge A.
      • Radnedge K.
      • Kasper K.
      • Mullins R.
      • Adsett J.
      • Rofail S.
      • et al.
      Effects of a pilot multidisciplinary clinic for frequent attending elderly patients on deprescribing.
      ,
      • Reeve E.
      • Andrews J.M.
      • Wiese M.D.
      • Hendrix I.
      • Roberts M.S.
      • Shakib S.
      The feasibility of a patient-centered deprescribing process to reduce inappropriate use of proton pump inhibitors.
      ].

      4.3 The process of deprescribing

      Common elements for deprescribing have been proposed; they provide practical guidance for conducting deprescribing in practice (Box 2). Generic processes/algorithms place these elements in a sequence which can then be applied to an individual patient by a skilled health care professional [
      • Woodward M.C.
      Deprescribing: achieving better health outcomes for older people through reducing medications.
      ,
      • Hardy J.E.
      • Hilmer S.N.
      Deprescribing in the last year of life.
      ,
      • Scott I.A.
      • Hilmer S.N.
      • Reeve E.
      • Potter K.
      • Le Couteur D.
      • Rigby D.
      • et al.
      Reducing inappropriate polypharmacy: the process of deprescribing.
      ,
      • Reeve E.
      • Shakib S.
      • Hendrix I.
      • Roberts M.S.
      • Wiese M.D.
      Review of deprescribing processes and development of an evidence based, patient-centred deprescribing process.
      ]. Explicit lists of medications considered inappropriate in older adults such as the Beers list and STOPP criteria may be used to assist the process, however, appropriateness in the individual and potential withdrawal of medications not on these lists also needs to be considered [
      • Mudge A.
      • Radnedge K.
      • Kasper K.
      • Mullins R.
      • Adsett J.
      • Rofail S.
      • et al.
      Effects of a pilot multidisciplinary clinic for frequent attending elderly patients on deprescribing.
      ,
      • Verdoorn S.
      • Kwint H.-F.
      • Faber A.
      • Gussekloo J.
      • Bouvy M.L.
      Majority of drug-related problems identified during medication review are not associated with STOPP/START criteria.
      ,
      • Barenholtz Levy H.
      • Marcus E.-L.
      Potentially inappropriate medications in older adults: why the revised criteria matter.
      ,
      • Garfinkel D.
      • Ilhan B.
      • Bahat G.
      Routine deprescribing of chronic medications to combat polypharmacy.
      ]. A study of 100,000 hospitalizations for ADRs in the USA found that warfarin and insulin were the most commonly implicated drugs, both of which are not part of the Beers criteria [
      • Budnitz D.S.
      • Lovegrove M.C.
      • Shehab N.
      • Richards C.L.
      Emergency hospitalizations for adverse drug events in older Americans.
      ]. An algorithm or set of principles for determining appropriateness of ongoing medication use has also been advocated (see Box 2).
      Elements of a deprescribing process [
      • Scott I.A.
      • Hilmer S.N.
      • Reeve E.
      • Potter K.
      • Le Couteur D.
      • Rigby D.
      • et al.
      Reducing inappropriate polypharmacy: the process of deprescribing.
      ,
      • Reeve E.
      • Shakib S.
      • Hendrix I.
      • Roberts M.S.
      • Wiese M.D.
      Review of deprescribing processes and development of an evidence based, patient-centred deprescribing process.
      ].
      Tabled 1
      • Collect a complete and comprehensive medication history
      • o
        Regular, intermittent and ‘as required’ prescription and non-prescription medications (including vitamins, supplements, “herbals”)
      • o
        Include dose, frequency, duration of use, indication and effectiveness
      • o
        Identify possible adverse drug reactions
      • o
        Assess adherence
      • Assess overall risk of harm and benefit and individual patient factors which may affect deprescribing
      • o
        Discuss patients'/caregivers' values, preferences, beliefs and goals of care surrounding continued medication use versus deprescribing
      • o
        Drug related factors: polypharmacy, pill burden (medication regimen complexity), drug-drug interactions, use of ‘high risk’ drugs
      • o
        Patient related factors: life expectancy, cognitive and functional impairments, falls risk, co-morbidities multiple prescribers, palliative care
      • o
        Ask “which medications are most important for you to keep taking? Why?”
      • Identify potentially inappropriate medications
      • o
        Consider medications without an indication (condition resolved, unconfirmed, questionable efficacy, altered risk, non-pharmacological alternative), part of a prescribing cascade, causing an adverse drug reaction, potential for future harm
      • o
        Use tools such as explicit lists of medications which are inappropriate in older adults, e.g. Beers list, STOPP criteria
        • The American Geriatrics Society Beers Criteria Update Expert Panel
