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Scoping Review of Randomized Trials With Discontinuation of Medicines in Older Adults

  • Jonatan Kornholt
    Correspondence
    Address correspondence to Jonatan Kornholt, Bispebjerg Bakke 23, entrance 20C, second floor, 2400 Copenhagen, NV, Denmark.
    Affiliations
    Department of Clinical Pharmacology, Copenhagen University Hospital - Bispebjerg and Frederiksberg, Copenhagen, Denmark
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  • Cille Bülow
    Affiliations
    Department of Clinical Pharmacology, Copenhagen University Hospital - Bispebjerg and Frederiksberg, Copenhagen, Denmark
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  • Anne Mette S. Sørensen
    Affiliations
    Department of Clinical Pharmacology, Copenhagen University Hospital - Bispebjerg and Frederiksberg, Copenhagen, Denmark
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  • Eckart Pressel
    Affiliations
    Department of Geriatric and Palliative Medicine, Copenhagen University Hospital - Bispebjerg and Frederiksberg, Copenhagen, Denmark

    Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark
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  • Tonny S. Petersen
    Affiliations
    Department of Clinical Pharmacology, Copenhagen University Hospital - Bispebjerg and Frederiksberg, Copenhagen, Denmark

    Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark
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  • Mikkel B. Christensen
    Affiliations
    Department of Clinical Pharmacology, Copenhagen University Hospital - Bispebjerg and Frederiksberg, Copenhagen, Denmark

    Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark

    Center for Translational Research, Copenhagen University Hospital - Bispebjerg and Frederiksberg, Copenhagen, Denmark

    Center for Clinical Metabolic Research, Copenhagen University Hospital - Herlev and Gentofte, Copenhagen, Denmark
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Open AccessPublished:July 15, 2022DOI:https://doi.org/10.1016/j.jamda.2022.06.010

      Abstract

      Objectives

      To map the randomized trial evidence describing the feasibility of discontinuing active medications with potential adverse effects in older patients.

      Design

      Scoping review with systematic search of PubMed, Embase, and Cochrane Library.

      Setting and Participants

      Randomized trials investigating discontinuation of a single medicine or medicine class in patients with mean age ≥65 years.

      Methods

      We extracted trial characteristics including study design and assessed bias. As proxies for the “feasibility of discontinuation,” we extracted the “dropout rate” and “disease recurrence rate.”

      Results

      We identified 40 trials investigating discontinuation of symptomatic (n = 26), preventive (n = 6), or both preventive and symptomatic medicines (n = 8) against psychiatric (n = 10), neurologic (n = 9), musculoskeletal (n = 8), cardiovascular (n = 5), respiratory (n = 4), and urologic diseases (n = 4). Five discontinuation designs were used, 75% (30/40) of trials were placebo-controlled, and 48% (19/40) of trials had bias disfavoring discontinuation. The dropout rate was similar between the discontinuation group and the continuation group in 79% of the trials (30/38), whereas disease recurrence was similar in 72% (23/32) of the trials. In 42% (13/31) of trials reporting both dropout rate and disease recurrence rate, the differences between groups were statistically insignificant and less than 10%; these trials investigated discontinuation of cholinesterase inhibitors for Alzheimer's disease in various settings (n = 3), alendronate for osteoporosis (n = 3), glucosamine for osteoarthritis, lithium as adjunct for unipolar depression, statins for cardiovascular disease in patients with limited life expectancy, droxidopa for neurogenic orthostatic hypotension, tamsulosin for lower urinary tract symptoms, sertraline for major depressive episode, and fentanyl patch for low back or osteoarthritis pain.

      Conclusions and Implications

      We identified 40 randomized trials using a variety of designs investigating discontinuation of both symptomatic and preventive medicines in older patients. Discontinuation of medicines seems feasible for most of the investigated medicines. This scoping review can guide clinical practice and future trials on deprescribing.

      Keywords

      Health care services throughout the world are faced with increasing challenges because of multimorbidity and polypharmacy.
      World Health Organization
      Multimorbidity.
      The prevalence of chronic diagnoses increases with age,
      • Barnett K.
      • Mercer S.W.
      • Norbury M.
      • Watt G.
      • Wyke S.
      • Guthrie B.
      Epidemiology of multimorbidity and implications for health care, research, and medical education: a cross-sectional study.
      and consequently older adults are increasingly exposed to polypharmacy.
      • Morin L.
      • Johnell K.
      • Laroche M.L.
      • Fastbom J.
      • Wastesson J.W.
      The epidemiology of polypharmacy in older adults: register-based prospective cohort study.
      As all medications carry a risk of adverse drug reactions, polypharmacy is associated with an increased risk of adverse drug reactions but also with increased risk of inappropriate medicine use and adverse health outcomes in general.
      • Bourgeois F.
      • Shannon M.
      • Valim C.
      • Mandl K.
      Adverse drug events in the outpatient setting: an 11-year national analysis.
      ,
      • Halli-Tierney A.D.
      • Scarbrough C.
      • Carroll D.
      Polypharmacy: evaluating risks and deprescribing.
      To deprescribe inappropriate medicines (ie, reducing the use of medicines with a negative risk-benefit profile in a particular patient), it is necessary to know which medicines can be safely continued or discontinued. Unfortunately, few randomized controlled trials investigate the efficacy and safety of medicines in older adults
      • Ruiter R.
      • Burggraaf J.
      • Rissmann R.
      Under-representation of elderly in clinical trials: an analysis of the initial approval documents in the Food and Drug Administration database.
      and even fewer trials investigate the effect of discontinuing medicines in older adults.
      • 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.T.
      • Clifford R.M.
      • Potter K.
      • Schwartz D.
      • Etherton-Beer C.D.
      The feasibility and effect of deprescribing in older adults on mortality and health: a systematic review and meta-analysis.
      The objective of this scoping review is to map the “evidence-landscape” of medication discontinuation in older patients. We aim to provide an overview of the existing randomized controlled trials and, based on the evidence, describe the feasibility of discontinuation of investigated medicines in older patients.

      Methods

      This article is structured according to the PRISMA extension for Scoping Reviews (PRISMA-ScR) (Supplementary Material 1).
      • Tricco A.C.
      • Lillie E.
      • Zarin W.
      • et al.
      PRISMA extension for scoping reviews (PRISMA-ScR): checklist and explanation.
      There is no published protocol for this review.

      Information Sources and Search Strategy

      We systematically searched PubMed (coverage 1966 to present), Embase (coverage 1947 to present), and the Cochrane Library (coverage 1992 to present) for publications on randomized discontinuation trials in older patients defined as patients aged ≥65 years. The search was last updated on the 11th of June 2021. The search strings are available in Supplementary Material 2.

      Selection of Sources of Evidence

      All references were imported into Covidence,
      Veritas Health Innovation
      Covidence Systematic Review Software.
      where 2 authors (J.K. and C.B./A.M.S.S.) independently screened abstracts and full texts and included studies according to the eligibility criteria. Consensus was reached through discussion or through judgment of a third author (M.B.C.).
      The eligibility criteria were as follows:
      • Randomized controlled trials investigating the discontinuation of a single medicine or a single medicine class, where medicine class was defined as medicines having a similar pharmacologic effect as judged by the authors
      • Mean age ≥ 65 years in total or in 1 or more arms
      The exclusion criteria were as follows:
      • No randomized discontinuation intervention
      • Full text not in English
      • More than 1 medicine or medicine class discontinued
      • Discontinued medicines targeting cancer, transplant complications, or infections, because these treatments are highly specialized or of limited duration
      • Not published as full-length, peer-reviewed manuscript (eg, poster publications or clinical trial registrations)
      • Temporary discontinuation, that is, pausing of medicines
      We limited the studies to discontinuation of a single medicine or a single medicine class with similar pharmacologic effect for ease of interpretability. As an example, antihypertensives cover a diverse range of pharmacologic effects and the choice of antihypertensive medicine for older patients may be influenced by the patient's comorbidities, other concurrent medication, frailty and fall risk,
      • Benetos A.
      • Petrovic M.
      • Strandberg T.
      Hypertension management in older and frail older patients.
      which makes generalizing the feasibility of discontinuation of such a medicine class difficult.

      Data Charting Process

      Data were extracted to a customized Google Sheet, and aggregated with the tidyverse package
      • Wickham H.
      • Averick M.
      • Bryan J.
      • et al.
      Welcome to the tidyverse.
      in R
      R Core Team
      R: A Language and Environment for Statistical Computing.
      via RStudio.
      RStudio Team
      RStudio: Integrated Development Environment for R.
      Figures were produced using ggplot2
      • Wickham H.
      Ggplot2: Elegant Graphics for Data Analysis. Springer-Verlag.
      and plotly
      Plotly Technologies Inc
      Collaborative data science.
      in R.
      R Core Team
      R: A Language and Environment for Statistical Computing.

      Data Items

      The extracted data items included author, publication year, number of patients, discontinued medicine or medicine class, population, setting and treatment indication, study design including blinding, “feasibility of discontinuation,” other relevant results such as particular treatment-related efficacy/harms, and comments (eg, limitations to the study).
      To describe the “feasibility of discontinuation,” we extracted 2 measures: (1) the “dropout” rate defined as the proportion of patients who did not complete the entire study per protocol in the discontinuation and continuation groups; and (2) the “disease recurrence” rate defined as the proportion of patients with disease appearance for preventive treatments (eg, fractures after discontinuation of bisphosphonate treatment) or clinical worsening of the treated disease only for primarily symptomatic treatments (eg, pain after opioid treatment withdrawal) in the discontinuation and continuation group. Although adverse drug withdrawal events (ADWEs) can be due to either disease recurrence or physiological reactions to the discontinuation of medicines,
      • Reeve E.
      • Moriarty F.
      • Nahas R.
      • Turner J.P.
      • Kouladjian O’Donnell L.
      • Hilmer S.N.
      A narrative review of the safety concerns of deprescribing in older adults and strategies to mitigate potential harms.
      this measure focused on disease recurrence as the dropout rate should capture serious ADWEs due to physiological reactions. Thus, if beta-blockers are used to treat congestive heart failure and a patient experiences worsening in heart failure, then it would be considered disease recurrence. In contrast, if the patient experiences tachycardia then it is not, but it may be captured in the dropout rate if the patient exits the study because of the ADWE. To identify disease recurrence, we categorized treatment as primarily “symptomatic” if used to alleviate symptoms present (eg, fentanyl for pain), “preventive” if primarily used to prevent future events in a condition that is asymptomatic (eg, statins for prevention of cardiovascular events), or both “symptomatic and preventive” (eg, selective serotonin reuptake inhibitors for depression) as judged by the authors. We defined a difference as less than 10% in both dropout and disease recurrence rate as “small.” For trials with more treatment groups than just randomized discontinuation and continuation, we only extracted and present data from the randomized discontinuation and continuation groups.

      Critical Appraisal of Evidence

      Existing risk of bias evaluation tools were not suitable in their entirety. We used the first domain from Cochrane Risk of Bias tool 2
      • Sterne J.A.C.
      • Savović J.
      • Page M.J.
      • et al.
      RoB 2: a revised tool for assessing risk of bias in randomised trials.
      to assess the risk of bias arising from the randomization process. In addition, we assessed the comparator bias that could lead to a differential dropout rate by answering the following 4 questions: (1) Were the discontinued medicine(s) primarily symptomatic, preventive or both? Our hypothesis was that symptomatic treatments are more prone to differential dropout rates because of poor blinding. (2) Was tapering needed and if so, was the tapering strategy adequate to avoid withdrawal symptoms? (3) Was the study adequately blinded? and (4) Any other design choices which may result in differential dropout rates? Two authors (J.K. and A.M.S.S.) independently answered these questions for each trial and assessed the risk of bias as “low risk,” “some concern,” or “high risk.” In general, nonblinded studies were classified as high risk for symptomatic medicines and some concern for preventive medicines, studies with inadequate tapering were high risk, and studies where tapering was needed and mentioned, but not described in detail, were classified as some concern. Consensus was reached through discussion or via the judgment of a third author (M.B.C.).

      Synthesis of the Results

      To identify disease areas and medicines where discontinuation trials exist, we aggregated the data on medical specialty, indication for the treatment, and the medicine(s) discontinued. To provide an overview of the feasibility of discontinuation of the individual medicines, we plotted the dropout rates and disease recurrence rates in the discontinuation and continuation group, the size of the studies, and the risk of bias. To identify treatment areas where discontinuation may not be feasible, we compared the difference between the discontinuation and the continuation group for both the dropout and disease recurrence rate. A priori, the dropout and disease recurrence rates were expected to be greater in the discontinuation group compared with the continuation group. Therefore, the differences in these rates were compared using a 1-sided Fisher exact test in R version 3.6.3,
      R Core Team
      R: A Language and Environment for Statistical Computing.
      and a 1-sided P < .05 was considered statistically significant. To identify treatment areas where discontinuation may be feasible, we extracted the trials where the above-mentioned differences were both statistically insignificant and where the absolute difference between groups for both rates was less than or equal to 10%, corresponding to a number to discontinue of 10 for 1 additional dropout and/or 1 additional disease recurrence. Other relevant outcomes could not be readily synthesized and are presented narratively or in tables.

