Trials evaluating drug discontinuation: a scoping review sub-analysis focusing on outcomes and research questions

Trials evaluating drug discontinuation: a scoping review sub-analysis focusing on outcomes and research questions | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Trials evaluating drug discontinuation: a scoping review sub-analysis focusing on outcomes and research questions Nele Kornder, Norbert Donner-Banzhoff, Ina Staudt, Nina Grede, and 2 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-5929100/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 27 May, 2025 Read the published version in BMC Medical Research Methodology → Version 1 posted 9 You are reading this latest preprint version Abstract Background: The widespread use of long-term pharmacological treatments for chronic conditions has led to polypharmacy, raising concerns about adverse effects and interactions. Deprescribing, the discontinuation of drugs with unfavorable benefit-risk ratios, is gaining attention. Studies evaluating the discontinuation of drugs have a broad methodological spectrum. The selection of outcomes poses a particular challenge. This scoping review addresses the methodological challenges of outcome selection in RCTs investigating drug discontinuation. Methods: The scoping review includes RCTs that investigated the discontinuation of drugs whose efficacy and/or safety was in doubt. Data on study characteristics, the motivation for evaluating drug discontinuation, the number and type of primary endpoints, and the stated hypotheses were extracted and analyzed. Results: We included 103 RCTs. Most studies were from Europe and the USA and mainly investigated antipsychotics/antidepressants, immunosuppressants, steroids and antiepileptics. The discontinuation studies were often conducted due to side effects of the treatment and doubts about the benefits of the drug. The primary endpoints reflected either the course of the disease ("justification of treatment") or the disadvantages of the drug ("justification of withdrawal”). Non-inferiority hypotheses were generally prevalent in justification of treatment studies, while superiority hypotheses were more commonly used in justification of withdrawal studies. However, due to methodological and practical challenges this was not always the case. Conclusion: We present a framework to choose outcomes and specify hypotheses for discontinuation studies. With regard to this, both key challenges (justification of treatment and justification of withdrawal) must be met. Polypharmacy Deprescribing Drug discontinuation Scoping Review Outcome Selection Figures Figure 1 Introduction Rationale Many chronic conditions that were once treatable only symptomatically are now amenable to long-term pharmacological therapy, improving patients’ long-term prognosis. Randomized controlled trials (RCTs) have established a robust evidence base for the safe and effective treatment of chronic diseases, such as heart failure ( 1 ), asthma( 2 ) or rheumatoid arthritis ( 3 ). Nevertheless, these improvements have contributed to a growing concern: polypharmacy. Since the prevalence of most chronic conditions increases with age ( 4 , 5 ), older persons are particularly affected, often receiving multiple concurrent prescriptions ( 6 ). Even when each drug is evidence-based and appropriate on its own, their combination may lead to adverse effects, drug interactions, and an increased risk of medication errors ( 7 ). Indeed, adverse drug reactions represent a major cause of hospital admissions ( 8 , 9 ). Polypharmacy has become an urgent topic for health policy, practice and research ( 10 ). Discontinuing drugs that no longer offer a favorable benefit–risk ratio for the individual patient appears to be a logical response to this dilemma. However, scientific evidence supporting this approach remains limited—especially when compared to the extensive research on initial drug prescribing. Concerns about potential harms, such as withdrawal symptoms or disease recurrence, further contribute to uncertainty and may impede the discontinuation of drugs in practice ( 11 ). Clinicians considering drug discontinuation and researchers studying this process face two main challenges: 1) treating the underlying condition for which the drug was prescribed, and 2) addressing the potential disadvantages of the treatment. While the latter motivates critical evaluation of the drug, the former must be carefully considered to avoid harm from under-treatment. Achieving a high drug discontinuation rate, whether in clinical practice or research, is not a success in itself. For instance, if patients experience harmful consequences such as disease flare-ups after discontinuation, the results of such studies may be ambiguous, and the implications for future care may be unclear. Thus, drug discontinuation studies often raise complex questions that extend beyond those typically addressed in studies of drug safety and efficacy. To gain a deeper understanding of the complexities of discontinuation studies, our research group has developed a typology that categorizes the different scientific questions related to drug discontinuation and offers type-specific methodological recommendations( 12 ). Among these, type 1 research questions, which concern doubts about the effectiveness and/or safety of a drug, are the focus of this paper. Objectives The selection of appropriate outcomes is crucial in this context, as it must align with the motivations for discontinuation while addressing both the challenges of treating the condition and evaluating the potential disadvantages of the treatment. Based on a systematic review of studies evaluating drug discontinuation ( 13 ), we analysed a subset of RCTs included in this paper. Our objectives were to: 1) assess the authors' motivations for conducting drug discontinuation studies, 2) examine how they addressed the dual challenges of treatment efficacy and discontinuation disadvantages, and 3) explore the outcomes they selected to evaluate these issues. Throughout the paper, we use the terms “drug withdrawal” and “drug discontinuation” interchangeably. Methods Eligibility Criteria In this scoping review, we identified studies on drug discontinuation, irrespective of the specific drug, disease, or outcome. For this analysis, we used a subset of the review by Grede et al. (13), consisting exclusively of RCTs classified as type 1 drug discontinuation studies, according to Viniol et al. (12). These studies focus on discontinuation due to concerns about the efficacy or safety of continued drug therapy. We included only original studies with a prospective RCT design. RCTs provide the highest level of evidence for evaluating the effects of drug discontinuation in clinical practice and represent the methodological standard that future discontinuation studies should adhere to. Eligible studies examined the discontinuation of at least one drug, focusing either on a single agent or one from the same pharmacological class. Type 2 and type 3 studies, which evaluate structured discontinuation procedures or complex discontinuation strategies, were excluded. We also excluded case reports with only one participant, studies that did not involve humans, and studies that have not been published in English, German, Spanish, or French. Retrospective studies were not included to ensure methodological consistency and avoid bias related to data collection and confounding variables. Observational studies, including cohort and case-control studies, were excluded to maintain comparability across trials. Furthermore, studies investigating on-demand medications were not considered, as these do not reflect continuous pharmacological treatment. Trials in which a drug was introduced and then discontinued as part of the study to demonstrate efficacy were also excluded, as these studies do not align with the aim of evaluating the discontinuation of established long-term therapies. Finally, we excluded studies focused on substitution therapies in the context of substance abuse or addiction due to their distinct clinical and methodological nature. Information Sources and Search Strategy The dataset was obtained following the systematic search strategy developed by Grede et al (13). The search encompassed multiple databases, including Medline (PubMed), The Cochrane Library, EMBASE, CINAHL, Web of Science, and PsycINFO. The original search was conducted in January 2016 and subsequently updated in March 2021 to include all references published up to the end of 2020. Search terms comprised “discontinuation” along with relevant synonyms, as well as the MeSH terms “Safety-Based Drug Withdrawals” and “Drug Therapy.” A comprehensive description of the search