        American Geriatrics Society Updated Beers Criteria for potentially inappropriate medication use in older adults.
        ,
        • Gallagher P.
        • Ryan C.
        • Byrne S.
        • Kennedy J.
        • O'Mahony D.
        STOPP (Screening Tool of Older Person's Prescriptions) and START (Screening Tool to Alert doctors to Right Treatment). Consensus validation.
      • o
        Use algorithms to determine drug appropriateness, e.g. Medication Appropriateness Index, Good Palliative-Geriatric Practice algorithm
        • Hanlon J.T.
        • Schmader K.E.
        The Medication Appropriateness Index at 20: where it started, where it has been, and where it may be going.
        ,
        • Garfinkel D.
        • Mangin D.
        Feasibility study of a systematic approach for discontinuation of multiple medications in older adults: addressing polypharmacy.
      • Decide on medication withdrawal (shared-decision making)
      • o
        If more than one medication identified for withdrawal prioritize order of drugs for discontinuation (e.g. based on potential for harm, patient preference)
      • Plan tapering or withdrawal process and monitoring with documentation and communication to all persons relevant to care
      • o
        Appropriate timing of withdrawal (e.g. consider patient's use of dosage administration aids)
      • o
        Tapering plan - Identify if the medication is commonly associated with an adverse drug withdrawal event (see Bain et al.
        • Bain K.T.
        • Holmes H.M.
        • Beers M.H.
        • Maio V.
        • Handler S.M.
        • Pauker S.G.
        Discontinuing medications: a novel approach for revising the prescribing stage of the medication-use process.
        and online resource medstopper.com). Slow dose reduction prior to discontinuation may also identify lowest effective dose, minimize the impact of return of symptoms if they do occur and increase patient comfort with the process.
      • o
        Patient management plan (symptoms to look out for, symptom action plan, monitoring required by a health care professional, person to contact)
      • Conduct monitoring and support
      • o
        Monitor for adverse drug withdrawal reactions, return of condition, reversal of drug-drug and drug-disease interactions
      • o
        Monitor for benefits (resolution of adverse drug reactions)
      • o
        Use non-pharmacological approaches to reduce reliance on medication where possible
      • Documentation
      • o
        Document reasons for, process and outcome (e.g. medication ceased, dose reduced or withdrawal attempted with reasons for failure) of deprescribing
      • o
        Share documentation with all relevant health care professionals
      In addition to this generic approach, drug specific evidence-based clinical deprescribing guidelines are being developed as resources with tools to increase the capacity of health care professionals to deprescribe in general practice [
      • Farrell B.
      • Pottie K.
      • Rojas-Fernandez C.
      • Bjerre L.
      Methodology for developing deprescribing guidelines: using evidence and GRADE to guide recommendations for deprescribing.
      ,
      • Farrell B.
      • Tsang C.
      • Raman-Wilms L.
      • Irving H.
      • Conklin J.
      • Pottie K.
      • et al.
      What are priorities for deprescribing for elderly patients? Capturing the voice of practitioners: a modified Delphi process.
      ]. Farrell and colleagues have developed a robust method of deprescribing guideline development based on a comprehensive checklist and utilising evidence and guideline assessment tools (i.e. GRADE and AGREE-II). They have thus far developed four guidelines to hone this process (decision-support algorithms for proton pump inhibitors, benzodiazepines, antipsychotics and antihyperglycemics found at http://deprescribing.org/) [
      • Farrell B.
      • Pottie K.
      • Rojas-Fernandez C.
      • Bjerre L.
      Methodology for developing deprescribing guidelines: using evidence and GRADE to guide recommendations for deprescribing.
      ]. They are also investing in implementation approaches, ensuring appropriate evaluation of implementation strategies [
      • Conklin J.
      • Farrell B.
      • Ward N.
      • McCarthy L.
      • Irving H.
      • Raman-Wilms L.
      • et al.
      Developmental evaluation as a strategy to enhance the uptake and use of deprescribing guidelines: protocol for a multiple case study.
      ]. In the implementation of their first guideline on proton pump inhibitors (PPI) at a single long-term care site, they were able to achieve an initial non-significant reduction in PPI use with a significant reduction in PPI costs [
      • Thompson W.
      • Hogel M.
      • Li Y.
      • Thavorn K.
      • O'Donnell D.
      • McCarthy L.
      • et al.
      Effect of a proton pump inhibitor deprescribing guideline on drug usage and costs in long-term care.
      ].