      Results

      Selection of Studies

      In total, we screened 3304 records and included 41 publications comprising 40 unique trials.
      • George J.
      • Kitzis I.
      • Zandorf D.
      • et al.
      Safety of nitrate withdrawal in angina-free and hemodynamically stable patients with coronary artery disease.
      • van Kraaij D.J.
      • Jansen R.W.
      • Bouwels L.H.
      • Go R.I.
      • Verheugt F.W.
      • Hoefnagels W.H.
      Use of Valsalva’s maneuver to detect early recurrence of congestive heart failure in a randomized trial of furosemide withdrawal in older patients.
      • van Kraaij D.J.W.
      • Jansen R.W.M.M.
      • Bouwels L.H.R.
      • Gribnau F.W.J.
      • Hoefnagels W.H.L.
      Furosemide withdrawal in elderly heart failure patients with preserved left ventricular systolic function.
      • Kutner J.S.
      • Blatchford P.J.
      • Taylor D.H.
      • et al.
      Safety and benefit of discontinuing statin therapy in the setting of advanced, life-limiting illness: a randomized clinical trial.
      • Sheppard J.P.
      • Lown M.
      • Burt J.
      • et al.
      Blood pressure changes following antihypertensive medication reduction, by drug class and dose chosen for withdrawal: exploratory analysis of data from the OPTiMISE trial.
      • Nijst P.
      • Martens P.
      • Dauw J.
      • et al.
      Withdrawal of neurohumoral blockade after cardiac resynchronization therapy.
      • Greenspan S.L.
      • Emkey R.D.
      • Bone H.G.
      • et al.
      Significant differential effects of alendronate, estrogen, or combination therapy on the rate of bone loss after discontinuation of treatment of postmenopausal osteoporosis. A randomized, double-blind, placebo-controlled trial.
      • Michalská D.
      • Stepan J.J.
      • Basson B.R.
      • Pavo I.
      The effect of raloxifene after discontinuation of long-term alendronate treatment of postmenopausal osteoporosis.
      • Black D.M.
      • Schwartz A.V.
      • Ensrud K.E.
      • et al.
      Effects of continuing or stopping alendronate after 5 years of treatment: the Fracture Intervention Trial Long-term Extension (FLEX): a randomized trial.
      • Wright N.C.
      • Foster P.J.
      • Mudano A.S.
      • et al.
      Assessing the feasibility of the effectiveness of discontinuing bisphosphonates trial: a pilot study.
      • Black D.M.
      • Reid I.R.
      • Boonen S.
      • et al.
      The effect of 3 versus 6 years of zoledronic acid treatment of osteoporosis: a randomized extension to the HORIZON-Pivotal Fracture Trial (PFT).
      • Cibere J.
      • Kopec J.A.
      • Thorne A.
      • et al.
      Randomized, double-blind, placebo-controlled glucosamine discontinuation trial in knee osteoarthritis.
      • Arai T.
      • Kashimoto Y.
      • Ukyo Y.
      • Tominaga Y.
      • Imanaka K.
      Two placebo-controlled, randomized withdrawal studies to evaluate the fentanyl 1 day patch in opioid-naïve patients with chronic pain.
      • Holmes C.
      • Wilkinson D.
      • Dean C.
      • et al.
      The efficacy of donepezil in the treatment of neuropsychiatric symptoms in Alzheimer disease.
      • Johannsen P.
      • Salmon E.
      • Hampel H.
      • et al.
      Assessing therapeutic efficacy in a progressive disease: a study of donepezil in Alzheimer’s disease.
      • Howard R.
      • McShane R.
      • Lindesay J.
      • et al.
      Donepezil and memantine for moderate-to-severe Alzheimer’s disease.
      • Gaudig M.
      • Richarz U.
      • Han J.
      • Van Baelen B.
      • Schauble B.
      Effects of galantamine in Alzheimer’s disease: double-blind withdrawal studies evaluating sustained versus interrupted treatment.
      • Scarpini E.
      • Bruno G.
      • Zappalà G.
      • et al.
      Cessation versus continuation of galantamine treatment after 12 months of therapy in patients with Alzheimer’s disease: a randomized, double blind, placebo controlled withdrawal trial.
      • Herrmann N.
      • O’Regan J.
      • Ruthirakuhan M.
      • et al.
      A randomized placebo-controlled discontinuation study of cholinesterase inhibitors in institutionalized patients with moderate to severe Alzheimer disease.
      • Ory-Magne F.
      • Corvol J.C.
      • Azulay J.P.
      • et al.
      Withdrawing amantadine in dyskinetic patients with Parkinson disease: The AMANDYSK trial.
      • Biaggioni I.
      • Freeman R.
      • Mathias C.J.
      • Low P.
      • Hewitt L.A.
      • Kaufmann H.
      Randomized withdrawal study of patients with symptomatic neurogenic orthostatic hypotension responsive to droxidopa.
      • Tse W.
      • Frisina P.
      • Halbig T.
      • et al.
      The effects of withdrawal of dopaminergic medication in nursing home patients with advanced parkinsonism.
      • Findlay D.J.
      • Sharma J.
      • McEwen J.
      • Ballinger B.R.
      • MacLennan W.J.
      • McHarg A.M.
      Double-blind controlled withdrawal of thioridazine treatment in elderly female inpatients with senile dementia.
      • Devanand D.P.
      • Pelton G.H.
      • Cunqueiro K.
      • Sackeim H.A.
      • Marder K.A.
      6-month, randomized, double-blind, placebo-controlled pilot discontinuation trial following response to haloperidol treatment of psychosis and agitation in Alzheimer’s disease.
      • Devanand D.P.
      • Mintzer J.
      • Schultz S.K.
      • et al.
      Relapse risk after discontinuation of risperidone in Alzheimer’s disease.
      • Patel A.N.
      • Lee S.
      • Andrews H.F.
      • et al.
      Prediction of relapse after discontinuation of antipsychotic treatment in Alzheimer’s disease: the role of hallucinations.
      • Bergh S.
      • Selbaek G.
      • Engedal K.
      Discontinuation of antidepressants in people with dementia and neuropsychiatric symptoms (DESEP study): double blind, randomised, parallel group, placebo controlled trial.
      • Hardy B.G.
      • Shulman K.I.
      • Zucchero C.
      Gradual discontinuation of lithium augmentation in elderly patients with unipolar depression.
      • Klysner R.
      • Bent-Hansen J.
      • Hansen H.L.
      • et al.
      Efficacy of citalopram in the prevention of recurrent depression in elderly patients: placebo-controlled study of maintenance therapy.
      • Wilson K.C.
      • Mottram P.G.
      • Ashworth L.
      • Abou-Saleh M.T.
      Older community residents with depression: long-term treatment with sertraline. Randomised, double-blind, placebo-controlled study.
      • Ulfvarson J.
      • Adami J.
      • Wredling R.
      • Kjellman B.
      • Reilly M.
      • von Bahr C.
      Controlled withdrawal of selective serotonin reuptake inhibitor drugs in elderly patients in nursing homes with no indication of depression.
      • Habraken H.
      • Soenen K.
      • Blondeel L.
      • et al.
      Gradual withdrawal from benzodiazepines in residents of homes for the elderly: experience and suggestions for future research.
      • Curran H.V.
      • Collins R.
      • Fletcher S.
      • Kee S.C.Y.
      • Woods B.
      • Iliffe S.
      Older adults and withdrawal from benzodiazepine hypnotics in general practice: effects on cognitive function, sleep, mood and quality of life.
      • O’Brien A.
      • Russo-Magno P.
      • Karki A.
      • et al.
      Effects of withdrawal of inhaled steroids in men with severe irreversible airflow obstruction.
      • Choudhury A.B.
      • Dawson C.M.
      • Kilvington H.E.
      • et al.
      Withdrawal of inhaled corticosteroids in people with COPD in primary care: a randomised controlled trial.
      • Borrill Z.
      • Roy K.
      • Kolsum U.
      • Southworth T.
      • Vestbo J.
      • Singh D.
      Seretide withdrawal increases airway inflammation in moderate COPD patients.
      • Rice K.L.
      • Rubins J.B.
      • Lebahn F.
      • et al.
      Withdrawal of chronic systemic corticosteroids in patients with COPD: a randomized trial.
      • Fabricius P.G.
      • Weizert P.
      • Dunzendorfer U.
      • Hannaford J.M.
      • Maurath C.
      Efficacy of once-a-day terazosin in benign prostatic hyperplasia: a randomized, double-blind placebo-controlled clinical trial.
      • Barkin J.
      • Guimarães M.
      • Jacobi G.
      • Pushkar D.
      • Taylor S.
      • van Vierssen Trip O.B.
      Alpha-blocker therapy can be withdrawn in the majority of men following initial combination therapy with the dual 5alpha-reductase inhibitor dutasteride.
      • Lee J.Y.
      • Kang D.H.
      • Park S.Y.
      • et al.
      Effect of discontinuation of tamsulosin in Korean men with benign prostatic hyperplasia taking tamsulosin and dutasteride: an open-label, prospective, randomized pilot study.
      • Matsukawa Y.
      • Takai S.
      • Funahashi Y.
      • et al.
      Effects of withdrawing α1-blocker from combination therapy with α1-blocker and 5α-reductase inhibitor in patients with lower urinary tract symptoms suggestive of benign prostatic hyperplasia: a prospective and comparative trial using urodynamics.
      See Figure 1 for study selection.
      Figure thumbnail gr1
      Fig. 1Flow of studies during study selection.

      Characteristics of Sources of Evidence

      An overview of the included trials is presented in Figure 2, where the medical specialty, indication for the treatment, and the discontinued medicine(s) are visualized. Additional information on the included trials is available in Supplementary Table 1. Of the included trials, 65% (26/40) of the discontinued medicines were primarily symptomatic, 15% (6/40) were primarily preventive, and 20% (8/40) were both preventive and symptomatic. The setting of the patient recruitment was outpatient clinics (20/40 = 50%); nursing homes (5/40 = 12.5%); the community, for example, using advertisements (5/40 = 12.5%); general practitioners (4/10 = 10%); unknown, that is, multicenter studies with no description of the setting (4/40 = 10%); hospital admissions (1/40 = 2.5%); and palliative care (1/40 = 2.5%).
      Figure thumbnail gr2
      Fig. 2Sunburst chart displaying the distribution of randomized discontinuation trials in older adults on medical specialty, the indication for the discontinued medicine(s), and medicine(s) discontinued. BPSD, behavioral and psychological symptoms of dementia; LUTS, lower urinary tract symptoms; HFpEF, heart failure with preserved ejection fraction; COPD, chronic obstructive pulmonary disease.
      The designs of the 40 included trials are presented in Figure 3 (designs A-E) along with the designs of the 64 excluded trials (designs F-J). Most of the included trials (20/40 = 50%) randomized patients already on the study medicine (design A), 10% (4/40) were an extension to a parent trial with randomized discontinuation for patients on the study medicine (design B), 15% (6/40) were randomized discontinuation of 1 medicine after combination therapy with 2 medicines (design C), 23% (9/40) were randomized discontinuation of the study medicine for patients with initial effect of the study medicine during a run-in phase (design D), and 1 trial (3%) was a crossover trial for patients already on the study medicine (design E). Of the included trials, 25% (10/40) were nonblinded and 75% (30/40) were placebo-controlled.
      Figure thumbnail gr3
      Fig. 3Overview of study designs containing an element of medicine discontinuation. The number of arms can vary and are not limited to those visualized in the figure. The discontinuation can be blinded (ie, continued placebo treatment) or nonblinded (no medicine taken in the discontinuation group).

      Critical Appraisal of Sources of Evidence

      The bias assessments are presented in Supplementary Table 2. In summary, 5% of the trials (2/40) had high risk of bias regarding randomization whereas 45% (18/35) had “some concern” (most of them due to an inadequate description of the randomization process). Regarding differential dropout rates, 48% (19/40) of the trials had bias disfavoring the discontinuation group. Of these 19 trials, 53% (10/19) had high risk of bias, while 47% (9/19) had “some concern.” There was low risk of bias across both domains in 25% of the trials (10/40).

      Results and Synthesis of Results of Sources of Evidence

      Dropout rate

      The dropout rate in the discontinuation group compared with the continuation group is presented in Figure 4 for all the included trials, except for 2 trials where this information was not reported.
      • Sheppard J.P.
      • Lown M.
      • Burt J.
      • et al.
      Blood pressure changes following antihypertensive medication reduction, by drug class and dose chosen for withdrawal: exploratory analysis of data from the OPTiMISE trial.
      ,
      • O’Brien A.
      • Russo-Magno P.
      • Karki A.
      • et al.
      Effects of withdrawal of inhaled steroids in men with severe irreversible airflow obstruction.
      The dropout rate varied from 0% in both groups
      • Findlay D.J.
      • Sharma J.
      • McEwen J.
      • Ballinger B.R.
      • MacLennan W.J.
      • McHarg A.M.
      Double-blind controlled withdrawal of thioridazine treatment in elderly female inpatients with senile dementia.
      to a maximum of 83% in the discontinuation group
      • Ory-Magne F.
      • Corvol J.C.
      • Azulay J.P.
      • et al.
      Withdrawing amantadine in dyskinetic patients with Parkinson disease: The AMANDYSK trial.
      and 70% in the continuation group.
      • Wilson K.C.
      • Mottram P.G.
      • Ashworth L.
      • Abou-Saleh M.T.
      Older community residents with depression: long-term treatment with sertraline. Randomised, double-blind, placebo-controlled study.
      The difference in dropout rates was statistically significantly greater in the discontinuation group compared with the continuation group in 21% of the trials (8/38). These 8 trials investigated discontinuation of amantadine for levodopa-induced dyskinesia in Parkinson's disease,
      • Ory-Magne F.
      • Corvol J.C.
      • Azulay J.P.
      • et al.
      Withdrawing amantadine in dyskinetic patients with Parkinson disease: The AMANDYSK trial.
      donepezil for dementia due to Alzheimer's disease,
      • Howard R.
      • McShane R.
      • Lindesay J.
      • et al.
      Donepezil and memantine for moderate-to-severe Alzheimer’s disease.
      citalopram for unipolar major depressive episode,
      • Klysner R.
      • Bent-Hansen J.
      • Hansen H.L.
      • et al.
      Efficacy of citalopram in the prevention of recurrent depression in elderly patients: placebo-controlled study of maintenance therapy.
      fentanyl patch for pain due to postherpetic neuralgia, complex regional pain syndrome, or chronic postoperative pain,
      • Arai T.
      • Kashimoto Y.
      • Ukyo Y.
      • Tominaga Y.
      • Imanaka K.
      Two placebo-controlled, randomized withdrawal studies to evaluate the fentanyl 1 day patch in opioid-naïve patients with chronic pain.
      fluticasone propionate for chronic obstructive pulmonary disease,
      • Choudhury A.B.
      • Dawson C.M.
      • Kilvington H.E.
      • et al.
      Withdrawal of inhaled corticosteroids in people with COPD in primary care: a randomised controlled trial.
      risperidone for psychosis or agitation-aggression due to Alzheimer's disease,
      • Devanand D.P.
      • Mintzer J.
      • Schultz S.K.
      • et al.
      Relapse risk after discontinuation of risperidone in Alzheimer’s disease.
      beta-blockers for heart failure after cardiac resynchronization therapy,
      • Nijst P.
      • Martens P.
      • Dauw J.
      • et al.
      Withdrawal of neurohumoral blockade after cardiac resynchronization therapy.
      and galantamine for dementia due to Alzheimer's disease.
      • Scarpini E.
      • Bruno G.
      • Zappalà G.
      • et al.
      Cessation versus continuation of galantamine treatment after 12 months of therapy in patients with Alzheimer’s disease: a randomized, double blind, placebo controlled withdrawal trial.
      Of these 8 trials, 3 trials had a high risk of bias for differential dropout rates because of inadequate tapering of amantadine
      • Ory-Magne F.
      • Corvol J.C.
      • Azulay J.P.
      • et al.
      Withdrawing amantadine in dyskinetic patients with Parkinson disease: The AMANDYSK trial.
      or citalopram
      • Klysner R.
      • Bent-Hansen J.
      • Hansen H.L.
      • et al.
      Efficacy of citalopram in the prevention of recurrent depression in elderly patients: placebo-controlled study of maintenance therapy.
      or due to nonblinded discontinuation of beta-blockers with more planned study visits in the discontinuation group.
      • Nijst P.
      • Martens P.
      • Dauw J.
      • et al.
      Withdrawal of neurohumoral blockade after cardiac resynchronization therapy.
      Figure thumbnail gr4
      Fig. 4Proportion of dropouts per group per medicine for the included discontinuation trials. The size of the circle symbolizes the number of patients in the trials. The colors symbolize the risk of bias regarding differential dropout rates. Crossover trials are not included in this graph. The gray line shows when the proportion of dropouts are equal in the 2 groups; if trials are below the gray line, then there were more dropouts in the continuation group compared with the discontinuation group and vice versa. SSRI, selective serotonin reuptake inhibitors.