methodology, including detailed examples for Medline, is available in the Supplementary Material of our previous publication (13). Data Charting Process To describe the sample, we extracted bibliographic data, including funding information, from all included studies (see Table 1). The investigated drugs were classified into distinct pharmacological groups (see Table 1). A pharmacological group was then redefined when medications from at least two studies could be assigned to it. This led to the creation of the category "Other drugs for chronic conditions", which includes pharmacological subclasses that appeared only once in the sample. An overview of the subclasses can be found in Table 1. We extracted information regarding the motivation for drug discontinuation, primary outcomes, and study hypotheses. Initially, the original wording was documented and then summarized and categorized. Categories were iteratively developed and validated by the study team. Data extraction was performed by IS, with ambiguous cases discussed with NDB, AV, and NK. Key Data Items and Synthesis of Results We extracted and analyzed key aspects of each included study to understand how drug discontinuation was conceptualized and evaluated. Motivation for evaluating drug discontinuation : We first identified the “initial therapeutic objective” of each drug, as specified by the authors (e.g., cure, prophylaxis). Subsequently, we grouped the reported reasons for drug discontinuation into predefined categories, such as “side effects” and “doubts about the benefits of the drug.” A complete list of these categories and their definitions is provided in Table 2. Primary outcomes: We recorded whether the primary outcome was explicitly defined, could be inferred from contextual information (e.g., sample size calculation), or was not discernible. The category “structure of primary outcome(s)” differentiates between single outcomes, composite outcomes (i.e., the endpoint occurs if any of several events occur, such as death, myocardial infarction, or stroke), co-primary outcomes (i.e., two or more distinct endpoints must be met), and multiple outcomes (neither co-primary nor composite) (see Table 3). The category “type of outcome” classifies primary outcomes as either clinical (e.g., symptoms, quality of life, mortality), subclinical (e.g., biochemical test results, imaging findings), or a combination of both. In addition, the discontinuation rate was included in this category. The discontinuation rate is defined as the proportion of patients who resumed medication following an initial discontinuation. We also categorized the primary outcome based on the clinical challenge it addresses: whether it aims to justify continued treatment (Justification of Treatment, JT), justify withdrawal (Justification of Withdrawal, JW), or both. Finally, we categorized the role of "time" in defining the endpoint (e.g., number of events during follow-up or time to event). Further details and definitions of the categories of interest can be found in Table 3. Study hypotheses: In the first step, we mapped the study hypotheses—when explicitly stated by the authors—to current definitions of “superiority” or “non-inferiority” designs ADDIN CitaviPlaceholder{{"$id":"1","$type":"SwissAcademic.Citavi.Citations.WordPlaceholder, SwissAcademic.Citavi","Entries":[{"$id":"2","$type":"SwissAcademic.Citavi.Citations.WordPlaceholderEntry, SwissAcademic.Citavi","Id":"9043d52d-3dd9-45cc-94ab-4250ed6baa4c","RangeLength":4,"ReferenceId":"7d3cec0c-81e9-40b1-a851-edaec3acf23d","PageRange":{"$id":"3","$type":"SwissAcademic.PageRange, SwissAcademic","EndPage":{"$id":"4","$type":"SwissAcademic.PageNumber, SwissAcademic","IsFullyNumeric":false,"NumberingType":0,"NumeralSystem":0},"NumberingType":0,"NumeralSystem":0,"StartPage":{"$id":"5","$type":"SwissAcademic.PageNumber, SwissAcademic","IsFullyNumeric":false,"NumberingType":0,"NumeralSystem":0}},"Reference":{"$id":"6","$type":"SwissAcademic.Citavi.Reference, 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This classification was only possible when the hypothesis was clearly stated, which was not always the case. Therefore, we created the category “no specification in the text” for studies in which the hypothesis was either not identifiable or not mentioned. In the second step, we evaluated the hypotheses or research questions based on their context and clinical relevance, which led to the category “appropriate hypotheses according to us.” For this classification, two authors (IS, NDB) independently assessed and categorized the hypotheses of the included studies as either superiority or non-inferiority. Each author conducted the classification independently. In cases of agreement, the categorization was accepted; in cases of disagreement, a third author (AV) reviewed the study and made the final decision (see Table 4). Statistical Analysis We calculated descriptive statistics (frequencies and percentages) for each extracted category. All statistical analyses were performed with SPSS software (v 22.0; IBM Corporation, Armonk, NY, USA). Results Study Selection The scoping review by Grede et al. (13) identified 581 discontinuation studies. Among them were 189 RCTs, of which 103 were type-1 drug discontinuation studies. Finally, 111 articles were selected for analysis, eight of which are associated with one of five studies that published multiple papers contributing to the analysis presented here (see Figure 1). The numbers of records identified, screened, excluded, and included are shown in the PRISMA—ScR flow diagram (15) (Fig. 1). Characteristics of Included Studies The majority of the studies we investigated were from Europe (62.1%) and the USA (21.4%). These studies have been published since the late 1970s, with a peak between 1990 and 2009 (61.1%) (see Table 1). In total, we identified and grouped the discontinued substances into 12 distinct drug classes. The 103 included trials evaluated drugs from a range of pharmacological classes, with the most common being immunosuppressants (18.4%) and antipsychotics (20.4%). An overview of the drug classes can be found in Table 1. In 58 studies (56.3%), the discontinuation of a single, prespecified drug was investigated (e.g., lithium for the treatment of depression (16)). In 39 studies (37.9%), the discontinued medication was selected from a drug class—such as antiepileptic drugs (AEDs), including carbamazepine, valproate, phenytoin, phenobarbital, or lamotrigine (17). 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(20) ), without specification of the individual agents. For a comprehensive listing of all included studies along with their characteristics, please refer to Supplementary Table 1 . Table 1: General characteristics of the included drug discontinuation trials (n = 103) no. (%) Publication year 1976-79 1 (1.0) 1980-89 21 (20.4) 1990-99 23 (22.3) 2000-09 40 (38,8) 2010-20 18 (17.5) Region USA 22 (21.4) South America 2 (1.9) Africa 2 (1.9) Europe 64 (62.1) Asia 11 (10.7) Oceania 2 (1.9) Evaluated (discontinued) active substances Immunosuppressants 19 (18.4) Steroids 11 (10.7) Antiepileptic drugs 6 (5.8) Antidepressants 10 (9,7) Antipsychotics 21 (20.4) Infection prophylaxis in chronic diseases 6 (5.8) Antihypertensive agents 9 (8.7) Sedatives and Anxiolytics 5 (4.8) Cardiac glycosides 2 (1.9) Antiviral agents 2 (1.9) Acid suppressive agents 2 (1.9) Other drugs for chronic conditions (e.g. Alendronate for the treatment of osteoporosis or Theophylline for the treatment of Chronic Obstructive Pulmonary Disease) 10 (9.7) Follow up time (Period after the medication has been discontinued / phased out in a study participant) ≤ 6 months 40 (38.8) month 18 (17.5) > 1 year 18 (17.5) Not specified 27 (26.2) Funding by (n=113) (more than one funding source in 9 studies) Pharmaceutical industries 14 (12.4) Governmental institutions 24 (21.2) Voluntary Foundations 19 (16.8) Not specified 56 (49.6) Table 1: This table summarizes the characteristics of the 103 drug discontinuation trials, including publication year, region, active substances evaluated, follow-up time after discontinuation, and funding sources Motivation for Treatment and Drug Discontinuation Nearly two-thirds (62.1%) of the drugs analyzed were initially prescribed to improve the prognosis of a chronic disease, such as statins for coronary heart disease (see Table 2). Approximately one-third (31.1 %) was administered for symptom control. Discontinuation studies involving drugs originally prescribed for curative (2.9 %) or prophylactic (4.9 %) purposes were comparatively rare. In nearly 40% of the studies, side effects were the primary reason for investigating drug discontinuation. This was particularly relevant in patients with stable disease, where long-term