      4.4 Opportunities for deprescribing: special populations

      Age, number of medications and use of inappropriate and/or high risk medications (identified using tools such as the STOPP criteria [
      • Gallagher P.
      • Ryan C.
      • Byrne S.
      • Kennedy J.
      • O'Mahony D.
      STOPP (Screening Tool of Older Person's Prescriptions) and START (Screening Tool to Alert doctors to Right Treatment). Consensus validation.
      ] and Drug Burden Index [
      • Kouladjian L.
      • Gnjidic D.
      • Chen T.F.
      • Mangoni A.A.
      • Hilmer S.N.
      Drug Burden Index in older adults: theoretical and practical issues.
      ]) can function as triggers to identify patients who would benefit from a medication review to identify deprescribing opportunities. Onder and colleagues have developed and validated an algorithm of the risk of experiencing an ADR in hospital [
      • Onder G.
      • Petrovic M.
      • Tangiisuran B.
      • Meinardi M.C.
      • Markito-Notenboom W.P.
      • Somers A.
      • et al.
      Development and validation of a score to assess risk of adverse drug reactions among in-hospital patients 65 years or older.
      ], while Nair and colleagues recently developed a tool for predicting preventable ADR-related hospital admissions in older adults [
      • Parameswaran Nair N.
      • Chalmers L.
      • Connolly M.
      • Bereznicki B.J.
      • Peterson G.M.
      • Curtain C.
      • et al.
      Prediction of hospitalization due to adverse drug reactions in elderly community-dwelling patients (the PADR-EC score).
      ]. These may be useful in identifying patients most likely to benefit from a deprescribing intervention.
      The majority of discussion and research surrounding deprescribing has focused on older adults but, younger patients and those without polypharmacy may still benefit from deprescribing. There are also several sub-populations in which targeted research and special deprescribing strategies are being developed. People with dementia provide unique challenges to deprescribing activities due to the difficulty in establishing appropriate goals of treatment, enacting shared decision making in cognitive decline in conjunction with caregivers and the limited evidence on benefits and harms of medications in this heterogeneous population [
      • Reeve E.
      • Bell S.
      • Hilmer S.N.
      Barriers to optimising prescribing and deprescribing in older adults with dementia: a narrative review.
      ]. Deprescribing in psychiatry is also gaining interest, based on the focus on patient-centred care in the setting of increasing rates of polypharmacy, concerns about non-adherence and potential for harms due to long term use [
      • Gupta S.
      • Cahill J.D.
      A prescription for “deprescribing” in psychiatry.
      ]. Turner et al. identified that a polypharmacy cut point of between 3.5 and 6.5 medications predicted negative outcomes in older adults with cancer [
      • Turner J.P.
      • Jamsen K.M.
      • Shakib S.
      • Singhal N.
      • Prowse R.
      • Bell J.S.
      Polypharmacy cut-points in older people with cancer: how many medications are too many?.
      ], while Lindsay and colleagues have developed a list of potentially inappropriate medications in this population to support deprescribing activities [
      • Lindsay J.
      • Dooley M.
      • Martin J.
      • Fay M.
      • Kearney A.
      • Khatun M.
      • et al.
      The development and evaluation of an oncological palliative care deprescribing guideline: the “OncPal deprescribing guideline”.
      ]. Optimising medication use and withdrawal of non-life sustaining medications is a recognised part of palliative care, however, opportunities for reducing polypharmacy are being missed which has led to a renewed focus on deprescribing in palliative care patients [
      • Hardy J.E.
      • Hilmer S.N.
      Deprescribing in the last year of life.
      ,
      • Todd A.
      • Holmes H.
      • Pearson S.
      • Hughes C.
      • Andrew I.
      • Baker L.
      • et al.
      ‘I don't think I'd be frightened if the statins went’: a phenomenological qualitative study exploring medicines use in palliative care patients, carers and healthcare professionals.
      ,
      • Todd A.
      • Husband A.
      • Andrew I.
      • Pearson S.-A.
      • Lindsey L.
      • Holmes H.
      Inappropriate prescribing of preventative medication in patients with life-limiting illness: a systematic review.
      ].