      Disease Recurrence Rate

      The disease recurrence rate was reported in 80% (32/40) of the included trials, and disease recurrence in the discontinuation group compared with the continuation group is presented in Figure 5. The disease recurrence rate varied from 0% in both groups
      • Wright N.C.
      • Foster P.J.
      • Mudano A.S.
      • et al.
      Assessing the feasibility of the effectiveness of discontinuing bisphosphonates trial: a pilot study.
      to a maximum of 80% in the discontinuation group
      • Devanand D.P.
      • Pelton G.H.
      • Cunqueiro K.
      • Sackeim H.A.
      • Marder K.A.
      6-month, randomized, double-blind, placebo-controlled pilot discontinuation trial following response to haloperidol treatment of psychosis and agitation in Alzheimer’s disease.
      and 70% in the continuation group.
      • Rice K.L.
      • Rubins J.B.
      • Lebahn F.
      • et al.
      Withdrawal of chronic systemic corticosteroids in patients with COPD: a randomized trial.
      The difference in disease recurrence rates was statistically significantly greater in the discontinuation group compared with the continuation group in 28% of the trials (9/32). Of these 9 trials, 5 trials also had greater dropout rates in the discontinuation groups and were described above, that is, amantadine,
      • Ory-Magne F.
      • Corvol J.C.
      • Azulay J.P.
      • et al.
      Withdrawing amantadine in dyskinetic patients with Parkinson disease: The AMANDYSK trial.
      risperidone,
      • Devanand D.P.
      • Mintzer J.
      • Schultz S.K.
      • et al.
      Relapse risk after discontinuation of risperidone in Alzheimer’s disease.
      fentanyl patch,
      • Arai T.
      • Kashimoto Y.
      • Ukyo Y.
      • Tominaga Y.
      • Imanaka K.
      Two placebo-controlled, randomized withdrawal studies to evaluate the fentanyl 1 day patch in opioid-naïve patients with chronic pain.
      citalopram,
      • Klysner R.
      • Bent-Hansen J.
      • Hansen H.L.
      • et al.
      Efficacy of citalopram in the prevention of recurrent depression in elderly patients: placebo-controlled study of maintenance therapy.
      and fluticasone propionate.
      • Choudhury A.B.
      • Dawson C.M.
      • Kilvington H.E.
      • et al.
      Withdrawal of inhaled corticosteroids in people with COPD in primary care: a randomised controlled trial.
      The remaining 4 trials not previously described investigated discontinuation of tamsulosin for lower urinary tract syndrome,
      • Barkin J.
      • Guimarães M.
      • Jacobi G.
      • Pushkar D.
      • Taylor S.
      • van Vierssen Trip O.B.
      Alpha-blocker therapy can be withdrawn in the majority of men following initial combination therapy with the dual 5alpha-reductase inhibitor dutasteride.
      citalopram or sertraline for patients living in nursing homes without a history of depression,
      • Ulfvarson J.
      • Adami J.
      • Wredling R.
      • Kjellman B.
      • Reilly M.
      • von Bahr C.
      Controlled withdrawal of selective serotonin reuptake inhibitor drugs in elderly patients in nursing homes with no indication of depression.
      SSRIs for neuropsychiatric symptoms due to dementia,
      • Bergh S.
      • Selbaek G.
      • Engedal K.
      Discontinuation of antidepressants in people with dementia and neuropsychiatric symptoms (DESEP study): double blind, randomised, parallel group, placebo controlled trial.
      and nitrates for angina pectoris.
      • George J.
      • Kitzis I.
      • Zandorf D.
      • et al.
      Safety of nitrate withdrawal in angina-free and hemodynamically stable patients with coronary artery disease.
      Of the 9 trials, 3 trials had a high risk of bias because of inadequate tapering of SSRIs,
      • Klysner R.
      • Bent-Hansen J.
      • Hansen H.L.
      • et al.
      Efficacy of citalopram in the prevention of recurrent depression in elderly patients: placebo-controlled study of maintenance therapy.
      ,
      • Ulfvarson J.
      • Adami J.
      • Wredling R.
      • Kjellman B.
      • Reilly M.
      • von Bahr C.
      Controlled withdrawal of selective serotonin reuptake inhibitor drugs in elderly patients in nursing homes with no indication of depression.
      amantadine,
      • Ory-Magne F.
      • Corvol J.C.
      • Azulay J.P.
      • et al.
      Withdrawing amantadine in dyskinetic patients with Parkinson disease: The AMANDYSK trial.
      or nonblinded discontinuation of nitrates.
      • George J.
      • Kitzis I.
      • Zandorf D.
      • et al.
      Safety of nitrate withdrawal in angina-free and hemodynamically stable patients with coronary artery disease.
      Figure thumbnail gr5
      Fig. 5Proportion of patients with disease recurrence or worsening per group per medicine for the included discontinuation trials. The size of the circle symbolizes the number of patients in the trials. The colors symbolize the risk of bias. The gray line shows when the proportion with recurrence are equal in the 2 groups; if trials are below the gray line, then there were more disease recurrences in the continuation group compared with the discontinuation group and vice versa. SSRI, selective serotonin reuptake inhibitors.

      Dropout and Disease Recurrence Rate

      In total, 31 trials reported both dropout rates and disease recurrence rates. In 13 of these 31 trials, the difference in both dropout rate and disease recurrence rate were statistically insignificant and less than 10% for the discontinuation group compared with the continuation group. These 13 trials investigated discontinuation of glucosamine for osteoarthritis,
      • Cibere J.
      • Kopec J.A.
      • Thorne A.
      • et al.
      Randomized, double-blind, placebo-controlled glucosamine discontinuation trial in knee osteoarthritis.
      donepezil for mild to moderate dementia due to Alzheimer's disease and with uncertain clinical benefit of the treatment,
      • Johannsen P.
      • Salmon E.
      • Hampel H.
      • et al.
      Assessing therapeutic efficacy in a progressive disease: a study of donepezil in Alzheimer’s disease.
      lithium as adjunct to treatment for unipolar depression,
      • Hardy B.G.
      • Shulman K.I.
      • Zucchero C.
      Gradual discontinuation of lithium augmentation in elderly patients with unipolar depression.
      alendronate for osteoporosis,
      • Michalská D.
      • Stepan J.J.
      • Basson B.R.
      • Pavo I.
      The effect of raloxifene after discontinuation of long-term alendronate treatment of postmenopausal osteoporosis.
      • Black D.M.
      • Schwartz A.V.
      • Ensrud K.E.
      • et al.
      Effects of continuing or stopping alendronate after 5 years of treatment: the Fracture Intervention Trial Long-term Extension (FLEX): a randomized trial.
      • Wright N.C.
      • Foster P.J.
      • Mudano A.S.
      • et al.
      Assessing the feasibility of the effectiveness of discontinuing bisphosphonates trial: a pilot study.
      statins as primary or secondary prevention of cardiovascular disease in patients with limited life expectancy,
      • Kutner J.S.
      • Blatchford P.J.
      • Taylor D.H.
      • et al.
      Safety and benefit of discontinuing statin therapy in the setting of advanced, life-limiting illness: a randomized clinical trial.
      droxidopa for neurogenic orthostatic hypotension,
      • Biaggioni I.
      • Freeman R.
      • Mathias C.J.
      • Low P.
      • Hewitt L.A.
      • Kaufmann H.
      Randomized withdrawal study of patients with symptomatic neurogenic orthostatic hypotension responsive to droxidopa.
      tamsulosin for lower urinary tract symptoms,
      • Lee J.Y.
      • Kang D.H.
      • Park S.Y.
      • et al.
      Effect of discontinuation of tamsulosin in Korean men with benign prostatic hyperplasia taking tamsulosin and dutasteride: an open-label, prospective, randomized pilot study.
      donepezil for dementia and neuropsychiatric symptoms due to Alzheimer's disease,
      • Holmes C.
      • Wilkinson D.
      • Dean C.
      • et al.
      The efficacy of donepezil in the treatment of neuropsychiatric symptoms in Alzheimer disease.
      sertraline for patients with major depressive episode,
      • Wilson K.C.
      • Mottram P.G.
      • Ashworth L.
      • Abou-Saleh M.T.
      Older community residents with depression: long-term treatment with sertraline. Randomised, double-blind, placebo-controlled study.
      cholinesterase inhibitors for dementia due to Alzheimer's disease in patients living in nursing homes,
      • Herrmann N.
      • O’Regan J.
      • Ruthirakuhan M.
      • et al.
      A randomized placebo-controlled discontinuation study of cholinesterase inhibitors in institutionalized patients with moderate to severe Alzheimer disease.
      and fentanyl patch for low back pain or pain due to osteoarthritis.
      • Arai T.
      • Kashimoto Y.
      • Ukyo Y.
      • Tominaga Y.
      • Imanaka K.
      Two placebo-controlled, randomized withdrawal studies to evaluate the fentanyl 1 day patch in opioid-naïve patients with chronic pain.

      Discussion

      Findings

      We identified 40 unique discontinuation trials with inclusion of older patients. Of these trials, 12 trials had dropout rates and/or disease recurrence rates that were statistically significantly higher in the discontinuation group compared with the continuation group, suggesting that discontinuation may not be feasible for these medicines in these populations. Further, we identified 13 trials where the difference in both dropout rates and disease recurrence rates were small (≤10%) and statistically insignificant, suggesting that discontinuation may be feasible. Interestingly, one study investigating discontinuation of nitrates for angina pectoris in stable patients
      • George J.
      • Kitzis I.
      • Zandorf D.
      • et al.
      Safety of nitrate withdrawal in angina-free and hemodynamically stable patients with coronary artery disease.
      resulted in a statistically significantly higher risk of disease recurrence (8/80 = 10% vs 0/40 = 0%), but with an absolute difference in disease recurrence of 10%. This highlights the complexity of the interpretation of these studies where statistical significance does not always equate clinically relevant differences and underlines why the results presented in this review must be interpreted in the context of the diseases studied. In addition, this example shows that for some of the therapeutic areas where there was a statistically significant difference in dropout rate or disease recurrence, discontinuation attempts may still be feasible in clinical practice, that is, in this study 90% of the attempts were successful and the few disease recurrences were successfully treated with reinstated therapy.
      Another complexity highlighted in the present review is the relatively high proportion of patients with disease recurrence in certain therapeutic areas, also in continuation groups (Figure 5); for example, 41% (13/32) of the trials reported disease recurrence rates ≥20% in both groups. A high baseline recurrence risk complicates discontinuation in clinical practice because patients may experience disease recurrence during discontinuation attempts that may in fact be unrelated to the discontinuation attempt, but this is in practice impossible to know and may lead to reinitiation of treatment. This underlines the importance of randomized discontinuation trials as the baseline risk of disease recurrence cannot be estimated from single-arm discontinuation trials.

      Diseases Where Discontinuation Trials Are Lacking

      The identified discontinuation trials covered many of the most prevalent diseases in older patients.
      • Hvidberg M.F.
      • Johnsen S.P.
      • Davidsen M.
      • Ehlers L.
      A nationwide study of prevalence rates and characteristics of 199 chronic conditions in Denmark.
      However, of the most commonly used medicines in older adults,
      • Kornholt J.
      • Christensen M.B.
      Prevalence of polypharmacy in Denmark.
      discontinuation trials were lacking for proton pump inhibitors and platelet inhibitors. Trials on discontinuation of treatment for common diseases such as type 2 diabetes and cardiovascular diseases such as atrial fibrillation were also lacking. In general, trials with discontinuation of purely preventive treatments were not very common (6/40 = 15%). We identified 5 trials with discontinuation of bisphosphonates for the treatment of osteoporosis (5/6 = 83%)
      • Greenspan S.L.
      • Emkey R.D.
      • Bone H.G.
      • et al.
      Significant differential effects of alendronate, estrogen, or combination therapy on the rate of bone loss after discontinuation of treatment of postmenopausal osteoporosis. A randomized, double-blind, placebo-controlled trial.
      • Michalská D.
      • Stepan J.J.
      • Basson B.R.
      • Pavo I.
      The effect of raloxifene after discontinuation of long-term alendronate treatment of postmenopausal osteoporosis.
      • Black D.M.
      • Schwartz A.V.
      • Ensrud K.E.
      • et al.
      Effects of continuing or stopping alendronate after 5 years of treatment: the Fracture Intervention Trial Long-term Extension (FLEX): a randomized trial.
      • Wright N.C.
      • Foster P.J.
      • Mudano A.S.
      • et al.
      Assessing the feasibility of the effectiveness of discontinuing bisphosphonates trial: a pilot study.
      • Black D.M.
      • Reid I.R.
      • Boonen S.
      • et al.
      The effect of 3 versus 6 years of zoledronic acid treatment of osteoporosis: a randomized extension to the HORIZON-Pivotal Fracture Trial (PFT).
      and only 1 trial investigating the effect of discontinuing statins for patients at the end of life.
      • Kutner J.S.
      • Blatchford P.J.
      • Taylor D.H.
      • et al.
      Safety and benefit of discontinuing statin therapy in the setting of advanced, life-limiting illness: a randomized clinical trial.
      This is probably due to the difficulty of conducting these trials as they require a long follow-up period. Trials with discontinuation of purely symptomatic medicines are simpler to conduct. Here, any recurrence of symptoms should be reversible with reinstated treatment of the discontinued medicines. It is therefore remarkable that we only identified 2 studies
      • Cibere J.
      • Kopec J.A.
      • Thorne A.
      • et al.
      Randomized, double-blind, placebo-controlled glucosamine discontinuation trial in knee osteoarthritis.
      ,
      • Arai T.
      • Kashimoto Y.
      • Ukyo Y.
      • Tominaga Y.
      • Imanaka K.
      Two placebo-controlled, randomized withdrawal studies to evaluate the fentanyl 1 day patch in opioid-naïve patients with chronic pain.
      with discontinuation trials of medicines for the treatment of pain because analgesics are among the most commonly used medicines for older citizens.
      • Kornholt J.
      • Christensen M.B.
      Prevalence of polypharmacy in Denmark.
      Further studies regarding discontinuation of analgesics in older patients seem warranted.

      Considerations for Discontinuation Trial Design

      As expected, the included trials were clinically and methodologically diverse with regard to therapeutic area, setting, study design, sample size, reporting of dropouts, harms, and risk of bias. Recently, the need to standardize and optimize the reporting of results from discontinuation trials was highlighted.
      • Blom J.W.
      • Muth C.
      • Glasziou P.
      • et al.
      Describing deprescribing trials better: an elaboration of the CONSORT statement.
      Based on this scoping review, identified trials can be divided into 10 different trial designs with an element of discontinuation (Figure 3). The numerous different designs of the included trials are a challenge for the external validity and renders it almost impossible to summarize and meta-analyze the findings. The design that most resembles the clinical situation is where patients are already receiving a given medicine (design A without a run-in period; Figure 3) or a combination of medicines (design C without a run-in period; Figure 3), but changes in prescription patterns over time (eg, new guidelines) or differences in prescription patterns across geographical regions (eg, countries) can limit the external validity of the findings, because the success of discontinuation will depend on how good those who have prescribed the medicine have been to prescribe to the right patients. Compared to these designs, trials where the medicine is started as part of the discontinuation trial (design A and C with a run-in period or design B; Figure 3) may have a more precisely defined population, but also a higher concentration of responders and are thereby more prone to showing lower feasibility of discontinuation. This feature is exacerbated in trials that only include patients who, in the short term, both tolerate the medicine and has apparent effect of the medicine (design D; Figure 3). Lastly, crossover trials with discontinuation (design E; Figure 3) may have problems with carryover effect and the high dropout rate in many discontinuation trials is problematic when analyzing data from these trials.
      Our risk of bias assessment revealed that adequate tapering, blinding, and randomization are key when designing future discontinuation studies, and that high dropout rates seem unavoidable even in studies with low risk of bias; for example, overall 45% (17/38) had dropout rates ≥20% in both groups (Figure 4). Therefore, study outcomes that are less affected by high dropout rates should be considered such as time-to-event analyses as seen in Arai et al.
      • Arai T.
      • Kashimoto Y.
      • Ukyo Y.
      • Tominaga Y.
      • Imanaka K.
      Two placebo-controlled, randomized withdrawal studies to evaluate the fentanyl 1 day patch in opioid-naïve patients with chronic pain.