treatment caused frequent or severe adverse effects. Common examples include antiepileptics, antipsychotics, diuretics, glucocorticoids, and other immunosuppressants. In more than half of the studies (53.4%) discontinuation was motivated by uncertainty regarding the clinical benefit of the drug or used as an indirect method of evaluating its efficacy (see Table 2). This was especially relevant for antidepressants and antipsychotics. For instance, the DESEP study examined dementia patients receiving long-term antidepressants and monitored depressive symptoms following discontinuation ADDIN 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(21) . A smaller proportion of studies (4.9%) investigated drugs that had entered clinical use prior to the implementation of rigorous trial requirements. In these cases, discontinuation served as a means to assess real-world effectiveness—such as in studies on long-term nitrate therapy for angina (22). In a few cases (2.9%), discontinuation was part of an intentional therapy adjustment, typically after a predefined treatment target had been reached (see Table 2). One example is the RCT by Lee et al. (23), in which statins were discontinued after achieving a target LDL cholesterol level. Table 2: Overview of drugs under study in the included trials (n = 103) no. (%) Initial therapeutic objective Symptom control - alleviation of discomfort, but no effect on the underlying disease (for example: Analgesic for pain syndromes or Metoclopramid or nausea) 32 (31.1) Cure - causal treatment of the disease; with the aim of cure (for example: H2-receptor antagonist for duodenal ulcer) 2 (1.9) Prognostic improvement - disease modification (for example: ACE inhibitor for heart failure or statin for coronary heart disease) 64 (62.1) Prophylaxis - currently non-existent but impending problem is to be prevented (for example: Antifungal drug to prevent mycosis in HIV) 5 (4.9) Motive for investigating drug discontinuation from the author’s perspective Side effects of drug 40 (38.8) Doubts about the benefit of drug (unclear/low/absent benefit) or indirectly proof of efficacy by discontinuation 55 (53.4) Established therapy despite low evidence level 5 (4.9) Modified therapy regime in course of time 3 (2.9) Table 2: This table summarizes the initial therapeutic objectives and the motivations for investigating drug discontinuation in the 103 included trials. Primary Outcome Definitions In 66% of the studies primary outcomes were explicitly defined. In approximately one-third, the outcome was not directly stated but could be inferred from contextual information such as the sample size calculation. In a small proportion of studies (4.9%), no primary outcome could be discerned (see Table 3). Most studies used a single primary outcome; composite and co-primary outcomes were relatively uncommon. Clinical endpoints were employed in the majority of trials (59.2%), while subclinical or mixed outcomes were used less frequently. Only a small subset of studies (5%) included discontinuation rates as part of the primary outcome (see Table 3). The majority of trials (65.0 %) focused on outcomes related to the condition for which the drug had originally been prescribed (JT). In these cases, researchers typically monitored symptom deterioration, relapse, or adverse events following discontinuation. Demonstrating that the discontinuation of therapy does not lead to clinical worsening is highly relevant. Thus, such studies are ideally based on a non-inferiority design, including a clearly defined non-inferiority margin and appropriate sample size calculation. In 20.4% of studies, outcomes were selected to assess the disadvantages of ongoing therapy (JW) such as side effects, costs, or patient burden. Here, superiority hypotheses are generally more appropriate, as they test whether discontinuation leads to measurable improvements compared to continuation. Both JT and JW challenges were reflected in 10 out of 103 studies. For instance, Curran et al. (24) investigated benzodiazepine withdrawal. Improvements in cognitive function and psychomotor performance supported discontinuation (JW), while outcomes such as mood, sleep, and quality of life reflected the original treatment intent (JT). Regarding temporal orientation, the majority of primary outcomes (66%) were based on the number of events occurring during follow-up. Fewer studies employed time-to-event or pre-post comparisons (see Table 3). Table 3: Overview of primary outcome definitions and challenges (n = 103) no. (%) Presentation of primary outcome Primary Outcome(s) explicitly defined in article 68 (66.0) Primary Outcome(s) not explicitly described, but can be assumed from context or the section on sample size calculation 30 (29.1) No primary outcome(s) discernible 5 (4.9) Structure of primary outcome(s) Single 69 (67) Composite outcome 11 (10.7) Co-primary outcome 5 (4.9) Multiple outcomes, neither composite nor co-primary 13 (12.6) No primary outcome(s) discernible 5 (4.9) Type of primary outcome Discontinuation rate 5 (4.9) Subclinical - endpoint not noticeable to the patient (e.g. laboratory values, imaging findings) 26 (25.2) Clinical – endpoints noticeable for the patient (e.g. symptoms, quality of life, morbidity, death) 61 (59.2) Combination of subclinical and clinical endpoint 6 (5.8) No primary outcome(s) discernible 5 (4.9) Challenges Justification of treatment – Outcome selection focus is on the disease and its course for which the medication was originally prescribed 67 (65.0) Justification of withdrawal - Outcome selection focuses on disadvantages of drugs 21 (20.4) Both (more than one outcome referring to justification of treatment and withdrawal) 10 (9.7) No primary outcome(s) discernible 5 (4.9) The role of "time" in endpoint definition Number of events during follow-up time (frequency of events, e.g., number of myocardial infarctions) 68 (66.0) Time to event , typically in weeks or month (definition can be clinical, biochemical, imaging etc.) 2 (1.9) Difference of a metric endpoint between study start and end (e.g., cognitive function after six weeks of follow-up) 28 (27.2) No primary outcome(s) discernible 5 (4.9) Table 3: This table summarizes the presentation, type, and challenges of primary outcomes, as well as the role of time in endpoint definition in the included trials. Hypotheses Evaluated In 43 (41.7 %) of the included studies, the hypothesis being investigated was explicitly stated. Specifically, 10 studies described a non-inferiority hypothesis, and 32 studies presented a superiority hypothesis (see Table 4). However, in more than half of the studies (58.3%), the hypothesis type was not explicitly mentioned. Table 4 shows the cross-classification of hypothesis types as reported by study authors and as assessed by us. We categorized all studies according to the most relevant research question, taking into account the study topic and clinical context. Based on our assessment, a non-inferiority hypothesis would have been appropriate in nearly half of all studies (48.5%). Among the 32 studies classified as superiority trials by the original authors, 16 (50.0%) were also categorized as superiority trials in our assessment, while 12 (37.5%) were categorized as non-inferiority trials and 4 (12.5%) as addressing both. Of the 10 studies described as non-inferiority trials, 9 (90.0%) were confirmed as such in our assessment, and 1 (10.0%) was assigned to both. Among the 60 studies without a stated hypothesis type, we assessed 29 (48.3%) as non-inferiority trials, 15 (25.0%) as superiority trials, and 16 (26.7%) as addressing both (see Table 4). For additional details, please refer to Supplementary Table 1, which provides further breakdowns and specific data points. Our findings suggest that several studies might have been more appropriately conceptualized as non-inferiority trials, although they were not presented as such. One example is the study by Chen et al. (25), which examined quetiapine discontinuation in patients with a first remitted psychotic episode. While the authors expected higher relapse rates in the discontinuation group, from a clinical perspective, a non-inferiority design would have been more suitable to assess whether discontinuation leads to recurrence within an acceptable margin, particularly considering the potential side effects of quetiapine. Table 4: Underlying hypotheses: Authors' perspective and our interpretation (n = 103) Appropriate hypotheses according to us Total (study authors) Hypotheses according to the study authors Superiority Non-inferiority both Superiority 16 12 4 32 Non-inferiority 0 9 1 10 both 0 0 1 1 No specification 15 29 16 60 Total (us) 31 50 22 103 Table 4: This table compares the hypotheses specified by the study