      5. Enacting a cultural shift towards deprescribing: what's next?

      Behavioural change requires shifts in education, guidelines, research, advocacy and policy. Health care professionals need to be exposed to deprescribing throughout their curriculum, and senior clinicians (e.g. consultants) should continue this education during residency/internship by regularly demonstrating medication review and deprescribing. Treatment guidelines and reference textbooks should include recommendations as to when it might be suitable to deprescribe [
      • Jansen J.
      • McKinn S.
      • Bonner C.
      • Irwig L.
      • Doust J.
      • Glasziou P.
      • et al.
      Systematic review of clinical practice guidelines recommendations about primary cardiovascular disease prevention for older adults.
      ].
      There are many avenues of future research to support deprescribing. The so-called ‘phase VI’ deprescribing trials and comprehensive recording and follow-up of drug discontinuation in phase I–V drug development studies could provide an opportunity to measure deprescribing outcomes [
      • Gnjidic D.
      • Le Couteur D.G.
      • Hilmer S.N.
      Discontinuing drug treatments.
      ]. Implementation studies should consider using established knowledge translation theories to address barriers to deprescribing to ensure that interventions are effective and sustainable [
      • Cadogan C.A.
      • Ryan C.
      • Francis J.J.
      • Gormley G.J.
      • Passmore P.
      • Kerse N.
      • et al.
      Improving appropriate polypharmacy for older people in primary care: selecting components of an evidence-based intervention to target prescribing and dispensing.
      ]. Utilisation of electronic decision tools to support deprescribing is another important area which will encourage integration of deprescribing in to regular clinical practice [
      • Scott I.A.
      • Le Couteur D.G.
      Physicians need to take the lead in deprescribing.
      ]. Tools to facilitate discussions with patients are also necessary to ensure shared decision making [
      • Jansen J.
      • Naganathan V.
      • Carter S.M.
      • McLachlan A.J.
      • Nickel B.
      • Irwig L.
      • et al.
      Too much medicine in older people? Deprescribing through shared decision making.
      ].
      Several national and international initiatives have been set up to support the cultural shift towards deprescribing. The Australian Deprescribing Network (ADeN) was formed in 2014 to promote research and awareness on deprescribing and support implementation of deprescribing activities as part of appropriate prescribing in routine clinical practice. Their first national workshop in 2014 led to a highly cited manuscript discussing the process of deprescribing [
      • Scott I.A.
      • Hilmer S.N.
      • Reeve E.
      • Potter K.
      • Le Couteur D.
      • Rigby D.
      • et al.
      Reducing inappropriate polypharmacy: the process of deprescribing.
      ] with two subsequent annual meetings hosted in different cities. The Canadian Deprescribing Network (CaDeN, http://deprescribing.org/caden/) was formed in 2015 and is a group of health care professionals, researchers, patient advocates and other health care stakeholders who aim to build capacity and catalyze action to promote deprescribing across Canada. On an international level, the International Group for Reducing Inappropriate Medication Use and Polypharmacy (IGRIMUP) was established in 2013 to address this growing global health concern [
      • Garfinkel D.
      • Ilhan B.
      • Bahat G.
      Routine deprescribing of chronic medications to combat polypharmacy.
      ]. The work of these networks and others to enact a cultural shift towards deprescribing as part of routine care is in line with the international ‘Choosing Wisely’ movement which seeks to encourage conversations about unnecessary tests, treatments and procedures with the message that more is not always better [
      • Levinson W.
      • Kallewaard M.
      • Bhatia R.S.
      • Wolfson D.
      • Shortt S.
      • Kerr E.A.
      • et al.
      “Choosing Wisely”: a growing international campaign.
      ].

      6. Conclusions

      The evidence supporting the benefits and safety of deprescribing continues to grow, strengthening the cause for greater integration of regular deprescribing into medical culture. The potential benefits of deprescribing are widespread, including health and quality of life benefits to patients and cost benefits to the health care system and the individual. There are many opportunities, tools and resources available to optimise deprescribing in routine clinical practice (Box 3).
      Resources available to support health care providers in deprescribing activities.
      Tabled 1
      Websites containing information, resources and tools to aid deprescribing

      Tools for consumer engagement

      Further reading

      Please note: The resources and tools listed above have been developed using a variety of methods including unstructured and structured literature reviews, expert consensus and external peer-review. The robustness of development and validity of the content have not been formally assessed by the authors of this article.

      Declarations of interest

      All authors disclose no actual or potential conflict of interest including any financial, personal or other relationships with other people or organizations within three years of beginning the submitted work that could inappropriately influence, or be perceived to influence, their work. ER is supported by a NHMRC-ARC Dementia Research Development Fellowship and has in the previous 3 years received honoraria for speaking engagements and preparation of manuscripts related to deprescribing from the Nova Scotia branch of the Canadian Society of Hospital Pharmacists, Australian Doctor and Society of Hospital Pharmacists of Australia. BF has received honoraria for speaking engagements related to deprescribing from Canadian Society of Hospital Pharmacists, Ontario Pharmacists Association, Nova Scotia Health Authority, Commonwealth Fund, Institute for Healthcare Improvement.
      This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

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