      Strengths and Limitations

      Limitations to this study include the exclusion of trials with patients with a mean age <65 years and the exclusion of trials investigating discontinuation of more than 1 medicine. Another limitation is that the proxies for feasibility of discontinuation we used, that is, disease recurrence rate and dropout rate, only imperfectly describe the feasibility of discontinuation. Disease recurrence, although easy to interpret, is not reported by all trials, and will generally favor continuation because no treatment-related harms (eg, adverse effects) are captured. In contrast, the dropout rate is more difficult to interpret, but this measure is reported univariately and should reflect a conservative estimate of the proportion of patients, where discontinuation is not feasible in clinical practice. As an example of the sometimes conflicting and complementary information these measures convey, a trial with discontinuation of beta-blockers for heart failure in patients with normalized ejection fraction following cardiac resynchronization therapy reported a similar low disease recurrence rate in the continuation and discontinuation groups, but a much higher dropout rate in the discontinuation group (because of withdrawal tachycardia).
      • Nijst P.
      • Martens P.
      • Dauw J.
      • et al.
      Withdrawal of neurohumoral blockade after cardiac resynchronization therapy.
      Thus, although a combination of the 2 measures provide some reassurance for the feasibility of discontinuation, a good measure of the feasibility of discontinuation is lacking.

      Conclusions and Implications

      We identified 40 trials with randomized discontinuation of single medicines or similar medicines in older adults. Based on disease recurrence and trial dropout rates, 13 trials were in therapeutic areas where discontinuation of medicines on average are feasible, and 12 trials were in therapeutic areas where discontinuation may not be feasible. The trials were clinically and methodologically diverse in terms of design, therapeutic areas, and reporting of outcomes and harms. Identified therapeutic areas lacking discontinuation trials in older adults include type 2 diabetes and atrial fibrillation. The identified randomized trial evidence may guide deprescribing in clinical practice as well as future clinical trials to avoid overtreatment of older patients.

      Supplementary Data

      Supplementary Material 1. Search strings

      Search string Embase:
      • 1.
        deprescriptions/
      • 2.
        (inappropriat∗ or unnecessar∗ or discontinu∗ or deprescrib∗ or deprescrip∗ or withdraw∗ or stop∗ or cessation).ti.
      • 3.
        1 or 2
      • 4.
        exp Aged/
      • 5.
        (elder∗ or “65” or frail or geriatric∗).ti,ab,kw,kf.
      • 6.
        (“nursing home” or “long-term care” or “residential aged care” or “skilled nursing facility” or “aged care facility” or “aged care facilities”).ti,ab,kw.
      • 7.
        nursing home/
      • 8.
        4 or 5 or 6 or 7
      • 9.
        random∗.ti,ab,kw.
      • 10.
        3 and 8 and 9
      Search string PubMed:
      • 1.
        “Deprescriptions”[Mesh]
      • 2.
        (inappropriat∗[Title] OR unnecessar∗[Title] OR discontinu∗[Title] OR deprescrib∗[Title] OR deprescrip∗[Title] OR withdraw∗[Title] OR stop∗[Title] OR cessation[Title])
      • 3.
        (#1 or #2)
      • 4.
        “Aged”[Mesh]
      • 5.
        (elder∗[Title/Abstract] OR “65”[Title/Abstract] OR frail[Title/Abstract] OR geriatric∗[Title/Abstract])
      • 6.
        (“nursing home”[Title/Abstract] OR “long-term care”[Title/Abstract] OR “residential aged care”[Title/Abstract] OR “skilled nursing facility”[Title/Abstract] OR “aged care facility”[Title/Abstract] OR “aged care facilities”[Title/Abstract])
      • 7.
        “Nursing Homes”[Mesh]
      • 8.
        (#4 OR #5 OR #6 OR #7)
      • 9.
        random∗[Title/Abstract]
      • 10.
        (#3 AND #8 AND #9)
      Search string Cochrane Library:
      • 1.
        MeSH descriptor: [Deprescriptions] explode all trees
      • 2.
        inappropriat∗ or unnecessar∗ or discontinu∗ or deprescrib∗ or deprescrip∗ or withdraw∗ or stop∗ or cessation:ti (Word variations have been searched)
      • 3.
        #1 or #2
      • 4.
        MeSH descriptor: [Aged] explode all trees
      • 5.
        elder∗ or “65” or frail or geriatric∗:ti,ab,kw (Word variations have been searched)
      • 6.
        “nursing home” or “long-term care” or “residential aged care” or “skilled nursing facility” or “aged care facility” or “aged care facilities”:ti,ab,kw (Word variations have been searched)
      • 7.
        MeSH descriptor: [Nursing Homes] explode all trees
      • 8.
        #4 or #5 or #6 or #7
      • 9.
        random∗:ti,ab,kw (Word variations have been searched)
      • 10.
        #3 and #8 and #9
      Supplementary Table 1Characteristics of Included Studies
      Author (Year)Medicine DiscontinuedIndicationPopulationDesign

      (See Figure 3)
      Follow-Up DurationDropoutsDisease RecurrenceOther Relevant Results and Comments
      George et al (2003)
      • George J.
      • Kitzis I.
      • Zandorf D.
      • et al.
      Safety of nitrate withdrawal in angina-free and hemodynamically stable patients with coronary artery disease.
      NitratesSymptomatic treatment of angina pectoris120 nitrate-treated patients without angina or heart failure who were hemodynamically stable for the last 3 moDesign A. Unblinded without a run-in period and with 2:1 discontinuation3 moDiscontinuation:

      8/80 = 10%

      Continuation:

      0/40 = 0%
      Discontinuation:

      8/80 = 10%

      Continuation:

      1/40 = 2.5%
      All subjects with angina after discontinuation experienced symptoms within the first month
      van Kraaij et al (1999)
      • van Kraaij D.J.
      • Jansen R.W.
      • Bouwels L.H.
      • Go R.I.
      • Verheugt F.W.
      • Hoefnagels W.H.
      Use of Valsalva’s maneuver to detect early recurrence of congestive heart failure in a randomized trial of furosemide withdrawal in older patients.
      and van Kraaij et al (2000)
      • van Kraaij D.J.W.
      • Jansen R.W.M.M.
      • Bouwels L.H.R.
      • Gribnau F.W.J.
      • Hoefnagels W.H.L.
      Furosemide withdrawal in elderly heart failure patients with preserved left ventricular systolic function.
      FurosemideSymptomatic treatment of heart failure with preserved ejection fraction (HFpEF)32 furosemide-treated patients with a history of HFpEF and left ventricular ejection fraction >40%Design A. Blinded without a run-in period and with 2:1 discontinuation3 moDiscontinuation:

      5/21 = 24%

      Continuation:

      1/11 = 9%
      Discontinuation:

      2/21 = 10%

      Continuation:

      1/11 = 9%
      There were no significant differences regarding heart failure score, blood pressure, heart rate, spirometry values, or functional status scores (per-protocol analysis)
      Kutner et al (2015)
      • Kutner J.S.
      • Blatchford P.J.
      • Taylor D.H.
      • et al.
      Safety and benefit of discontinuing statin therapy in the setting of advanced, life-limiting illness: a randomized clinical trial.
      StatinsPrimary or secondary prevention of cardiovascular disease, and no recent active cardiovascular disease381 adults with advanced, life-limiting illness with an estimated life expectancy of between 1 mo and 1 y and recent deterioration in functional status taking statins for 3 mo or moreDesign A. Unblinded without a run-in period and with 1:1 discontinuation1 yDiscontinuation:

      94/189 = 50%

      Continuation:

      101/192 = 53%
      Discontinuation:

      13/189 = 7%

      Continuation:

      11/192 = 6%
      Total quality of life was better for the group discontinuing statin therapy (mean McGill QOL score, 7.11 vs 6.85; P = .04)
      Sheppard et al (2021)
      • Sheppard J.P.
      • Lown M.
      • Burt J.
      • et al.
      Blood pressure changes following antihypertensive medication reduction, by drug class and dose chosen for withdrawal: exploratory analysis of data from the OPTiMISE trial.
      AntihypertensivesSymptomatic and preventive treatment of hypertension569 patients aged ≥80 y with controlled systolic blood pressure, receiving ≥2 antihypertensive medicationsDesign C. Unblinded with 1:1 discontinuation. Post hoc subgroup analyses12 wkNot reported per medicineNot reported per medicinePost hoc analyses and details of dropout and disease recurrence are not reported per medicine
      Nijst et al (2020)
      • Nijst P.
      • Martens P.
      • Dauw J.
      • et al.
      Withdrawal of neurohumoral blockade after cardiac resynchronization therapy.
      Beta-blockersSymptomatic and preventive treatment of heart failure40 patients with heart failure with normalized ejection fractions after cardiac resynchronization therapy (CRT) and no symptoms of heart failure for the past 6 mo on optimal pharmacologic therapyDesign A. Part of 2 × 2 design with discontinuation of RAAS and/or beta blockers. Unblinded with 1:1 discontinuation. Only discontinuation of beta-blockers is eligible for inclusion in this review24 moDiscontinuation:

      12/20 = 60%

      Continuation:

      4/20 = 20%
      Discontinuation:

      1/20 = 5%

      Continuation:

      2/20 = 10%
      Prompt reinitiation of therapy led to recovery of ejection fraction in 100% of subjects within 6 mo.

      58% (7/12) dropouts in the discontinuation group were due to tachycardia
      Greenspan et al (2002)
      • Greenspan S.L.
      • Emkey R.D.
      • Bone H.G.
      • et al.
      Significant differential effects of alendronate, estrogen, or combination therapy on the rate of bone loss after discontinuation of treatment of postmenopausal osteoporosis. A randomized, double-blind, placebo-controlled trial.
      AlendronatePreventive treatment of fractures85 women who had completed 2 y of treatment with alendronate and conjugated estrogen in the parent trial. Patients in the parent trial were hysterectomized postmenopausal women with lumbar BMD T score < −1.65.Design B + C. Blinded with 1:1 discontinuation1 yDiscontinuation:

      6/41 = 15%

      Continuation:

      7/44 = 16%
      Not reportedFour-armed study with a different focus and no additional relevant outcomes were reported for the 2 arms included in this review
      Michalská et al (2006)
      • Michalská D.
      • Stepan J.J.
      • Basson B.R.
      • Pavo I.
      The effect of raloxifene after discontinuation of long-term alendronate treatment of postmenopausal osteoporosis.
      AlendronatePreventive treatment of fractures66 women with postmenopausal osteoporosis and at least 3 y of treatment with alendronateDesign A. Unblinded without a run-in period and with 1:1 discontinuation2 yDiscontinuation:

      0/33 = 0%

      Continuation:

      2/33 = 6%
      Discontinuation:

      2/33 = 6%

      Continuation:

      1/33 = 3%
      The change in BMD from baseline was higher in the continuation group compared with the discontinuation group at multiple sites, eg, for total body BMD; difference in change from baseline ≈ 2%, P < .05 (read from Figure 2 in the publication)
      Black et al (2006)
      • Black D.M.
      • Schwartz A.V.
      • Ensrud K.E.
      • et al.
      Effects of continuing or stopping alendronate after 5 years of treatment: the Fracture Intervention Trial Long-term Extension (FLEX): a randomized trial.
      AlendronatePreventive treatment of fractures1099 patients with total hip bone mineral density (BMD) T score > −3.5 and without declining BMD during at least 3 y of treatment with alendronate in the parent trial. Patients in the parent trial were postmenopausal women aged 55-80 y with femoral neck BMD T score < −1.6
      Veritas Health Innovation
      Covidence Systematic Review Software.
      ,
      • Benetos A.
      • Petrovic M.
      • Strandberg T.
      Hypertension management in older and frail older patients.
      Design B. Blinded with 4:10 discontinuation5 yDiscontinuation:

      36/437 = 8%

      Continuation:

      68/662 = 10%
      Discontinuation:

      93/437 = 21%

      Continuation:

      132/662 = 20%
      Disease recurrence is all clinical fractures. The decline in BMD from baseline was lower in the continuation group compared with the discontinuation group at multiple sites, eg, for total hip BMD the decline was −1.02% vs −3.38%; difference in decline = 2.36%, 95% CI: 1.81%-2.90%
      Wright et al (2017)
      • Wright N.C.
      • Foster P.J.
      • Mudano A.S.
      • et al.
      Assessing the feasibility of the effectiveness of discontinuing bisphosphonates trial: a pilot study.
      AlendronatePreventive treatment of fractures27 women older than 65 y with at least 3 y of treatment with alendronateDesign A. Unblinded without a run-in period and with 1:1 discontinuation6 moDiscontinuation:

      2/14 = 14%

      Continuation:

      4/13 = 31%
      Discontinuation:

      0/14 = 0%

      Continuation:

      0/13 = 0%
      Pilot study and mostly administrative outcome measures were reported
      Black et al (2012)
      • Black D.M.
      • Reid I.R.
      • Boonen S.
      • et al.
      The effect of 3 versus 6 years of zoledronic acid treatment of osteoporosis: a randomized extension to the HORIZON-Pivotal Fracture Trial (PFT).
      Zoledronic acidPreventive treatment of fractures1233 women who had completed 3 y of treatment in the parent trial. Patients in the parent trial were women aged >65 y with BMD T score < −2.5 or T score < −1.5 with osteoporotic vertebral fractures
      • Black D.M.
      • Delmas P.D.
      • Eastell R.
      • et al.
      Once-yearly zoledronic acid for treatment of postmenopausal osteoporosis.
      Design B. Blinded with 1:1 discontinuation3 yDiscontinuation:

      146/616 = 24%

      Continuation:

      165/613 = 27%
      Not reportedBMD increased in the continuation group and decreased in the discontinuation group; the mean difference in change ranged from 1.04% to 2.03% depending on site (max P = .002). There was no statistically significant difference in incidence of clinical fractures at any site.
      Cibere et al (2004)
      • Cibere J.
      • Kopec J.A.
      • Thorne A.
      • et al.
      Randomized, double-blind, placebo-controlled glucosamine discontinuation trial in knee osteoarthritis.
      GlucosamineSymptomatic treatment of pain137 patients with pain due to osteoarthritis who were not taking any opioid analgesics and had improvement in pain after at least 1 month of treatment with glucosamineDesign A. Blinded without a run-in period and with 1:1 discontinuation24 wkDiscontinuation:

      0/66 = 0%

      Continuation:

      3/71 = 4%
      Discontinuation:

      28/66 = 42%

      Continuation:

      32/71 = 45%
      Excluded patients on narcotic analgesics
      Arai et al (2015)
      • Arai T.
      • Kashimoto Y.
      • Ukyo Y.
      • Tominaga Y.
      • Imanaka K.
      Two placebo-controlled, randomized withdrawal studies to evaluate the fentanyl 1 day patch in opioid-naïve patients with chronic pain.
      Fentanyl patchSymptomatic treatment of pain150 opioid-naïve patients with low back pain or pain due to osteoarthritis. Only patients without AEs and with sufficient pain relief on fentanyl during a 20-d run-in period were includedDesign D. Blinded with 20 days run-in period and with 1:1 discontinuation12 wkDiscontinuation:

      38/77 = 49%

      Continuation:

      36/73 = 49%
      Discontinuation:

      29/77 = 38%

      Continuation:

      21/73 = 29%
      During run-in, 15% (33/218) discontinued treatment because of AEs and 9% (20/218) were not eligible for discontinuation because of lack of pain relief. The change in pain scores favored continuation; change −6.9 mm on the visual analog scale (VAS) vs 0.2 mm, adjusted mean difference = 7.3 mm, 95% CI: 1.1-13.5.
      Arai et al (2015)
      • Arai T.
      • Kashimoto Y.
      • Ukyo Y.
      • Tominaga Y.
      • Imanaka K.
      Two placebo-controlled, randomized withdrawal studies to evaluate the fentanyl 1 day patch in opioid-naïve patients with chronic pain.
      Fentanyl patchSymptomatic treatment of pain163 opioid-naïve patients with pain due to post-herpetic neuralgia, complex regional pain syndrome, or chronic postoperative pain. Only patients without AEs and with sufficient pain relief on fentanyl during a 20-days run-in period were includedDesign D. Blinded with 20 days run-in period and with 1:1 discontinuation12 weeksDiscontinuation:

      51/79 = 65%

      Continuation:

      37/84 = 44%
      Discontinuation:

      35/79 = 44%

      Continuation:

      18/84 = 21%
      During run-in, 12% (33/280) discontinued treatment due to AEs and 18% (50/280) were not eligible for discontinuation due to lack of pain relief. The change in pain scores favored continuation; change in VAS -9.6 mm vs 0.3 mm, adjusted mean difference = 8.7 mm, 95% CI: 2.4 to 15.0 mm.
      Holmes et al (2004)
      • Holmes C.
      • Wilkinson D.
      • Dean C.
      • et al.
      The efficacy of donepezil in the treatment of neuropsychiatric symptoms in Alzheimer disease.
      DonepezilSymptomatic treatment of Alzheimer's disease134 treatment-naïve patients with mild to moderate Alzheimer's disease and marked neuropsychiatric symptoms; Neuropsychiatric Inventory (NPI > 11)Design A. Blinded with 12 wk run-in period and 3:2 discontinuation12 wkDiscontinuation:

      10/55 = 18%

      Continuation:

      6/41 = 15%
      Discontinuation:

      6/55 = 11%

      Continuation:

      2/41 = 5%
      There were differences in cognition, neuropsychiatric symptoms, and caregiver's distress in favor of continuation; change in Mini Mental State Examination (MMSE) scores of −0.1 vs −1.8, P = .02; change in NPI of −2.9 vs 3.3, P = .02; and change in NPI distress score of −2.0 vs 1.0, P = .01
      Johannsen et al (2006)
      • Johannsen P.
      • Salmon E.
      • Hampel H.
      • et al.
      Assessing therapeutic efficacy in a progressive disease: a study of donepezil in Alzheimer’s disease.
      DonepezilSymptomatic treatment of Alzheimer's disease202 treatment-naïve patients with mild to moderate, probable, or possible Alzheimer's disease with uncertain benefit on donepezil in the run-in phaseDesign A. Blinded with 12- to 24-wk run-in period and 1:1 discontinuation12 wkDiscontinuation:

      20/103 = 19%

      Continuation:

      11/99 = 11%
      Discontinuation:

      0/103 = 0%

      Continuation:

      2/99 = 2%
      There were differences in cognition and neuropsychiatric symptoms in favor of continuation: difference in MMSE scores = 1.13, P = .02; difference in NPI scores = 2.87, P = .02. There was no statistically significant difference in activities of daily living between the 2 groups
      Howard et al (2012)
      • Howard R.
      • McShane R.
      • Lindesay J.
      • et al.
      Donepezil and memantine for moderate-to-severe Alzheimer’s disease.
      DonepezilSymptomatic treatment of Alzheimer's disease145 donepezil-treated, community-dwelling patients with moderate to severe Alzheimer's diseaseDesign A. Blinded without a run-in period and 1:1 discontinuation. Part of a 2 × 2 factorial design where discontinuation of donepezil only involves arm 1 and 352 wkDiscontinuation:

      43/72 = 60%

      Continuation:

      23/73 = 32%
      Discontinuation:

      11/72 = 15%

      Continuation:

      7/73 = 10%
      There were differences in cognition and activities of daily living in favor of continuation; average difference in MMSE = 2.4, 95% CI: 1.5-3.2; average difference in Bristol Activities of Daily Living Scale = −4.1, 95% CI: −5.8 to −2.4
      Gaudig et al (2011)
      • Gaudig M.
      • Richarz U.
      • Han J.
      • Van Baelen B.
      • Schauble B.
      Effects of galantamine in Alzheimer’s disease: double-blind withdrawal studies evaluating sustained versus interrupted treatment.
      GalantamineSymptomatic treatment of Alzheimer's disease72 patients who had completed treatment with galantamine for 3 months in the parent trial.
      • Wilson K.C.
      • Mottram P.G.
      • Ashworth L.
      • Abou-Saleh M.T.
      Older community residents with depression: long-term treatment with sertraline. Randomised, double-blind, placebo-controlled study.
      Patients in the parent trial had mild to moderate Alzheimer's disease
      • Rockwood K.
      • Mintzer J.
      • Truyen L.
      • Wessel T.
      • Wilkinson D.
      Effects of a flexible galantamine dose in Alzheimer’s disease: a randomised, controlled trial.
      Design B. Blinded with 1:1 discontinuation. Only study 2 and only those on galantamine in the parent trial is relevant for this review6 wkDiscontinuation:

      0/39 = 0%

      Continuation:

      1/32 = 3%
      Not reportedThere was no statistically significant difference in cognitive function between the discontinuation and continuation group
      Scarpini et al (2011)
      • Scarpini E.
      • Bruno G.
      • Zappalà G.
      • et al.
      Cessation versus continuation of galantamine treatment after 12 months of therapy in patients with Alzheimer’s disease: a randomized, double blind, placebo controlled withdrawal trial.
      GalantamineSymptomatic treatment of Alzheimer's disease139 treatment-naïve patients with mild to moderate Alzheimer's disease. Only patients without AEs and with sufficient effect of the treatment during a 1-year run-in period were includedDesign D. Blinded with a 1-y run-in period and 1:1 discontinuation2 yDiscontinuation:

      44/63 = 70%

      Continuation:

      40/76 = 53%
      Discontinuation:

      26/63 = 41%

      Continuation:

      23/76 = 30%
      During run-in, 15% (38/254) discontinued treatment because of AEs, 0.4% died (1/254), and 12% (30/254) were not eligible for discontinuation because of lack of effect
      Herrmann et al (2016)
      • Herrmann N.
      • O’Regan J.
      • Ruthirakuhan M.
      • et al.
      A randomized placebo-controlled discontinuation study of cholinesterase inhibitors in institutionalized patients with moderate to severe Alzheimer disease.
      Donepezil, galantamine, rivastigmineSymptomatic treatment of Alzheimer's disease40 institutionalized patients with moderate to severe Alzheimer's diseaseDesign A. Blinded without a run-in period and with 1:1 discontinuation8 wkDiscontinuation:

      4/19 = 21%

      Continuation:

      3/21 = 14%
      Discontinuation:

      7/19 = 37%

      Continuation:

      6/21 = 29%
      Multiple different cholinesterase inhibitors discontinued
      Ory-Magne et al (2014)
      • Ory-Magne F.
      • Corvol J.C.
      • Azulay J.P.
      • et al.
      Withdrawing amantadine in dyskinetic patients with Parkinson disease: The AMANDYSK trial.
      AmantadineSymptomatic treatment of levodopa-induced dyskinesia56 amantadine-treated patients with Parkinson's disease and levodopa-induced dyskinesiaDesign A. Blinded without a run-in period and 1:1 discontinuation3 moDiscontinuation:

      24/29 = 83%

      Continuation:

      5/27 = 19%
      Discontinuation:

      18/29 = 62%

      Continuation:

      3/27 = 11%
      The change in dyskinesia (measured with the Unified Parkinson's Disease Rating Scale dyskinesia subscore) was worse in the discontinuation group (1.7) compared with the continuation group (0.2), P = .003
      Biaggioni et al (2015)
      • Biaggioni I.
      • Freeman R.
      • Mathias C.J.
      • Low P.
      • Hewitt L.A.
      • Kaufmann H.
      Randomized withdrawal study of patients with symptomatic neurogenic orthostatic hypotension responsive to droxidopa.
      DroxidopaSymptomatic treatment of neurogenic orthostatic hypotension101 patients with symptomatic neurogenic orthostatic hypotension due to Parkinson's disease, multiple system atrophy, pure autonomic failure, or nondiabetic autonomic neuropathy. Only patients without AEs and with sufficient effect of the treatment during a 14-d run-in period were includedDesign D. Blinded with 14-d run-in period and 1:1 discontinuation14 dDiscontinuation:

      8/51 = 16%

      Continuation:

      6/50 = 12%
      Discontinuation:

      2/51 = 4%

      Continuation:

      1/50 = 2%
      During run-in, 24% (43/181) discontinued treatment because of AEs and 13% (24/181) were not eligible for discontinuation because of lack of effect. There was no statistically significant difference in the change from baseline in symptoms of dizziness and lightheadedness or systolic standing blood pressure between the discontinuation group and the continuation group.
      Tse et al (2008)
      • Tse W.
      • Frisina P.
      • Halbig T.
      • et al.
      The effects of withdrawal of dopaminergic medication in nursing home patients with advanced parkinsonism.
      LevodopaSymptomatic treatment of Parkinson's disease11 levodopa-treated, institutionalized patients with Parkinson's disease and dementiaDesign A without a run-in period and 1:1 discontinuation blinded4 wkDiscontinuation:

      1/6 = 17%

      Continuation:

      0/5 = 0%
      Discontinuation:

      1/6 = 17%

      Continuation:

      0/5 = 0%
      There were no statistically significant changes in cognitive, behavioral, or motor function between the discontinuation and continuation groups.
      Psychiatry
       Findlay et al (1989)
      • Findlay D.J.
      • Sharma J.
      • McEwen J.
      • Ballinger B.R.
      • MacLennan W.J.
      • McHarg A.M.
      Double-blind controlled withdrawal of thioridazine treatment in elderly female inpatients with senile dementia.
      ThioridazineSymptomatic treatment of behavioral and psychological symptoms of dementia (BPSD)36 thioridazine-treated women with Alzheimer's disease and BPSD who were admitted to a long-stay psychogeriatric wardDesign A. Blinded without a run-in period and 1:1 discontinuation4 wkDiscontinuation:

      0/18 = 0%

      Continuation:

      0/18 = 0%
      Not reportedThere were no statistically significant differences between the 2 groups regarding mental function, mobility, balance, or orthostatic blood pressure
       Devanand et al (2011)
      • Devanand D.P.
      • Pelton G.H.
      • Cunqueiro K.
      • Sackeim H.A.
      • Marder K.A.
      6-month, randomized, double-blind, placebo-controlled pilot discontinuation trial following response to haloperidol treatment of psychosis and agitation in Alzheimer’s disease.
      HaloperidolSymptomatic treatment of BPSD20 outpatients with Alzheimer's disease and BPSD. Only patients without AEs and with sufficient effect of haloperidol during a 20-wk run-in period were includedDesign D. Blinded with a 20-wk run-in period and 1:1 discontinuation6 moDiscontinuation:

      8/10 = 80%

      Continuation:

      4/10 = 40%
      Discontinuation:

      8/10 = 80%

      Continuation:

      4/10 = 40%
      During run-in, 14% (6/44) discontinued treatment because of AEs and 20% (9/44) were not eligible for discontinuation because of lack of effect. The time to relapse was shorter in the discontinuation group (mean = 5.8 wk) compared with the continuation group (mean = 8.0 wk); log rank test, P = .04
       Devanand et al (2012)
      • Devanand D.P.
      • Mintzer J.
      • Schultz S.K.
      • et al.
      Relapse risk after discontinuation of risperidone in Alzheimer’s disease.
      RisperidoneSymptomatic treatment of BPSD110 patients with Alzheimer's disease and BPSD. Only patients without AEs and with sufficient effect of risperidone during a 16-wk run-in period were includedDesign D. Blinded with a 16-wk run-in period and with 1:1:1 staggered discontinuation; 2 arms with discontinuation16 wk (staggered)Discontinuation:

      27/40 = 68%

      Continuation:

      30/70 = 43%
      Discontinuation:

      23/40 = 58%

      Continuation:

      22/70 = 31%
      During run-in, 9% (17/180) discontinued treatment because of AEs, 2% (3/180) died, and 20% (36/180) were not eligible for discontinuation because of lack of effect. Severe hallucinations were a predictor for relapse (HR = 2.70, 95% CI: 1.19-6.12)
      • Patel A.N.
      • Lee S.
      • Andrews H.F.
      • et al.
      Prediction of relapse after discontinuation of antipsychotic treatment in Alzheimer’s disease: the role of hallucinations.
       Bergh et al (2012)
      • Bergh S.
      • Selbaek G.
      • Engedal K.
      Discontinuation of antidepressants in people with dementia and neuropsychiatric symptoms (DESEP study): double blind, randomised, parallel group, placebo controlled trial.
      Escitalopram, citalopram, sertraline, paroxetineSymptomatic treatment of BPSD128 SSRI-treated nursing home residents without depressive disorders with Alzheimer's disease, vascular dementia, or mixed dementiaDesign A. Blinded without a run-in period and 1:1 discontinuation25 wkDiscontinuation:

      28/63 = 44%

      Continuation:

      19/65 = 29%
      Discontinuation:

      13/63 = 21%

      Continuation:

      4/65 = 6%
      Depressive symptoms increased more in the discontinuation group than the continuation group; Cornell scale 6.03 vs 4.42, mean difference adjusted for baseline values = 2.89, 95% CI: 1.02-4.76
       Hardy et al (1997)
      • Hardy B.G.
      • Shulman K.I.
      • Zucchero C.
      Gradual discontinuation of lithium augmentation in elderly patients with unipolar depression.
      LithiumSymptomatic and preventive treatment of depression12 patients treated with lithium as adjunct to other antidepressive medicine(s) for refractory major unipolar depression with at least 1 y of remissionDesign C. Blinded without run-in and 1:1 discontinuation2 yDiscontinuation:

      3/6 = 50%

      Continuation:

      4/6 = 67%
      Discontinuation:

      3/6 = 33%

      Continuation:

      4/6 = 33%
      The discontinuation group experienced less AEs, especially urinary urgency at night, urination of more than usual volumes, urinary incontinence, and neurotoxicity (ie, hand tremor, lightheadedness, dizziness, and unsteady gait); lower mean composite side-effect symptom score (no estimates reported), P < .05
       Klysner et al (2002)
      • Klysner R.
      • Bent-Hansen J.
      • Hansen H.L.
      • et al.
      Efficacy of citalopram in the prevention of recurrent depression in elderly patients: placebo-controlled study of maintenance therapy.
      CitalopramSymptomatic and preventive treatment of depression121 patients with unipolar major depressive episode of at least moderate severity without antidepressive treatment. Only patients without AEs and with sufficient effect of citalopram during a 24-wk run-in period were includedDesign D. Blinded with a 24-wk run-in phase and 1:1 discontinuation48 wkDiscontinuation:

      49/61 = 80%

      Continuation:

      34/60 = 57%
      Discontinuation:

      38/61 = 62%

      Continuation:

      18/60 = 30%
      During run-in, 17% (39/230) discontinued treatment because of AEs and 6% (14/230) were not eligible for discontinuation because of lack of efficacy. The time to recurrence differed significantly between the treatment groups in favor of continuation; HR = 0.32, 95% CI: 0.19-0.56, log-rank test P < .001
       Wilson et al (2003)
      • Wilson K.C.
      • Mottram P.G.
      • Ashworth L.
      • Abou-Saleh M.T.
      Older community residents with depression: long-term treatment with sertraline. Randomised, double-blind, placebo-controlled study.
      SertralineSymptomatic and preventive treatment of depression113 patients with major depressive episode of at least moderate severity without antidepressive treatment. Only patients without AEs and with sufficient effect of sertraline during a 24- to 28-wk run-in period were includedDesign D. Blinded with a 24- to 28-wk run-in period and 1:1 discontinuation100 wkDiscontinuation:

      43/57 = 75%

      Continuation:

      39/56 = 70%
      Discontinuation:

      30/57 = 53%

      Continuation:

      25/56 = 45%
      During run-in, 26% (66/254) discontinued treatment because of AEs and 11% (29/254) were not eligible for discontinuation because of lack of efficacy.
       Ulfvarson et al (2003)
      • Ulfvarson J.
      • Adami J.
      • Wredling R.
      • Kjellman B.
      • Reilly M.
      • von Bahr C.
      Controlled withdrawal of selective serotonin reuptake inhibitor drugs in elderly patients in nursing homes with no indication of depression.
      Citalopram, sertralineSymptomatic and preventive treatment of depression70 SSRI-treated nursing home residents without a history of depression, anxiety, or dementiaDesign A. Blinded without a run-in period and 1:1 discontinuation6 moDiscontinuation:

      10/35 = 29%

      Continuation:

      8/35 = 23%
      Discontinuation:

      7/35 = 20%

      Continuation:

      0/35 = 0%
      There were no statistically significant differences in depression rating scale, global assessment of functioning, health-related quality of life, symptoms of depression or side effects of SSRIs between the discontinuation and continuation group.
       Habraken et al (1997)
      • Habraken H.
      • Soenen K.
      • Blondeel L.
      • et al.
      Gradual withdrawal from benzodiazepines in residents of homes for the elderly: experience and suggestions for future research.
      LorazepamSymptomatic treatment of insomnia55 nursing home residents without dementia or other serious medical diseases and with at least 1 y of stable benzodiazepine treatmentDesign A. Blinded with a run-in period and 1:1 discontinuation1 yDiscontinuation:

      10/27 = 37%

      Continuation:

      9/28 = 32%
      Discontinuation:

      5/27 = 19%

      Continuation:

      2/28 = 7%
      All benzodiazepines were switched to lorazepam before randomization. The discontinuation group was tapered over 5 wk. There was no statistically significant difference in the level of daily functioning between the discontinuation and continuation group.
       Curran et al (2003)
      • Curran H.V.
      • Collins R.
      • Fletcher S.
      • Kee S.C.Y.
      • Woods B.
      • Iliffe S.
      Older adults and withdrawal from benzodiazepine hypnotics in general practice: effects on cognitive function, sleep, mood and quality of life.
      Temazepam, nitrazepam, loprazolamSymptomatic treatment of insomnia104 patients without dementia or other diseases associated with cognitive impairment and with at least 6 mo use of benzodiazepinesDesign A (at 12 weeks). Blinded without a run-in period and 1:1 discontinuation12 wkDiscontinuation:

      7/55 = 13%

      Continuation:

      6/49 = 12%
      Not reportedThe discontinuation group was tapered over 4-6 wk. There were no statistically significant differences in sleep quality and several cognitive tests between the discontinuation group and the continuation group
       O'Brien et al (2001)
      • O’Brien A.
      • Russo-Magno P.
      • Karki A.
      • et al.
      Effects of withdrawal of inhaled steroids in men with severe irreversible airflow obstruction.
      Beclomethasone dipropionateSymptomatic and preventive treatment of chronic obstructive pulmonary disease (COPD)24 outpatients with severe irreversible airway obstruction (mean forced expiratory volume in 1 second [FEV1] 47% of predicted)Design E. Blinded crossover trial6 weeks per phaseCrossover trial with randomized order of discontinuation and continuation. Dropout per phase not reported. Dropout during the entire study: 9/24 = 38%Discontinuation phase:

      3/18 = 17%

      Continuation phase:

      0/16 = 0%
      There were no statistically significant differences in lung function or walking distance between the discontinuation phase and the continuation phase.
       Choudhury et al (2007)
      • Choudhury A.B.
      • Dawson C.M.
      • Kilvington H.E.
      • et al.
      Withdrawal of inhaled corticosteroids in people with COPD in primary care: a randomised controlled trial.
      Fluticasone propionateSymptomatic and preventive treatment of chronic obstructive pulmonary disease (COPD)260 patients with COPD with irreversible airway obstruction and no other chronic active lung diseases treated with inhaled corticosteroidsDesign A. Blinded with a run-in period and 1:1 discontinuation1 yDiscontinuation:

      78/132 = 59%

      Continuation:

      56/128 = 44%
      Discontinuation:

      61/132 = 46%

      Continuation:

      34/128 = 27%
      In the per-protocol analysis, there was an increased risk of exacerbations in the discontinuation group compared with the continuation group; 279 exacerbations during a mean study duration of 179 d vs 293 exacerbations during a mean study duration of 235 d, RR = 1.48, 95% CI: 1.17-1.86. Time to first exacerbation was shorter in the discontinuation group (median 44 d) compared with the continuation group (median 63 d); log-rank test, P = .05, adjusted Cox regression analysis OR = 1.43, 95% CI: 1.08-1.96. The discontinuation group had an increase in wheeze (OR = 1.83, 95% CI: 1.06-3.18), an increase in shortness of breath (OR = 2.11, 95% CI: 1.25-3.57) and cough (during the first 3 mo; OR = 1.95, 95% CI: 1.16-3.29). There were no statistically significant differences in sputum production, lung function, or quality of life between the 2 groups.
       Borrill et al (2009)
      • Borrill Z.
      • Roy K.
      • Kolsum U.
      • Southworth T.
      • Vestbo J.
      • Singh D.
      Seretide withdrawal increases airway inflammation in moderate COPD patients.
      Fluticasone propionate and salmeterol, fixed dose combinationSymptomatic and preventive treatment of chronic obstructive pulmonary disease (COPD)14 patients with stable, moderate COPD (GOLD stage-II)Design A. Nonblinded without a run-in period and 3:2 discontinuation6 wkDiscontinuation:

      4/9 = 44%

      Continuation:

      0/5 = 0%
      Discontinuation:

      4/9 = 44%

      Continuation:

      0/5 = 0%
      There was a decrease in lung function in the discontinuation group compared with the continuation group; difference in change in FEV1 = 0.35, P = .017. The percentage of sputum neutrophil increased more in the continuation group compared with the continuation group; difference in change from baseline = 16.5%, P = .03.
       Rice et al (2000)
      • Rice K.L.
      • Rubins J.B.
      • Lebahn F.
      • et al.
      Withdrawal of chronic systemic corticosteroids in patients with COPD: a randomized trial.
      PrednisoneSymptomatic and preventive treatment of chronic obstructive pulmonary disease (COPD)38 patients with steroid-dependent COPDDesign C. Blinded with a run-in period with addition of ICS and with 1:1 discontinuation6 moDiscontinuation:

      10/18 = 56%

      Continuation:

      8/20 = 40%
      Discontinuation:

      14/18 = 78%

      Continuation:

      14/20 = 70%
      There were no statistically significant differences regarding exacerbations, lung function, or quality of life between the 2 groups. There was a difference in change in weight from baseline between the discontinuation group (−4.8 kg) and the continuation group (0.5 kg); P = .007.
       Fabricius et al (1990)
      • Fabricius P.G.
      • Weizert P.
      • Dunzendorfer U.
      • Hannaford J.M.
      • Maurath C.
      Efficacy of once-a-day terazosin in benign prostatic hyperplasia: a randomized, double-blind placebo-controlled clinical trial.
      TerazosinSymptomatic treatment of lower urinary tract symptoms (LUTS)30 men with moderate obstructive symptoms due to benign prostatic hyperplasia (BPH). Only patients with sufficient effect of terazosin during a 24-wk run-in period were included.Design D. Blinded with a 24-week run-in period and 1:1 discontinuation12 wkDiscontinuation:

      0/15 = 0%

      Continuation:

      0/15 = 0%
      Not reportedDuring run-in, 47% (27/57) were not eligible for discontinuation because of lack of efficacy and 30% (17/57) experienced adverse events.
       Barkin et al (2003)
      • Barkin J.
      • Guimarães M.
      • Jacobi G.
      • Pushkar D.
      • Taylor S.
      • van Vierssen Trip O.B.
      Alpha-blocker therapy can be withdrawn in the majority of men following initial combination therapy with the dual 5alpha-reductase inhibitor dutasteride.
      TamsulosinSymptomatic treatment of LUTS305 men with moderate to severe urinary symptoms due to BPHDesign C. Blinded with a run-in period with dutasteride and tamsulosin and with 1:1 discontinuation6 wkDiscontinuation:

      2/151 = 1%

      Continuation:

      1/154 = 1%
      Discontinuation:

      35/151 = 23%

      Continuation:

      14/154 = 9%
      There was a difference in urinary symptoms with more patients feeling the same or better in the continuation group (91%) compared with the discontinuation group (77%); difference = 14%, 95% CI: 4%-18%; P = .001.
       Lee et al (2012)
      • Lee J.Y.
      • Kang D.H.
      • Park S.Y.
      • et al.
      Effect of discontinuation of tamsulosin in Korean men with benign prostatic hyperplasia taking tamsulosin and dutasteride: an open-label, prospective, randomized pilot study.
      TamsulosinSymptomatic treatment of LUTS86 treatment-naïve men with moderate urinary symptoms due to BPHDesign C. Nonblinded with a run-in period with dutasteride and tamsulosin and with 1:1 discontinuation24 wkDiscontinuation:

      10/43 = 23%

      Continuation:

      7/43 = 16%
      Discontinuation:

      6/43 = 14%

      Continuation:

      4/43 = 9%
      There was no statistically significant differences between groups in voiding symptoms and related measures, quality of life, adverse effects, or blood pressure.
       Matsukawa et al (2017)
      • Matsukawa Y.
      • Takai S.
      • Funahashi Y.
      • et al.
      Effects of withdrawing α1-blocker from combination therapy with α1-blocker and 5α-reductase inhibitor in patients with lower urinary tract symptoms suggestive of benign prostatic hyperplasia: a prospective and comparative trial using urodynamics.
      SilodosinSymptomatic treatment of LUTS132 treatment-naïve men with moderate to severe urinary symptoms due to BPHDesign C. Nonblinded with a run-in period with dutasteride and silodosin and with 1:1 discontinuation12 moDiscontinuation:

      6/66 = 9%

      Continuation:

      9/66 = 14%
      Discontinuation:

      23/66 = 35%

      Continuation:

      15/66 = 23%
      There was no statistically significant differences between groups in subjective symptoms or bladder outlet obstruction.
      Supplementary Table 2Risk of Bias Assessment of the Included Studies.
      Author (year)Medicine(s) DiscontinuedRisk of Bias Assessment
      Randomization ProcessDifferential Dropout Rate: Blinding, Tapering, etc
      George et al (2003)
      • George J.
      • Kitzis I.
      • Zandorf D.
      • et al.
      Safety of nitrate withdrawal in angina-free and hemodynamically stable patients with coronary artery disease.
      NitratesSome concernHigh risk
      van Kraaij et al (1999 and 2000)
      • Barnett K.
      • Mercer S.W.
      • Norbury M.
      • Watt G.
      • Wyke S.
      • Guthrie B.
      Epidemiology of multimorbidity and implications for health care, research, and medical education: a cross-sectional study.
      ,
      • Morin L.
      • Johnell K.
      • Laroche M.L.
      • Fastbom J.
      • Wastesson J.W.
      The epidemiology of polypharmacy in older adults: register-based prospective cohort study.
      FurosemideSome concernLow risk
      Kutner et al (2015)
      • Kutner J.S.
      • Blatchford P.J.
      • Taylor D.H.
      • et al.
      Safety and benefit of discontinuing statin therapy in the setting of advanced, life-limiting illness: a randomized clinical trial.
      StatinsLow riskSome concern
      Sheppard et al (2021)
      • Sheppard J.P.
      • Lown M.
      • Burt J.
      • et al.
      Blood pressure changes following antihypertensive medication reduction, by drug class and dose chosen for withdrawal: exploratory analysis of data from the OPTiMISE trial.
      AntihypertensivesLow riskSome concern
      Nijst et al (2020)
      • Nijst P.
      • Martens P.
      • Dauw J.
      • et al.
      Withdrawal of neurohumoral blockade after cardiac resynchronization therapy.
      Beta-blockersLow riskHigh risk
      Greenspan et al (2002)
      • Greenspan S.L.
      • Emkey R.D.
      • Bone H.G.
      • et al.
      Significant differential effects of alendronate, estrogen, or combination therapy on the rate of bone loss after discontinuation of treatment of postmenopausal osteoporosis. A randomized, double-blind, placebo-controlled trial.
      AlendronateLow riskLow risk
      Michalská et al (2006)
      • Michalská D.
      • Stepan J.J.
      • Basson B.R.
      • Pavo I.
      The effect of raloxifene after discontinuation of long-term alendronate treatment of postmenopausal osteoporosis.
      AlendronateSome concernSome concern
      Black et al (2006)
      • Black D.M.
      • Schwartz A.V.
      • Ensrud K.E.
      • et al.
      Effects of continuing or stopping alendronate after 5 years of treatment: the Fracture Intervention Trial Long-term Extension (FLEX): a randomized trial.
      AlendronateLow riskLow risk
      Wright et al (2017)
      • Wright N.C.
      • Foster P.J.
      • Mudano A.S.
      • et al.
      Assessing the feasibility of the effectiveness of discontinuing bisphosphonates trial: a pilot study.
      AlendronateLow riskSome concern
      Black et al (2012)
      • Black D.M.
      • Reid I.R.
      • Boonen S.
      • et al.
      The effect of 3 versus 6 years of zoledronic acid treatment of osteoporosis: a randomized extension to the HORIZON-Pivotal Fracture Trial (PFT).
      Zoledronic acidLow riskLow risk
      Cibere et al (2004)
      • Cibere J.
      • Kopec J.A.
      • Thorne A.
      • et al.
      Randomized, double-blind, placebo-controlled glucosamine discontinuation trial in knee osteoarthritis.
      GlucosamineLow riskLow risk
      Arai et al (2015), study 1
      • Arai T.
      • Kashimoto Y.
      • Ukyo Y.
      • Tominaga Y.
      • Imanaka K.
      Two placebo-controlled, randomized withdrawal studies to evaluate the fentanyl 1 day patch in opioid-naïve patients with chronic pain.
      Fentanyl patchSome concernSome concern
      Arai et al (2015), study 2
      • Arai T.
      • Kashimoto Y.
      • Ukyo Y.
      • Tominaga Y.
      • Imanaka K.
      Two placebo-controlled, randomized withdrawal studies to evaluate the fentanyl 1 day patch in opioid-naïve patients with chronic pain.
      Fentanyl patchSome concernSome concern
      Holmes et al (2004)
      • Holmes C.
      • Wilkinson D.
      • Dean C.
      • et al.
      The efficacy of donepezil in the treatment of neuropsychiatric symptoms in Alzheimer disease.
      DonepezilLow riskLow risk
      Johannsen et al (2006)
      • Johannsen P.
      • Salmon E.
      • Hampel H.
      • et al.
      Assessing therapeutic efficacy in a progressive disease: a study of donepezil in Alzheimer’s disease.
      DonepezilSome concernLow risk
      Howard et al (2012)
      • Howard R.
      • McShane R.
      • Lindesay J.
      • et al.
      Donepezil and memantine for moderate-to-severe Alzheimer’s disease.
      DonepezilLow riskLow risk
      Gaudig et al (2011)
      • Gaudig M.
      • Richarz U.
      • Han J.
      • Van Baelen B.
      • Schauble B.
      Effects of galantamine in Alzheimer’s disease: double-blind withdrawal studies evaluating sustained versus interrupted treatment.
      GalantamineSome concernLow risk
      Scarpini et al (2011)
      • Scarpini E.
      • Bruno G.
      • Zappalà G.
      • et al.
      Cessation versus continuation of galantamine treatment after 12 months of therapy in patients with Alzheimer’s disease: a randomized, double blind, placebo controlled withdrawal trial.
      GalantamineLow riskLow risk
      Herrmann et al (2016)
      • Herrmann N.
      • O’Regan J.
      • Ruthirakuhan M.
      • et al.
      A randomized placebo-controlled discontinuation study of cholinesterase inhibitors in institutionalized patients with moderate to severe Alzheimer disease.
      Cholinesterase inhibitorsLow riskLow risk
      Ory-Magne et al (2014)
      • Ory-Magne F.
      • Corvol J.C.
      • Azulay J.P.
      • et al.
      Withdrawing amantadine in dyskinetic patients with Parkinson disease: The AMANDYSK trial.
      AmantadineLow riskHigh risk
      Biaggioni et al (2015)
      • Biaggioni I.
      • Freeman R.
      • Mathias C.J.
      • Low P.
      • Hewitt L.A.
      • Kaufmann H.
      Randomized withdrawal study of patients with symptomatic neurogenic orthostatic hypotension responsive to droxidopa.
      DroxidopaSome concernHigh risk
      Tse et al (2008)
      • Tse W.
      • Frisina P.
      • Halbig T.
      • et al.
      The effects of withdrawal of dopaminergic medication in nursing home patients with advanced parkinsonism.
      LevodopaSome concernLow risk
      Findlay et al (1989)
      • Findlay D.J.
      • Sharma J.
      • McEwen J.
      • Ballinger B.R.
      • MacLennan W.J.
      • McHarg A.M.
      Double-blind controlled withdrawal of thioridazine treatment in elderly female inpatients with senile dementia.
      ThioridazineSome concernLow risk
      Devanand et al (2011)
      • Devanand D.P.
      • Pelton G.H.
      • Cunqueiro K.
      • Sackeim H.A.
      • Marder K.A.
      6-month, randomized, double-blind, placebo-controlled pilot discontinuation trial following response to haloperidol treatment of psychosis and agitation in Alzheimer’s disease.
      HaloperidolSome concernLow risk
      Devanand et al (2012)
      • Devanand D.P.
      • Mintzer J.
      • Schultz S.K.
      • et al.
      Relapse risk after discontinuation of risperidone in Alzheimer’s disease.
      RisperidoneLow riskLow risk
      Bergh et al (2012)
      • Bergh S.
      • Selbaek G.
      • Engedal K.
      Discontinuation of antidepressants in people with dementia and neuropsychiatric symptoms (DESEP study): double blind, randomised, parallel group, placebo controlled trial.
      SSRIsLow riskSome concern
      Hardy et al (1997)
      • Hardy B.G.
      • Shulman K.I.
      • Zucchero C.
      Gradual discontinuation of lithium augmentation in elderly patients with unipolar depression.
      LithiumSome concernLow risk
      Klysner et al (2002)
      • Klysner R.
      • Bent-Hansen J.
      • Hansen H.L.
      • et al.
      Efficacy of citalopram in the prevention of recurrent depression in elderly patients: placebo-controlled study of maintenance therapy.
      CitalopramSome concernHigh risk
      Wilson et al (2003)
      • Wilson K.C.
      • Mottram P.G.
      • Ashworth L.
      • Abou-Saleh M.T.
      Older community residents with depression: long-term treatment with sertraline. Randomised, double-blind, placebo-controlled study.
      SertralineLow riskHigh risk
      Ulfvarson et al (2003)
      • Ulfvarson J.
      • Adami J.
      • Wredling R.
      • Kjellman B.
      • Reilly M.
      • von Bahr C.
      Controlled withdrawal of selective serotonin reuptake inhibitor drugs in elderly patients in nursing homes with no indication of depression.
      Citalopram, sertralineSome concernHigh risk
      Habraken et al (1997)
      • Habraken H.
      • Soenen K.
      • Blondeel L.
      • et al.
      Gradual withdrawal from benzodiazepines in residents of homes for the elderly: experience and suggestions for future research.
      LorazepamSome concernSome concern
      Curran et al (2003)
      • Curran H.V.
      • Collins R.
      • Fletcher S.
      • Kee S.C.Y.
      • Woods B.
      • Iliffe S.
      Older adults and withdrawal from benzodiazepine hypnotics in general practice: effects on cognitive function, sleep, mood and quality of life.
      BenzodiazepinesSome concernSome concern
      O'Brien et al (2001)
      • O’Brien A.
      • Russo-Magno P.
      • Karki A.
      • et al.
      Effects of withdrawal of inhaled steroids in men with severe irreversible airflow obstruction.
      Inhaled beclomethasoneHigh riskLow risk
      Choudhury et al (2007)
      • Choudhury A.B.
      • Dawson C.M.
      • Kilvington H.E.
      • et al.
      Withdrawal of inhaled corticosteroids in people with COPD in primary care: a randomised controlled trial.
      Inhaled fluticasoneLow riskLow risk
      Borrill et al (2009)
      • Borrill Z.
      • Roy K.
      • Kolsum U.
      • Southworth T.
      • Vestbo J.
      • Singh D.
      Seretide withdrawal increases airway inflammation in moderate COPD patients.
      Inhaled fluticasone + salmeterolSome concernHigh risk
      Rice et al (2000)
      • Rice K.L.
      • Rubins J.B.
      • Lebahn F.
      • et al.
      Withdrawal of chronic systemic corticosteroids in patients with COPD: a randomized trial.
      PrednisoneSome concernLow risk
      Fabricius et al (1990)
      • Fabricius P.G.
      • Weizert P.
      • Dunzendorfer U.
      • Hannaford J.M.
      • Maurath C.
      Efficacy of once-a-day terazosin in benign prostatic hyperplasia: a randomized, double-blind placebo-controlled clinical trial.
      TerazosinSome concernLow risk
      Barkin et al (2003)
      • Barkin J.
      • Guimarães M.
      • Jacobi G.
      • Pushkar D.
      • Taylor S.
      • van Vierssen Trip O.B.
      Alpha-blocker therapy can be withdrawn in the majority of men following initial combination therapy with the dual 5alpha-reductase inhibitor dutasteride.
      TamsulosinSome concernLow risk
      Lee et al (2012)
      • Lee J.Y.
      • Kang D.H.
      • Park S.Y.
      • et al.
      Effect of discontinuation of tamsulosin in Korean men with benign prostatic hyperplasia taking tamsulosin and dutasteride: an open-label, prospective, randomized pilot study.
      TamsulosinHigh riskHigh risk
      Matsukawa et al (2017)
      • Matsukawa Y.
      • Takai S.
      • Funahashi Y.
      • et al.
      Effects of withdrawing α1-blocker from combination therapy with α1-blocker and 5α-reductase inhibitor in patients with lower urinary tract symptoms suggestive of benign prostatic hyperplasia: a prospective and comparative trial using urodynamics.
      SilodosinLow riskHigh risk
      Supplementary Table 3Harms Reported in the Included Studies
      Author (Year)Medicine(s) DiscontinuedHarms
      Discontinuation GroupContinuation Group
      George et al (2003)
      • George J.
      • Kitzis I.
      • Zandorf D.
      • et al.
      Safety of nitrate withdrawal in angina-free and hemodynamically stable patients with coronary artery disease.
      Nitrates8 with recurrent angina with prompt effect of reinstated therapy (1 of the patients hospitalized, catheterized, and underwent coronary angioplasty)1 patient with angina
      van Kraaij et al (1999 and 2000)
      • Barnett K.
      • Mercer S.W.
      • Norbury M.
      • Watt G.
      • Wyke S.
      • Guthrie B.
      Epidemiology of multimorbidity and implications for health care, research, and medical education: a cross-sectional study.
      ,
      • Morin L.
      • Johnell K.
      • Laroche M.L.
      • Fastbom J.
      • Wastesson J.W.
      The epidemiology of polypharmacy in older adults: register-based prospective cohort study.
      Furosemide2 recurrence of congestive heart failure, 2 requested restart because ankle edema without heart failure, 1 hypertension1 recurrence of congestive heart failure
      Kutner et al (2015)
      • Kutner J.S.
      • Blatchford P.J.
      • Taylor D.H.
      • et al.
      Safety and benefit of discontinuing statin therapy in the setting of advanced, life-limiting illness: a randomized clinical trial.
      StatinsNot specified per group. There were 33 AEs experienced by 19 of the patients (5.0%). No serious AEs were determined to be study related
      Sheppard et al (2021)
      • Sheppard J.P.
      • Lown M.
      • Burt J.
      • et al.
      Blood pressure changes following antihypertensive medication reduction, by drug class and dose chosen for withdrawal: exploratory analysis of data from the OPTiMISE trial.
      AntihypertensivesAEs not reported per group in this post hoc analysis
      Nijst et al (2020)
      • Nijst P.
      • Martens P.
      • Dauw J.
      • et al.
      Withdrawal of neurohumoral blockade after cardiac resynchronization therapy.
      Beta-blockers1 death noncardiovascular cause, 1 disease recurrence, 6 supraventricular tachycardia, 1 nonsustained ventricular tachycardia2 disease recurrence, 1 death noncardiovascular cause
      Greenspan et al (2002)
      • Greenspan S.L.
      • Emkey R.D.
      • Bone H.G.
      • et al.
      Significant differential effects of alendronate, estrogen, or combination therapy on the rate of bone loss after discontinuation of treatment of postmenopausal osteoporosis. A randomized, double-blind, placebo-controlled trial.
      AlendronateAEs not described for the individual groups. Overall, no difference in AEs between the discontinuation and continuation group, including no difference in gastrointestinal AEs
      Michalská et al (2006)
      • Michalská D.
      • Stepan J.J.
      • Basson B.R.
      • Pavo I.
      The effect of raloxifene after discontinuation of long-term alendronate treatment of postmenopausal osteoporosis.
      Alendronate1 leg cramp, 1 upper gastrointestinal symptoms2 upper gastrointestinal symptoms, 2 bone pain, 1 allergic skin reactions, 1 gastric pain
      Black et al (2006)
      • Black D.M.
      • Schwartz A.V.
      • Ensrud K.E.
      • et al.
      Effects of continuing or stopping alendronate after 5 years of treatment: the Fracture Intervention Trial Long-term Extension (FLEX): a randomized trial.
      AlendronateAEs not systematically described
      Wright et al (2017)
      • Wright N.C.
      • Foster P.J.
      • Mudano A.S.
      • et al.
      Assessing the feasibility of the effectiveness of discontinuing bisphosphonates trial: a pilot study.
      AlendronateNo AEs were reported
      Black et al (2012)
      • Black D.M.
      • Reid I.R.
      • Boonen S.
      • et al.
      The effect of 3 versus 6 years of zoledronic acid treatment of osteoporosis: a randomized extension to the HORIZON-Pivotal Fracture Trial (PFT).
      Zoledronic acidTotal patients with any AE = 552; total patients with any SAE = 168; total patients discontinuing because of AE = 11; renal events = 26; any of the most common postdose symptoms (pyrexia, myalgia, influenza-like illness, headache og arthralgia): First year = 29, second year = 14, third year = 7; cardiovascular AEs: 52 arrhythmia, 13 atrial fibrillation, 9 stroke, 4 myocardial infarction, 93 hypertension, 3 death from cardiovascular causesTotal patients with any AE = 552; total patients with any SAE = 191; total patients discontinuing because of AE = 14; renal events = 48; any of the most common postdose symptoms (pyrexia, myalgia, influenza-like illness, headache og arthralgia): First year = 36, second year = 24, third year = 14; cardiovascular AEs: 60 arrythmia, 21 atrial fibrillation, 19 stroke, 6 myocardial infarction, 48 hypertension, 8 death from cardiovascular causes
      Cibere et al (2004)
      • Cibere J.
      • Kopec J.A.
      • Thorne A.
      • et al.
      Randomized, double-blind, placebo-controlled glucosamine discontinuation trial in knee osteoarthritis.
      GlucosamineNo SAEs were reported during the study, and there were no differences in AEs between the glucosamine and placebo groups
      Arai et al (2015), study 1
      • Arai T.
      • Kashimoto Y.
      • Ukyo Y.
      • Tominaga Y.
      • Imanaka K.
      Two placebo-controlled, randomized withdrawal studies to evaluate the fentanyl 1 day patch in opioid-naïve patients with chronic pain.
      Fentanyl patch6 nervous system, 11 infections and infestations, 5 metabolism and nutrition disorders, 5 psychiatric disorders, 15 gastrointestinal disorders, 13 general disorders and administration, 1 opioid withdrawal syndrome5 nervous system, 12 infections and infestations, 3 metabolism and nutrition disorders, 7 psychiatric disorders, 21 gastrointestinal disorders, 13 general disorders and administration, 4 opioid withdrawal syndrome
      Arai et al (2015), study 2
      • Arai T.
      • Kashimoto Y.
      • Ukyo Y.
      • Tominaga Y.
      • Imanaka K.
      Two placebo-controlled, randomized withdrawal studies to evaluate the fentanyl 1 day patch in opioid-naïve patients with chronic pain.
      Fentanyl patch12 nervous system, 9 infections and infestations, 5 metabolism and nutrition disorders, 27 gastrointestinal disorders, 16 general disorders and administration, 8 skin and subcutaneous tissue disorders24 nervous system, 8 infections and infestations, 8 metabolism and nutrition disorders, 36 gastrointestinal disorders, 21 general disorders and administration, 13 skin and subcutaneous tissue disorders
      Holmes et al (2004)
      • Holmes C.
      • Wilkinson D.
      • Dean C.
      • et al.
      The efficacy of donepezil in the treatment of neuropsychiatric symptoms in Alzheimer disease.
      DonepezilNone reportedAEs: 1 rhinitis and 2 diarrhea
      Johannsen et al (2006)
      • Johannsen P.
      • Salmon E.
      • Hampel H.
      • et al.
      Assessing therapeutic efficacy in a progressive disease: a study of donepezil in Alzheimer’s disease.
      DonepezilAny AE (n = 33); 10 treatment-related AEs, 6 digestive system, 8 nervous system, 10 body as a whole, 4 musculoskeletal system, 7 respiratory system, 4 cardiovascular system, 2 urogenital systemAny AE (n = 27); 8 treatment-related AEs, 7 digestive system, 14 nervous system, 4 body as a whole, 4 musculoskeletal system, 2 respiratory system, 4 cardiovascular system, 3 urogenital system
      Howard et al (2012)
      • Howard R.
      • McShane R.
      • Lindesay J.
      • et al.
      Donepezil and memantine for moderate-to-severe Alzheimer’s disease.
      DonepezilOnly SAEs reported. Discontinuation group: total of 46 SAEs; 12 fall, 6 respiratory tract infection, 2 urinary tract infection, 7 deterioration of AD, 4 behavioral symptoms of AD, 2 gastrointestinal, 3 stroke, 1 cardiac, 1 dysphagia, 2 psychosis, 2 unknown (died), 1 venous embolus, 3 otherOnly SAEs reported. Continuation group: Total of 46 SAEs; 9 fall, 6 respiratory tract infection, 5 urinary tract infection, 2 deterioration of AD, 5 behavioral symptoms of AD, 4 gastrointestinal, 5 stroke, 1 cardiac, 2 dysphagia, 1 unknown (died), 2 cancer, 2 syncope, 2 other
      Gaudig et al (2011)
      • Gaudig M.
      • Richarz U.
      • Han J.
      • Van Baelen B.
      • Schauble B.
      Effects of galantamine in Alzheimer’s disease: double-blind withdrawal studies evaluating sustained versus interrupted treatment.
      GalantamineTotal patients with any AE = 16; total patients with any SAE = 1; total patients discontinuing because of AE = 0; AEs occurring in at least 2.5% of patients: 3 headache, 1 confusion, 0 dizziness, 0 agitation, 1 tremor, 0 vomitingTotal patients with any AE = 17; total patients with any SAE = 1; total patients discontinuing because of AE = 0; AEs occurring in at least 2.5% of patients: 0 headache, 2 confusion, 2 dizziness, 1 agitation, 1 tremor, 2 vomiting
      Scarpini et al (2011)
      • Scarpini E.
      • Bruno G.
      • Zappalà G.
      • et al.
      Cessation versus continuation of galantamine treatment after 12 months of therapy in patients with Alzheimer’s disease: a randomized, double blind, placebo controlled withdrawal trial.
      GalantamineAssumed related: 1 cardiac disorder, 1 investigation, 3 psychiatric disorder; assumed not related: 1 gastrointestinal disorder, 2 general disorders and administration site conditions, 2 infections and infestations, 3 investigations, 1 metabolism and nutrition disorder, 1 musculoskeletal and connective tissue disorder, 1 neoplasm benign, malignant, and unspecified, 7 nervous system disorder, 5 psychiatric disorder, 1 renal and urinary disorderAssumed related: 1 investigation; assumed not-related: 2 cardiac disorder, 1 gastrointestinal disorder, 3 general disorders and administration site conditions, 3 infections and infestations, 1 injury, poisoning and procedural complications, 3 investigations, 1 metabolism and nutrition disorder, 1 musculoskeletal and connective tissue disorder, 3 neoplasm benign, malignant, and unspecified, 5 nervous system disorder, 4 psychiatric disorder, 2 respiratory, thoracic and mediastinal disorder, 3 vascular disorder
      Herrmann et al (2016)
      • Herrmann N.
      • O’Regan J.
      • Ruthirakuhan M.
      • et al.
      A randomized placebo-controlled discontinuation study of cholinesterase inhibitors in institutionalized patients with moderate to severe Alzheimer disease.
      Cholinesterase inhibitors5 unintentional weight loss, 3 falls, 1 oval thrush, 1 IV due to poor appetite, 1 respiratory tract infection, 1 cognitive decline, 3 deterioration in behavior, 1 bowel obstruction3 unintentional weight loss, 3 falls, 1 loss of consciousness, 2 vomiting, 1 perineum wound, 1 respiratory tract infection, 1 conjunctivitis, 1 dizziness, 1 rash, 1 acute cough, 2 deterioration in behavior, 1 bradycardia, 1 seizure, 1 atrial fibrillation
      Ory-Magne et al (2014)
      • Ory-Magne F.
      • Corvol J.C.
      • Azulay J.P.
      • et al.
      Withdrawing amantadine in dyskinetic patients with Parkinson disease: The AMANDYSK trial.
      Amantadine19 worsening of dyskinesia, 8 worsening of parkinsonism, 4 pain, 2 fatigue, 1 sweat/flushing, 2 asthenia, 2 nausea/vomiting, 2 drowsiness, 1 cephalgia, 2 cough7 worsening of dyskinesia, 7 worsening of parkinsonism, 3 pain, 3 fatigue, 2 sweat/flushing, 2 asthenia, 2 nausea/vomiting, 2 drowsiness, 2 cephalgia, 3 falls, 1 cough
      Biaggioni et al (2015)
      • Biaggioni I.
      • Freeman R.
      • Mathias C.J.
      • Low P.
      • Hewitt L.A.
      • Kaufmann H.
      Randomized withdrawal study of patients with symptomatic neurogenic orthostatic hypotension responsive to droxidopa.
      DroxidopaTotal 19 (37%) patients experienced ≥ 1 AEs; these included 4 headache, 1 dizziness, 1 fatigue, 6 falls, 2 nausea, 1 diarrhea, 2 urinary tract infectionTotal 15 (30%) patients experienced ≥ 1 AEs; these included 2 headache, 2 dizziness, 1 fall, 1 diarrhea, 1 urinary tract infection
      Tse et al (2008)
      • Tse W.
      • Frisina P.
      • Halbig T.
      • et al.
      The effects of withdrawal of dopaminergic medication in nursing home patients with advanced parkinsonism.
      Levodopa1 fever and worsening of mental status and parkinsonian symptomsNone described
      Findlay et al (1989)
      • Findlay D.J.
      • Sharma J.
      • McEwen J.
      • Ballinger B.R.
      • MacLennan W.J.
      • McHarg A.M.
      Double-blind controlled withdrawal of thioridazine treatment in elderly female inpatients with senile dementia.
      ThioridazineNone described
      Devanand et al (2011)
      • Devanand D.P.
      • Pelton G.H.
      • Cunqueiro K.
      • Sackeim H.A.
      • Marder K.A.
      6-month, randomized, double-blind, placebo-controlled pilot discontinuation trial following response to haloperidol treatment of psychosis and agitation in Alzheimer’s disease.
      HaloperidolAEs not systematically described
      Devanand et al (2012)
      • Devanand D.P.
      • Mintzer J.
      • Schultz S.K.
      • et al.
      Relapse risk after discontinuation of risperidone in Alzheimer’s disease.
      RisperidoneSAE: 1 died, 1 cardiovascular events, 1 neurologic event, 2 agitation-aggression, 1 pulmonary event, 2 other SAE.