authors (e.g., superiority, non-inferiority) with our interpretation Hypotheses and the JW/JT Challenges In our analysis of 67 studies with a primary outcome addressing JT, 41 studies aimed to investigate non-inferiority. In six of these studies, however, a non-inferiority hypothesis was not explicitly stated. Instead, outcomes related to JW were used, although the research question appeared more closely aligned with a non-inferiority framework focused on JT. Concrete examples of such cases are presented and discussed below. In 13 studies, a JW outcome was investigated, and we considered a superiority design to be appropriate for these. Conversely, 18 studies employed a superiority design while addressing outcomes related to JT. For instance, McMillan et al. (26) used a statistical approach consistent with superiority testing (t-test or Mann–Whitney U test) to examine the discontinuation of growth hormone substitution and its effect on psychological well-being (JT) in patients with severe hormone deficiency. This suggests that their primary motivation was to demonstrate effectiveness, which seems plausible given the state of the evidence. Overall, we observed two recurring patterns: (1) a shift in the selected outcome type (between JT and JW) and (2) the use of a superiority design where a non-inferiority design may have been more appropriate. In several cases, an outcome switch from JT to JW was observed, which potentially avoided the methodological requirements of a non-inferiority trial, such as a larger sample size. Discussion Summary of our findings Our review of discontinuation studies (type 1 according to Viniol et al. ( 12 )) reveals the complexity of this kind of research, especially in selecting the primary outcome and formulating study hypotheses. We explored the motivations, challenges, and consequences of discontinuation studies regarding primary outcome selection. In most studies, primary outcomes were clearly defined, with a majority using a single primary outcome and some using either composite or co-primary outcomes. Clinically relevant endpoints such as symptoms, quality of life, and death were frequently used, while subclinical measurements were less common. Discontinuation rates were considered in only a small fraction of the studies. However, our evaluation also highlights that discontinuation studies pose substantial methodological challenges—particularly regarding outcome specification, hypothesis formulation, and study design. Choice of outcomes and formulation of hypotheses Discontinuation studies must address two distinct perspectives: the justification for continuing treatment (JT) and for withdrawing it (JW). While JT outcomes assess disease control and typically necessitate non-inferiority designs, JW outcomes highlight drawbacks of ongoing treatment and are best addressed using superiority designs. Although most studies aligned broadly with these principles, several cases revealed inconsistencies between stated goals and methodological choices. For example, Höcker et al. ( 27 ) investigated steroid withdrawal in pediatric kidney transplant recipients and chose longitudinal growth (JW) as the primary endpoint. However, the clinically critical outcome—graft function (JT)—was only analyzed descriptively as a secondary endpoint. A non-inferiority design focused on graft survival would have been more appropriate, though it would have required a substantially larger sample size (see Table 5 ). Table 5 Study Example – Steroid discontinuation in Pediatric Kidney Transplantation Study description 42 low-immunologic risk pediatric kidney transplant recipients on cyclosporine micro-emulsion, mycophenolate mofetil, and corticosteroids were randomly assigned to either continue steroids or withdraw them over 3 months. The primary outcome was longitudinal growth. Problem Statement The key issue with steroid withdrawal is the safety of graft function. Theoretically, safety should be the primary endpoint and adequately powered to show at least non-inferiority of the proposed regimen. Sample Size Considerations A non-inferiority study would require at least 196 patients per treatment arm to detect a ≤ 5% difference in glomerular filtration rate (GFR) with 90% power and a 15% coefficient of variation. Due to the limited number of pediatric renal transplant patients, such a study would not be feasible. Reference Höcker B, Weber LT, Feneberg R, Drube J, John U, Fehrenbach H et al. Nephrol Dial Transplant 2010; 25( 2 ):617–24. doi: 10.1093/ndt/gfp506 . Table 5 : This table presents a typical study example that illustrates the challenges involved in hypothesis formulation and outcome selection. A similar issue arises in the study by Kendrick et al. ( 28 ), which prioritized cognitive function (JW) after antiepileptic withdrawal, while seizure frequency (JT) was a secondary outcome and not part of the sample size calculation. These examples illustrate that, while both perspectives are often acknowledged, they are rarely addressed equally in study design and statistical planning. This imbalance poses a problem. As shown in the study by Höcker et al. ( 27 ), the omission of an adequately powered primary endpoint for a rare but severe outcome—such as graft failure—limits interpretability. Severe outcomes not only require narrow non-inferiority margins but also demand ethical scrutiny, as they cannot be dismissed as rare side effects. Statistical parameters like alpha, beta, and acceptable risk thresholds must therefore be clinically and ethically justified, not treated as formalities. Borm et al. ( 29 ) emphasized that a study's evidential strength should be judged by its overall success, not just by the power of isolated results. They further developed this concept, stressing that the selection of endpoints should not be based solely on statistical properties—clinical relevance must always take precedence ( 30 ). In this light, a trial that shows improved growth (JW) after discontinuing immunosuppressive therapy but cannot rule out an increased risk of graft rejection (JT) remains inconclusive. A more meaningful design would enable conclusions on both dimensions—treatment safety and benefit of withdrawal—even if this increases the complexity and resource demands of the study. Despite this, none of the 103 studies we reviewed explicitly defined both JT and JW as co-primary endpoints. Most studies chose a single primary outcome, and only five included co-primary outcomes. The likely reason is feasibility: powering a study for both hypotheses often requires much larger sample sizes. Nevertheless, integrating both perspectives is essential to ensure that drug discontinuation studies are methodologically sound and clinically meaningful. Clinical Relevance In clinical studies, researchers choose between clinical endpoints and surrogate markers based on the study goals, constraints, and disease characteristics. Clinical endpoints, which assess a patient's well-being, function, or survival, provide the most reliable measure of an intervention's impact but often require long follow-ups or large samples. Surrogate markers are useful in phase 2 trials to assess feasibility but become problematic in definitive phase 3 trials ( 31 ). The validity of a surrogate depends on how well it captures the causal pathways between the intervention and the outcome. For example, Thyroid Stimulating Hormone (TSH) is a justified surrogate when discontinuing thyroid hormones, as regular monitoring helps prevent overt hypothyroidism and its associated harms. In contrast, Low-Density Lipoprotein cholesterol (LDL-C), as used by Lee et al. ( 23 ), is an inadequate surrogate for cardiovascular events. While cholesterol levels correlate with cardiovascular disease, they do not reliably predict individual risk ( 32 , 33 ). Thus, monitoring TSH to prevent overt hypothyroidism is appropriate when discontinuing thyroid hormones. However, using LDL-C instead of clinical events to assess statin discontinuation in older adults is inappropriate. Discontinuation Rate and follow-up Discontinuation rates can be a key outcome in drug discontinuation studies ( 13 ). When a drug is stopped as part of the study protocol, reinstitution rates can indicate "failed discontinuation" and offer valuable insights. Disease flares or symptom recurrence are common reasons for resuming treatment, reflecting JT. For example, restarting antipsychotics due to neuropsychiatric symptoms or reintroducing thyroxine when TSH levels rise are both instances of JT. In these cases, TSH could also serve as a safety measure. However, in patients who tolerate increased disease activity after discontinuation, a mechanism justifying withdrawal can be identified. For instance, in the treatment of autoimmune diseases, glucocorticoids are often discontinued due to metabolic side effects, such as weight gain ( 34 ). Psychological factors, like patient or clinician reactions, may also influence the decision to reinstitute treatment, particularly in blinded trials. For example, statin discontinuation could reveal unmasked treatment arms due to rising LDL-cholesterol levels, leading to concerns and, consequently, treatment resumption. Thus, the discontinuation rate is a complex measure that reflects JT, JW, and psychological factors. Additional outcomes may be needed to assess the reasons behind treatment reinstitution, depending on the drug and its indication. The follow-up period must also be considered when evaluating discontinuation rates. For diseases with long-term clinical consequences, such as statin use in cardiovascular prevention, longer follow-up is necessary to capture adverse events, like stroke. If a strong surrogate marker exists, such as HBV DNA levels after discontinuing tenofovir, a shorter follow-up period may be justified ( 35 ). What do others say? In 2022, the US Deprescribing Research Network (USDeN) published recommendations on outcome selection in discontinuation studies ( 36 ). A year later, Nizet et al. compared their systematic review of deprescribing implementation trials with these recommendations ( 37 ). Unlike our approach, they did not distinguish between the three types of discontinuation studies ( 12 ) and instead analyzed studies of all three types together. In contrast, we focused specifically on Type 1 studies. Given the differing goals and design requirements, we advocate for considering these study types separately. Additionally, the authors did not address the key challenge of discontinuation studies—balancing JT and JW—and its implications for study design and hypothesis formulation. However, they underscored the importance of clinically relevant outcomes, adequate power, and sufficient follow-up time. Strength and Limitations of our review This scoping review provides a comprehensive analysis of studies on drug discontinuation, examining motivations, challenges, outcomes, and hypotheses. Based on an extensive literature search, it also proposes a systematic framework to categorize key research questions and guide future studies. Our review specifically focused on randomized controlled trials (RCTs) of type 1 drug discontinuation studies. Although we may have overlooked relevant findings from other study types, we believe this limitation is justified given the higher risk of bias associated with non-RCT designs. Therefore, we chose to focus solely on RCTs to ensure the reliability of our analysis. The studies included in our review were limited to those examined by Grede et al., who published a scoping review in 2023 covering publications up to 2020. Since our study aims to develop a structured synthesis rather than provide a fully up-to-date systematic review of the drug discontinuation literature, we do not believe extending the time frame would have substantially altered our findings. While the field of drug discontinuation is evolving rapidly, the 103 studies included in our analysis provide a solid and comprehensive foundation for this work. The primary objective of this study is to synthesize and conceptualize existing knowledge, and the patterns, barriers, and facilitators of drug withdrawal identified in these studies form the basis of our model. Although two authors independently interpreted the hypotheses, some subjectivity inevitably remains in the interpretation process. This subjectivity may have influenced of our conclusions regarding study designs and hypotheses to some extent. Conclusion: Recommendations of outcome selection in drug discontinuation studies In conclusion, drug discontinuation studies must address both key clinical and methodological challenges. The selection of endpoints should prioritize clinical relevance, emphasizing meaningful outcomes or appropriate surrogate markers over purely statistical considerations. This approach should inform the formulation of hypotheses, carefully balancing non-inferiority and superiority designs. Such studies typically require large sample sizes and extended follow-up periods. The field of drug discontinuation research is rapidly evolving, with many questions still to be answered. These include the comparative valuation of outcomes, the definition of error margins, and strategies for determining sample sizes. Securing funding remains a significant challenge due to the lack of commercial incentives, and public or independent funding sources are often insufficient to support the scale of these studies. Governments must play a central role in addressing this funding gap by supporting research that aligns with public health priorities. The example of Canada, with initiatives like the Canadian Institutes of Health Research (CIHR) and the Canadian Deprescribing Network (CaDeN), highlights how national networks can drive research on drug discontinuation and the development of specific guidelines. Similar efforts, along with international collaboration, are essential to advancing evidence-based approaches to medication discontinuation and ensuring the safe reduction of unnecessary or potentially harmful drugs ( 38 ). Abbreviations ACE : Angiotensin-Converting Enzyme AED: Antiepileptic Drugs CIHR: Canadian Institutes of Health Research DNA: Deoxyribonucleic Acid GFR: Glomerular Filtration Rate HBV : Hepatitis B Virus HIV: Human Immunodeficiency Virus JT: Justification of Treatment JW: Justification of Withdrawal LDL-C: Low-Density Lipoprotein Cholesterol PPI: Proton Pump Inhibitor PRISMA: Preferred Reporting Items for Systematic Reviews and Meta-Analyses RCT: Randomized Controlled Trial SPSS : Statistical Package for the Social Sciences TNF: Tumor Necrosis Factor TSH : Thyroid-Stimulating Hormone US: United States USA: United States of America USDeN : US Deprescribing Research Network Declarations Ethics approval and consent to participate Not applicable. Consent for publication Not applicable. Availability of data and materials The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request. Competing interests NK, NG, IS, AB and AV declare that they have no competing interests NDB is co-chairman of Gesellschaft für Patientenzentrierte Kommunikation, a non-profit organization developing and distributing the decision-support software arriba, which among others includes a module for drug discontinuation. Funding This work was funded by the Federal Ministry of Education and Research (BMBF, Bundesministerium für Bildung und Forschung) as part of the project “DRUG-STOP” (Grant Number: 01KG1507). The funders had no role in the design of the study, analysis and interpretation of data, or in writing the manuscript. Authors' contributions AV and NDB conceptualized and supervised this scoping review. IS, NG, NK and AB contributed significantly to the development of the study. IS, NDB and NK screened the abstracts and full-texts, extracted and analyzed the data. NDB, NK and AV prepared this manuscript. All authors read and approved the final manuscript. Acknowledgements We would like to thank Kiana Rafat for her valuable support in preparing various materials for this manuscript. References Zhang H, Huang T, Shen W, Xu X, Yang P, Zhu D et al. Efficacy and safety of sacubitril-valsartan in heart failure: a meta-analysis of randomized controlled trials. ESC Heart Fail 2020; 7(6):3841–50. doi: 10.1002/ehf2.12974. Walters EH, Gibson PG, Lasserson TJ, Walters JAE. Long-acting beta2-agonists for chronic asthma in adults and children where background therapy contains varied or no inhaled corticosteroid. Cochrane Database Syst Rev 2007; 2007(1):CD001385. doi: 10.1002/14651858.CD001385.pub2. Kerschbaumer A, Sepriano A, Smolen JS, van der Heijde D, Dougados M, van Vollenhoven R et al. Efficacy of pharmacological treatment in rheumatoid arthritis: a systematic literature research informing the 2019 update of the EULAR recommendations for management of rheumatoid arthritis. Ann Rheum Dis 2020; 79(6):744–59. doi: 10.1136/annrheumdis-2019-216656. Wolff JL, Starfield B, Anderson G. Prevalence, expenditures, and complications of multiple chronic conditions in the elderly. Arch Intern Med 2002; 162(20):2269–76. doi: 10.1001/archinte.162.20.2269. Moore KL, Boscardin WJ, Steinman MA, Schwartz JB. Age and sex variation in prevalence of chronic medical conditions in older residents of U.S. nursing homes. J Am Geriatr Soc 2012; 60(4):756–64. doi: 10.1111/j.1532-5415.2012.03909.x. Liu Q, Schwartz JB, Slattum PW, Lau SWJ, Guinn D, Madabushi R et al. Roadmap to 2030 for Drug Evaluation in Older Adults. Clin Pharmacol Ther 2022; 112(2):210–23. doi: 10.1002/cpt.2452. Davies LE, Spiers