      AE: 10 extrapyramidal signs, 10 akathisia or restlessness, 7 sedation, 2 insomnia, 8 confusion, 3 agitation-aggression, 1 falls, 3 nausea or vomiting
      SAE: 2 died, 2 cardiovascular events, 1 pulmonary event, 2 other SAEs.

      AE: 17 extrapyramidal signs, 5 akathisia or restlessness, 8 sedation, 3 insomnia, 5 confusion, 1 agitation-aggression, 2 falls, 4 nausea or vomiting
      Bergh et al (2012)
      • Bergh S.
      • Selbaek G.
      • Engedal K.
      Discontinuation of antidepressants in people with dementia and neuropsychiatric symptoms (DESEP study): double blind, randomised, parallel group, placebo controlled trial.
      SSRIsAEs not systematically described. 13 increased depressive or neuropsychiatric symptomsAEs not systematically described; 4 increased depressive or neuropsychiatric symptoms
      Hardy et al (1997)
      • Hardy B.G.
      • Shulman K.I.
      • Zucchero C.
      Gradual discontinuation of lithium augmentation in elderly patients with unipolar depression.
      LithiumAEs not systematically described; AEs were registered using a composite side-effect symptom score; at all clinic visits, the mean score was less in the discontinuation group compared with the continuation group (P < .05)
      Klysner et al (2002)
      • Klysner R.
      • Bent-Hansen J.
      • Hansen H.L.
      • et al.
      Efficacy of citalopram in the prevention of recurrent depression in elderly patients: placebo-controlled study of maintenance therapy.
      Citalopram2 nausea, 3 diarrhea, 4 headache, 3 increased sweating, 4 dizziness, 6 fatigue, 3 hot flushes, 1 vertigo, 2 dry mouth, 3 insomnia, 1 vomiting, 1 abdominal pain, 2 hypokalemia, 2 hypertension, 4 influenza-like symptoms, 4 traumatic injury, 1 pain, 2 back pain, 1 cystitis, 2 bronchitis3 diarrhea, 1 headache, 4 increased sweating, 3 tremor, 1 dizziness, 10 fatigue, 1 hot flushes, 3 abdominal pain, 2 hypokalemia, 1 hypertension, 9 influenza-like symptoms, 7 traumatic injury, 2 pain, 9 back pain, 3 dyspepsia, 3 cystitis, 3 bronchitis
      Wilson et al (2003)
      • Wilson K.C.
      • Mottram P.G.
      • Ashworth L.
      • Abou-Saleh M.T.
      Older community residents with depression: long-term treatment with sertraline. Randomised, double-blind, placebo-controlled study.
      Sertraline3 unspecified AEs2 unspecified AEs
      Ulfvarson et al (2003)
      • Ulfvarson J.
      • Adami J.
      • Wredling R.
      • Kjellman B.
      • Reilly M.
      • von Bahr C.
      Controlled withdrawal of selective serotonin reuptake inhibitor drugs in elderly patients in nursing homes with no indication of depression.
      Citalopram, sertralineAEs not systematically described
      Habraken et al (1997)
      • Habraken H.
      • Soenen K.
      • Blondeel L.
      • et al.
      Gradual withdrawal from benzodiazepines in residents of homes for the elderly: experience and suggestions for future research.
      LorazepamAEs not systematically described
      Curran et al (2003)
      • Curran H.V.
      • Collins R.
      • Fletcher S.
      • Kee S.C.Y.
      • Woods B.
      • Iliffe S.
      Older adults and withdrawal from benzodiazepine hypnotics in general practice: effects on cognitive function, sleep, mood and quality of life.
      BenzodiazepinesNo AEs were reported
      O'Brien et al (2001)
      • O’Brien A.
      • Russo-Magno P.
      • Karki A.
      • et al.
      Effects of withdrawal of inhaled steroids in men with severe irreversible airflow obstruction.
      Inhaled beclomethasone3 severe exacerbations during discontinuation
      Choudhury et al (2007)
      • Choudhury A.B.
      • Dawson C.M.
      • Kilvington H.E.
      • et al.
      Withdrawal of inhaled corticosteroids in people with COPD in primary care: a randomised controlled trial.
      Inhaled fluticasoneThere was no significant difference in reporting of skin bruising, thinning of skin, sore throat, oral thrush, or hoarseness of voice between fluticasone and placebo groups during the study; there were 3 COPD-related deaths in the continuation group
      Borrill et al (2009)
      • Borrill Z.
      • Roy K.
      • Kolsum U.
      • Southworth T.
      • Vestbo J.
      • Singh D.
      Seretide withdrawal increases airway inflammation in moderate COPD patients.
      Inhaled fluticasone + salmeterolNo AEs were reported
      Rice et al (2000)
      • Rice K.L.
      • Rubins J.B.
      • Lebahn F.
      • et al.
      Withdrawal of chronic systemic corticosteroids in patients with COPD: a randomized trial.
      PrednisoneWeight loss = –4.8 ± 2.0 kgWeight gain = 0.5 ± 3.5 kg
      Fabricius et al (1990)
      • Fabricius P.G.
      • Weizert P.
      • Dunzendorfer U.
      • Hannaford J.M.
      • Maurath C.
      Efficacy of once-a-day terazosin in benign prostatic hyperplasia: a randomized, double-blind placebo-controlled clinical trial.
      TerazosinNo AEs during the discontinuation phase
      Barkin et al (2003)
      • Barkin J.
      • Guimarães M.
      • Jacobi G.
      • Pushkar D.
      • Taylor S.
      • van Vierssen Trip O.B.
      Alpha-blocker therapy can be withdrawn in the majority of men following initial combination therapy with the dual 5alpha-reductase inhibitor dutasteride.
      Tamsulosin2 dysuria, 2 urinary frequency, 2 urinary infections, 2 ejaculation disorders, 2 musculoskeletal pain, 2 viral respiratory tract infection2 dysuria, 1 urinary frequency, 1 ejaculation disorders, 2 musculoskeletal pain, 2 viral respiratory tract infection
      Lee et al (2012)
      • Lee J.Y.
      • Kang D.H.
      • Park S.Y.
      • et al.
      Effect of discontinuation of tamsulosin in Korean men with benign prostatic hyperplasia taking tamsulosin and dutasteride: an open-label, prospective, randomized pilot study.
      TamsulosinAEs not specified per group; in total: 2 reduced libido, 2 ejaculatory problem
      Matsukawa et al (2017)
      • Matsukawa Y.
      • Takai S.
      • Funahashi Y.
      • et al.
      Effects of withdrawing α1-blocker from combination therapy with α1-blocker and 5α-reductase inhibitor in patients with lower urinary tract symptoms suggestive of benign prostatic hyperplasia: a prospective and comparative trial using urodynamics.
      Silodosin1 chest pain and 1 anthema1 chest pain, 1 postural hypotension, 1 dizziness
      AE, adverse events; COPD, chronic obstructive pulmonary disorder; SAEs, serious adverse events.

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