G, Kingston A, Todd A, Adamson J, Hanratty B. Adverse Outcomes of Polypharmacy in Older People: Systematic Review of Reviews. J Am Med Dir Assoc 2020; 21(2):181–7. doi: 10.1016/j.jamda.2019.10.022. Schurig AM, Böhme M, Just KS, Scholl C, Dormann H, Plank-Kiegele B et al. Adverse Drug Reactions (ADR) and Emergencies. Dtsch Arztebl Int 2018; 115(15):251–8. doi: 10.3238/arztebl.2018.0251. Osanlou R, Walker L, Hughes DA, Burnside G, Pirmohamed M. Adverse drug reactions, multimorbidity and polypharmacy: a prospective analysis of 1 month of medical admissions. BMJ Open 2022; 12(7):e055551. doi: 10.1136/bmjopen-2021-055551. Department of Health & Social Care (UK). Good for you, good for us, good for everybody: A plan to reduce overprescribing to make patient care better and safer, support the NHS, and reduce carbon emissions; 2021. In:. Reeve E, Moriarty F, Nahas R, Turner JP, Kouladjian O'Donnell L, Hilmer SN. A narrative review of the safety concerns of deprescribing in older adults and strategies to mitigate potential harms. Expert Opin Drug Saf 2018; 17(1):39–49. doi: 10.1080/14740338.2018.1397625. Viniol A, Haasenritter J, Grede N, Wegscheider K, Becker A, Sitter H et al. Typology of drug discontinuation trials - Methodological recommendations. J Clin Epidemiol 2021; 137:23–30. doi: 10.1016/j.jclinepi.2021.03.017. Grede N, Kuss K, Staudt I, Donner-Banzhoff N, Viniol A. Mapping the methodological diversity of published drug discontinuation studies-a scoping review of study topics, objectives, and designs. Trials 2023; 24(1):58. doi: 10.1186/s13063-023-07105-6. Wang B, Wang H, Tu XM, Feng C. Comparisons of Superiority, Non-inferiority, and Equivalence Trials. Shanghai Arch Psychiatry 2017; 29(6):385–8. doi: 10.11919/j.issn.1002-0829.217163. Tricco AC, Lillie E, Zarin W, O'Brien KK, Colquhoun H, Levac D et al. PRISMA Extension for Scoping Reviews (PRISMA-ScR): Checklist and Explanation. Ann Intern Med 2018; 169(7):467–73. doi: 10.7326/M18-0850. Hardy BG, Shulman KI, Zucchero C. Gradual discontinuation of lithium augmentation in elderly patients with unipolar depression. J Clin Psychopharmacol 1997; 17(1):22–6. doi: 10.1097/00004714-199702000-00005. Hessen E, Lossius MI, Reinvang I, Gjerstad L. Influence of major antiepileptic drugs on attention, reaction time, and speed of information processing: results from a randomized, double-blind, placebo-controlled withdrawal study of seizure-free epilepsy patients receiving monotherapy. Epilepsia 2006; 47(12):2038–45. doi: 10.1111/j.1528-1167.2006.00805.x. Miro JM, Lopez JC, Podzamczer D, Peña JM, Alberdi JC, Martínez E et al. Discontinuation of primary and secondary Toxoplasma gondii prophylaxis is safe in HIV-infected patients after immunological restoration with highly active antiretroviral therapy: results of an open, randomized, multicenter clinical trial. Clin Infect Dis 2006; 43(1):79–89. doi: 10.1086/504872. Srivanichakorn W, Sriwijitkamol A, Kongchoo A, Sriussadaporn S, Plengvidhya N, Lertwattanarak R et al. Withdrawal of sulfonylureas from patients with type 2 diabetes receiving long-term sulfonylurea and insulin combination therapy results in deterioration of glycemic control: a randomized controlled trial. Diabetes Metab Syndr Obes 2015; 8:137–45. doi: 10.2147/DMSO.S78008. Reimer C, Bytzer P. Discontinuation of long-term proton pump inhibitor therapy in primary care patients: a randomized placebo-controlled trial in patients with symptom relapse. Eur J Gastroenterol Hepatol 2010; 22(10):1182–8. doi: 10.1097/MEG.0b013e32833d56d1. Bergh S, Selbæk G, Engedal K. Discontinuation of antidepressants in people with dementia and neuropsychiatric symptoms (DESEP study): double blind, randomised, parallel group, placebo controlled trial. BMJ 2012; 344:e1566. doi: 10.1136/bmj.e1566. Lemos KF, Rabelo-Silva ER, Ribeiro LW, Cruz LN, Polanczyk CA. Effect of nitrate withdrawal on quality of life and adherence to treatment in patients with stable angina: evidence from a randomized clinical trial. Coron Artery Dis 2014; 25(3):215–23. doi: 10.1097/MCA.0000000000000083. Lee S-H, Kwon H-S, Park Y-M, Ko S-H, Choi Y-H, Yoon K-H et al. Statin Discontinuation after Achieving a Target Low Density Lipoprotein Cholesterol Level in Type 2 Diabetic Patients without Cardiovascular Disease: A Randomized Controlled Study. Diabetes Metab J 2014; 38(1):64–73. doi: 10.4093/dmj.2014.38.1.64. Curran HV, Collins R, Fletcher S, Kee SCY, Woods B, Iliffe S. Older adults and withdrawal from benzodiazepine hypnotics in general practice: effects on cognitive function, sleep, mood and quality of life. Psychol Med 2003; 33(7):1223–37. doi: 10.1017/s0033291703008213. Chen EYH, Hui CLM, Lam MML, Chiu CPY, Law CW, Chung DWS et al. Maintenance treatment with quetiapine versus discontinuation after one year of treatment in patients with remitted first episode psychosis: randomised controlled trial. BMJ 2010; 341:c4024. doi: 10.1136/bmj.c4024. McMillan CV, Bradley C, Gibney J, Healy ML, Russell-Jones DL, Sönksen PH. Psychological effects of withdrawal of growth hormone therapy from adults with growth hormone deficiency. Clin Endocrinol (Oxf) 2003; 59(4):467–75. doi: 10.1046/j.1365-2265.2003.01870.x. Höcker B, Weber LT, Feneberg R, Drube J, John U, Fehrenbach H et al. Improved growth and cardiovascular risk after late steroid withdrawal: 2-year results of a prospective, randomised trial in paediatric renal transplantation. Nephrol Dial Transplant 2010; 25(2):617–24. doi: 10.1093/ndt/gfp506. Kendrick AM, Duncan JS, Trimble MR. Effects of discontinuation of individual antiepileptic drugs on mood. Human Psychopharmacology 1993; 8(4):263–70. doi: 10.1002/hup.470080405. Borm GF, van der Wilt GJ, Kremer JAM, Zielhuis GA. A generalized concept of power helped to choose optimal endpoints in clinical trials. J Clin Epidemiol 2007; 60(4):375–81. doi: 10.1016/j.jclinepi.2006.06.015. Borm GF, Teerenstra S, Zielhuis GA. Objective and perspective determine the choice of composite endpoint. J Clin Epidemiol 2008; 61(2):99–101. doi: 10.1016/j.jclinepi.2007.10.001. Fleming TR, DeMets DL. Surrogate end points in clinical trials: are we being misled? Ann Intern Med 1996; 125(7):605–13. doi: 10.7326/0003-4819-125-7-199610010-00011. Donner-Banzhoff N, Sönnichsen A. Strategies for prescribing statins. BMJ 2008; 336(7639):288–9. doi: 10.1136/bmj.39387.573947.80. Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebo-controlled trial. Lancet 2002; 360(9326):7–22. doi: 10.1016/S0140-6736(02)09327-3. Kulkarni S, Durham H, Glover L, Ather O, Phillips V, Nemes S et al. Metabolic adverse events associated with systemic corticosteroid therapy-a systematic review and meta-analysis. BMJ Open 2022; 12(12):e061476. doi: 10.1136/bmjopen-2022-061476. Buti M, Casillas R, Riveiro-Barciela M, Homs M, Tabernero D, Salcedo MT et al. Tenofovir discontinuation after long-term viral suppression in HBeAg negative chronic hepatitis B. Can HBsAg levels be useful? J Clin Virol 2015; 68:61–8. doi: 10.1016/j.jcv.2015.05.002. Bayliss EA, Albers K, Gleason K, Pieper LE, Boyd CM, Campbell NL et al. Recommendations for outcome measurement for deprescribing intervention studies. J Am Geriatr Soc 2022; 70(9):2487–97. doi: 10.1111/jgs.17894. Nizet P, Evin A, Brociero E, Vigneau CV, Huon J-F. Outcomes in deprescribing implementation trials and compliance with expert recommendations: a systematic review. BMC Geriatr 2023; 23(1):428. doi: 10.1186/s12877-023-04155-y. Deprescribing.org. Deprescribing guidelines and algorithms. Verfügbar unter: https://deprescribing.org/resources/deprescribing-guidelines-algorithms/. Abramowicz D, Manas D, Lao M, Vanrenterghem Y, Del Castillo D, Wijngaard P et al. Cyclosporine withdrawal from a mycophenolate mofetil-containing immunosuppressive regimen in stable kidney transplant recipients: a randomized, controlled study. Transplantation 2002; 74(12):1725–34. doi: 10.1097/00007890-200212270-00015. Andrews P, Hall JN, Snaith RP. A controlled trial of phenothiazine withdrawal in chronic schizophrenic patients. Br J Psychiatry 1976; 128:451–5. doi: 10.1192/bjp.128.5.451. Baker LA, Cheng LY, Amara IB. The withdrawal of benztropine mesylate in chronic schizophrenic patients. Br J Psychiatry 1983; 143:584–90. doi: 10.1192/bjp.143.6.584. Ballard C, Lana MM, Theodoulou M, Douglas S, McShane R, Jacoby R et al. A randomised, blinded, placebo-controlled trial in dementia patients continuing or stopping neuroleptics (the DART-AD trial). PLoS Med 2008; 5(4):e76. doi: 10.1371/journal.pmed.0050076. Bykerk V., Sampalis J., Esdaile J.M., Choquette D., Senecal J.-L., Danoff D. et al. A randomized study of the effect of withdrawing hydroxychloroquine sulfate in systemic lupus erythematosus. N Engl J Med 1991; 324(3):150–4. doi: 10.1056/NEJM199101173240303. Campbell AJ, Robertson MC, Gardner MM, Norton RN, Buchner DM. Psychotropic medication withdrawal and a home-based exercise program to prevent falls: a randomized, controlled trial. J Am Geriatr Soc 1999; 47(7):850–3. doi: 10.1111/j.1532-5415.1999.tb03843.x. Campbell JD, Moore D, Degerman R, Kaharuza F, Were W, Muramuzi E et al. HIV-infected ugandan adults taking antiretroviral therapy with CD4 counts 200 cells/μL who discontinue cotrimoxazole prophylaxis have increased risk of malaria and diarrhea. Clin Infect Dis 2012; 54(8):1204–11. doi: 10.1093/cid/cis013. Chaiwarith R, Praparattanapan J, Nuntachit N, Kotarathitithum W, Supparatpinyo K. Discontinuation of primary and secondary prophylaxis for opportunistic infections in HIV-infected patients who had CD4+ cell count <200 cells/mm(3) but undetectable plasma HIV-1 RNA: an open-label randomized controlled trial. AIDS Patient Care STDS 2013; 27(2):71–6. doi: 10.1089/apc.2012.0303. Cheng C-Y, Chen M-Y, Hsieh S-M, Sheng W-H, Sun H-Y, Lo Y-C et al. Risk of pneumocystosis after early discontinuation of prophylaxis among HIV-infected patients receiving highly active antiretroviral therapy. BMC Infect Dis 2010; 10:126. doi: 10.1186/1471-2334-10-126. Choudhury AB, Dawson CM, Kilvington HE, Eldridge S, James W-Y, Wedzicha JA et al. Withdrawal of inhaled corticosteroids in people with COPD in primary care: a randomised controlled trial. Respir Res 2007; 8(1):93. doi: 10.1186/1465-9921-8-93. Cook BL, Helms PM, Smith RE, Tsai M. Unipolar depression in the elderly. Reoccurrence on discontinuation of tricyclic antidepressants. J Affect Disord 1986; 10(2):91–4. doi: 10.1016/0165-0327(86)90031-5. Coulter DL. Withdrawal of barbiturate anticonvulsant drugs: prospective controlled study. Am J Ment Retard 1988; 93(3):320–7. Jonge JW de, Knottnerus JA, van Zutphen WM, Bruijne GA de, Struijker Boudier HA. Short term effect of withdrawal of diuretic drugs prescribed for ankle oedema. BMJ 1994; 308(6927):511–3. doi: 10.1136/bmj.308.6927.511. Farmer CKT, Hampson G, Abbs IC, Hilton RM, Koffman CG, Fogelman I et al. Late low-dose steroid withdrawal in renal transplant recipients increases bone formation and bone mineral density. Am J Transplant 2006; 6(12):2929–36. doi: 10.1111/j.1600-6143.2006.01557.x. Findlay DJ, Sharma J, McEwen J, Ballinger BR, MaClennan WJ, McHarg AM. Double‐blind controlled withdrawal of thioridazine treatment in elderly female inpatients with senile dementia. Int J Geriat Psychiatry 1989; 4(2):115–20. doi: 10.1002/gps.930040210. George J, Kitzis I, Zandorf D, Golovner M, Shapira I, Laniado S et al. Safety of nitrate withdrawal in angina-free and hemodynamically stable patients with coronary artery disease. Chest 2003; 124(5):1652–7. doi: 10.1016/s0012-3692(15)33392-4. Ghaemi SN, Ostacher MM, El-Mallakh RS, Borrelli D, Baldassano CF, Kelley ME et al. Antidepressant discontinuation in bipolar depression: a Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) randomized clinical trial of long-term effectiveness and safety. J Clin Psychiatry 2010; 71(4):372–80. doi: 10.4088/JCP.08m04909gre. Giller E, Bialos D, Harkness L, Jatlow P, Waldo M. Long-term amitriptyline in chronic depression. Hillside J Clin Psychiatry 1985; 7(1):16–33. Gleissner CA, Doesch A, Ehlermann P, Koch A, Sack FU, Katus HA et al. Cyclosporine withdrawal improves renal function in heart transplant patients on reduced-dose cyclosporine therapy. Am J Transplant 2006; 6(11):2750–8. doi: 10.1111/j.1600-6143.2006.01527.x. Gøtzsche PC, Hansen M, Stoltenberg M, Svendsen A, Beier J, Faarvang KL et al. Randomized, placebo controlled trial of withdrawal of slow-acting antirheumatic drugs and of observer bias in rheumatoid arthritis. Scand J Rheumatol 1996; 25(4):194–9. doi: 10.3109/03009749609069987. Greil W, Haag H, Rossnagl G, Rüther E. Effect of anticholinergics on tardive dyskinesia. A controlled discontinuation study. Br J Psychiatry 1984; 145:304–10. doi: 10.1192/bjp.145.3.304. Habraken H, Soenen K, Blondeel L, van Elsen J, Bourda J, Coppens E et al. Gradual withdrawal from benzodiazepines in residents of homes for the elderly: experience and suggestions for future research. Eur J Clin Pharmacol 1997; 51(5):355–8. doi: 10.1007/s002280050213. Hausberg M, Lang D, Levers A, Suwelack B, Kisters K, Tokmak F et al. Sympathetic nerve activity in renal transplant patients before and after withdrawal of cyclosporine. J Hypertens 2006; 24(5):957–64. doi: 10.1097/01.hjh.0000222767.15100.e4. Hawthorne AB, Logan RF, Hawkey CJ, Foster PN, Axon AT, Swarbrick ET et al. Randomised controlled trial of azathioprine withdrawal in ulcerative colitis. BMJ 1992; 305(6844):20–2. doi: 10.1136/bmj.305.6844.20. Hessen E, Lossius MI, Reinvang I, Gjerstad L. Slight improvement in mood and irritability after antiepileptic drug withdrawal: a controlled study in patients on monotherapy. Epilepsy Behav 2007; 10(3):449–55. doi: 10.1016/j.yebeh.2007.01.014. Hollander AA, Hene RJ, Hermans J, van Es LA, van der Woude FJ. Late prednisone withdrawal in cyclosporine-treated kidney transplant patients: a randomized study. J Am Soc Nephrol 1997; 8(2):294–301. doi: 10.1681/ASN.V82294. Jellinek T, Gardos G, Cole JO. Adverse effects of antiparkinson drug withdrawal. Am J Psychiatry 1981; 138(12):1567–71. doi: 10.1176/ajp.138.12.1567. Kim MN, Lee CK, Ahn SH, Lee S, Kim SU, Kim DY et al. Maintaining remission in lamivudine-resistant patients with a virological response to adefovir add-on lamivudine after stopping lamivudine therapy. Liver Int 2014; 34(10):1543–9. doi: 10.1111/liv.12437. Kirsten DK, Wegner RE, Jörres RA, Magnussen H. Effects of theophylline withdrawal in severe chronic obstructive pulmonary disease. Chest 1993; 104(4):1101–7. doi: 10.1378/chest.104.4.1101. Korman MG, Hetzel DJ, Hansky J, Shearman DJ, Don G. Relapse rate of duodenal ulcer after cessation of long-term cimetidine treatment: a double-blind controlled study. Dig Dis Sci 1980; 25(2):88–91. doi: 10.1007/BF01308302. Kosch M, Hausberg M, Suwelack B. Studies on effects of calcineurin inhibitor withdrawal on arterial distensibility and endothelial function in renal transplant recipients. Transplantation 2003; 76(10):1516–9. doi: 10.1097/01.TP.0000092521.57633.BD. Le Cesne A, Ray-Coquard I, Bui BN, Adenis A, Rios M, Bertucci F et al. Discontinuation of imatinib in patients with advanced gastrointestinal stromal tumours after 3 years of treatment: an open-label multicentre randomised phase 3 trial. Lancet Oncol 2010; 11(10):942–9. doi: 10.1016/S1470-2045(10)70222-9. Legendre C, Brault Y, Morales JM, Oberbauer R, Altieri P, Riad H et al. Factors influencing glomerular filtration rate in renal transplantation after cyclosporine withdrawal using sirolimus-based therapy: a multivariate analysis of results at five years. Clin Transplant 2007; 21(3):330–6. doi: 10.1111/j.1399-0012.2007.00645.x. Lémann M, Mary J-Y, Colombel J-F, Duclos B, Soule J-C, Lerebours E et al. A randomized, double-blind, controlled withdrawal trial in Crohn's disease patients in long-term remission on azathioprine. Gastroenterology 2005; 128(7):1812–8. doi: 10.1053/j.gastro.2005.03.031. Lossius MI, Hessen E, Mowinckel P, Stavem K, Erikssen J, Gulbrandsen P et al. Consequences of antiepileptic drug withdrawal: a randomized, double-blind study (Akershus Study). Epilepsia 2008; 49(3):455–63. doi: 10.1111/j.1528-1167.2007.01323.x. Maland LJ, Lutz LJ, Castle CH. Effects of withdrawing diuretic therapy on blood pressure in mild hypertension. Hypertension 1983; 5(4):539–44. doi: 10.1161/01.hyp.5.4.539. Margo A, McMahon P. Lithium withdrawal triggers psychosis. Br J Psychiatry 1982; 141:407–10. doi: 10.1192/bjp.141.4.407. Mayur PM, Gangadhar BN, Subbakrishna DK, Janakiramaiah N. Discontinuation of antidepressant drugs during electroconvulsive therapy: a controlled study. J Affect Disord 2000; 58(1):37–41. doi: 10.1016/s0165-0327(99)00096-8. McDiarmid SV, Farmer DA, Goldstein LI, Martin P, Vargas J, Tipton JR et al. A randomized prospective trial of steroid withdrawal after liver transplantation. Transplantation 1995; 60(12):1443–50. doi: 10.1097/00007890-199560120-00013. McInnis M, Petursson H. Withdrawal of trihexyphenidyl. Acta Psychiatr Scand 1985; 71(3):297–303. doi: 10.1111/j.1600-0447.1985.tb01287.x. McLennan J, Findlay DJ, Sharma J, McEwen J, Ballinger BR, MaClennan WJ et al. Prolactin response to withdrawal of thioridazine in dementia. Int J Geriat Psychiatry 1992; 7(10):739–42. doi: 10.1002/gps.930071009. Mellman TA, Uhde TW. Withdrawal syndrome with gradual tapering of alprazolam. Am J Psychiatry 1986; 143(11):1464–6. doi: 10.1176/ajp.143.11.1464. Michalská D, Stepan JJ, Basson BR, Pavo I. The effect of raloxifene after discontinuation of long-term alendronate treatment of postmenopausal osteoporosis. J Clin Endocrinol Metab 2006; 91(3):870–7. doi: 10.1210/jc.2004-2212. Mussini C, Pezzotti P, Govoni A, Borghi V, Antinori A, d'Arminio Monforte A et al. Discontinuation of primary prophylaxis for Pneumocystis carinii pneumonia and toxoplasmic encephalitis in human immunodeficiency virus type I-infected patients: the changes in opportunistic prophylaxis study. J Infect Dis 2000; 181(5):1635–42. doi: 10.1086/315471. Mussini C, Pezzotti P, Antinori A, Borghi V, Monforte Ad, Govoni A et al. Discontinuation of secondary prophylaxis for Pneumocystis carinii pneumonia in human immunodeficiency virus-infected patients: a randomized trial by the CIOP Study Group. Clin Infect Dis 2003; 36(5):645–51. doi: 10.1086/367659. Odejide OA, Aderounmu AF. Double-blind placebo substitution: withdrawal of fluphenazine decanoate in schizophrenic patients. J Clin Psychiatry 1982; 43(5):195–6. Ory-Magne F, Corvol J-C, Azulay J-P, Bonnet A-M, Brefel-Courbon C, Damier P et al. Withdrawing amantadine in dyskinetic patients with Parkinson disease: the AMANDYSK trial. Neurology 2014; 82(4):300–7. doi: 10.1212/WNL.0000000000000050. Packer M, Gheorghiade M, Young JB, Costantini PJ, Adams KF, Cody RJ et al. Withdrawal of digoxin from patients with chronic heart failure treated with angiotensin-converting-enzyme inhibitors. RADIANCE Study. N Engl J Med 1993; 329(1):1–7. doi: 10.1056/NEJM199307013290101. Pato MT, Zohar-Kadouch R, Zohar J, Murphy DL. Return of symptoms after discontinuation of clomipramine in patients with obsessive-compulsive disorder. Am J Psychiatry 1988; 145(12):1521–5. doi: 10.1176/ajp.145.12.1521. Petursson H, Gudjonsson GH, Lader MH. Psychometric performance during withdrawal from long-term benzodiazepine treatment. Psychopharmacology (Berl) 1983; 81(4):345–9. doi: 10.1007/BF00427575. Pincus T, Swearingen CJ, Luta G, Sokka T. Efficacy of prednisone 1-4 mg/day in patients with rheumatoid arthritis: a randomised, double-blind, placebo controlled withdrawal clinical trial. Ann Rheum Dis 2009; 68(11):1715–20. doi: 10.1136/ard.2008.095539. Ratcliffe PJ, Dudley CR, Higgins RM, Firth JD, Smith B, Morris PJ. Randomised controlled trial of steroid withdrawal in renal transplant recipients receiving triple immunosuppression. Lancet 1996; 348(9028):643–8. doi: 10.1016/s0140-6736(96)02510-x. Rice KL, Rubins JB, Lebahn F, Parenti CM, Duane PG, Kuskowski M et al. Withdrawal of chronic systemic corticosteroids in patients with COPD: a randomized trial. Am J Respir Crit Care Med 2000; 162(1):174–8. doi: 10.1164/ajrccm.162.1.9909066. Ruskin PE, Nyman G. Discontinuation of neuroleptic medication in older, outpatient schizophrenics. A placebo-controlled, double-blind trial. J Nerv Ment Dis 1991; 179(4):212–4. doi: 10.1097/00005053-199104000-00006. Ruths S, Straand J, Nygaard HA, Aarsland D. Stopping antipsychotic drug therapy in demented nursing home patients: a randomized, placebo-controlled study--the Bergen District Nursing Home Study (BEDNURS). Int J Geriat Psychiatry 2008; 23(9):889–95. doi: 10.1002/gps.1998. Ruths S, Straand J, Nygaard HA, Bjorvatn B, Pallesen S. Effect of antipsychotic withdrawal on behavior and sleep/wake activity in nursing home residents with dementia: a randomized, placebo-controlled, double-blinded study. The Bergen District Nursing Home Study. J Am Geriatr Soc 2004; 52(10):1737–43. doi: 10.1111/j.1532-5415.2004.52470.x. Saksa JR, Baker CB, Woods SW. Mood-stabilizer-maintained, remitted bipolar patients: taper and discontinuation of adjunctive antipsychotic medication. Gen Hosp Psychiatry 2004; 26(3):233–6. doi: 10.1016/j.genhosppsych.2004.02.002. Sampath G, Shah A, Krska J, Soni SD. Neuroleptic discontinuation in the very stable schizophrenic patient: Relapse rates and serum neuroleptic levels. Human Psychopharmacology 1992; 7(4):255–64. doi: 10.1002/hup.470070405. Schnuelle P, van der Heide JH, Tegzess A, Verburgh CA, Paul LC, van der Woude FJ et al. Open randomized trial comparing early withdrawal of either cyclosporine or mycophenolate mofetil in stable renal transplant recipients initially treated with a triple drug regimen. J Am Soc Nephrol 2002; 13(2):536–43. doi: 10.1681/ASN.V132536. Smak Gregoor PJH, Sévaux RGL de, Ligtenberg G, Hoitsma AJ, Hené RJ, Weimar W et al. Withdrawal of cyclosporine or prednisone six months after kidney transplantation in patients on triple drug therapy: a randomized, prospective, multicenter study. J Am Soc Nephrol 2002; 13(5):1365–73. doi: 10.1097/01.asn.0000013298.11876.bf. Stellon AJ, Keating JJ, Johnson PJ, McFarlane IG, Williams R. Maintenance of remission in autoimmune chronic active hepatitis with azathioprine after corticosteroid withdrawal. Hepatology 1988; 8(4):781–4. doi: 10.1002/hep.1840080414. Stellon AJ, Hegarty JE, Portmann B, Williams R. Randomised controlled trial of azathioprine withdrawal in autoimmune chronic active hepatitis. Lancet 1985; 1(8430):668–70. doi: 10.1016/s0140-6736(85)91329-7. Takata Y, Yoshizumi T, Ito Y, Ueno M, Tsukashima A, Iwase M et al. Comparison of withdrawing antihypertensive therapy between diuretics and angiotensin converting enzyme inhibitors in essential hypertensives. Am Heart J 1992; 124(6):1574–80. doi: 10.1016/0002-8703(92)90075-7. Tengstrand B, Larsson E, Klareskog L, Hafström I. Randomized withdrawal of long-term prednisolone treatment in rheumatoid arthritis: effects on inflammation and bone mineral density. Scand J Rheumatol 2007; 36(5):351–8. doi: 10.1080/03009740701394021. Thielen N, van der Holt B, Cornelissen JJ, Verhoef GEG, Gussinklo T, Biemond BJ et al. Imatinib discontinuation in chronic phase myeloid leukaemia patients in sustained complete molecular response: a randomised trial of the Dutch-Belgian Cooperative Trial for Haemato-Oncology (HOVON). Eur J Cancer 2013; 49(15):3242–6. doi: 10.1016/j.ejca.2013.06.018. Tse W, Frisina PG, Hälbig TD, Gracies J-M, Liang L, Tarshish C et al. The effects of withdrawal of dopaminergic medication in nursing home patients with advanced parkinsonism. J Am Med Dir Assoc 2008; 9(9):670–5. doi: 10.1016/j.jamda.2008.07.001. Ulfvarson J, Adami J, Wredling R, Kjellman B, Reilly M, Bahr C von. Controlled withdrawal of selective serotonin reuptake inhibitor drugs in elderly patients in nursing homes with no indication of depression. Eur J Clin Pharmacol 2003; 59(10):735–40. doi: 10.1007/s00228-003-0687-y. Ungvari GS, Chiu HF, Lam LC, Pang AH, Chung DW, Li SW et al. Gradual withdrawal of long-term anticholinergic antiparkinson medication in Chinese patients with chronic schizophrenia. J Clin Psychopharmacol 1999; 19(2):141–8. doi: 10.1097/00004714-199904000-00009. Uretsky BF, Young JB, Shahidi FE, Yellen LG, Harrison MC, Jolly MK. Randomized study assessing the effect of digoxin withdrawal in patients with mild to moderate chronic congestive heart failure: results of the PROVED trial. PROVED Investigative Group. J Am Coll Cardiol 1993; 22(4):955–62. doi: 10.1016/0735-1097(93)90403-n. van den Ham ECH, Kooman JP, Christiaans ML, van Hooff JP. The influence of early steroid withdrawal on body composition and bone mineral density in renal transplantation patients. Transpl Int 2003; 16(2):82–7. doi: 10.1007/s00147-002-0488-8. van der Leeden H, Dijkmans BA, Hermans J, Cats A. A double-blind study on the effect of discontinuation of gold therapy in patients with rheumatoid arthritis. Clin Rheumatol 1986; 5(1):56–61. doi: 10.1007/BF02030968. van Herwaarden N, van der Maas A, Minten MJM, van den Hoogen FHJ, Kievit W, van Vollenhoven RF et al. Disease activity guided dose reduction and withdrawal of adalimumab or etanercept compared with usual care in rheumatoid arthritis: open label, randomised controlled, non-inferiority trial. BMJ 2015; 350:h1389. doi: 10.1136/bmj.h1389. van Kraaij DJ, Jansen RW, Bouwels LH, Gribnau FW, Hoefnagels WH. Furosemide withdrawal in elderly heart failure patients with preserved left ventricular systolic function. Am J Cardiol 2000; 85(12):1461–6. doi: 10.1016/s0002-9149(00)00795-5. van Kraaij DJ, Jansen RW, Bouwels LH, Hoefnagels WH. Furosemide withdrawal improves postprandial hypotension in elderly patients with heart failure and preserved left ventricular systolic function. Arch Intern Med 1999; 159(14):1599–605. doi: 10.1001/archinte.159.14.1599. van Kraaij DJW, Jansen RWMM, Sweep FCGJ, Hoefnagels WHL. Neurohormonal effects of furosemide withdrawal in elderly heart failure patients with normal systolic function. Eur J Heart Fail 2003; 5(1):47–53. doi: 10.1016/s1388-9842(02)00205-2. van Reekum R, Clarke D, Conn D, Herrmann N, Eryavec G, Cohen T et al. A randomized, placebo-controlled trial of the discontinuation of long-term antipsychotics in dementia. Int Psychogeriatr 2002; 14(2):197–210. doi: 10.1017/s1041610202008396. Vibhagool A, Sungkanuparph S, Mootsikapun P, Chetchotisakd P, Tansuphaswaswadikul S, Bowonwatanuwong C et al. Discontinuation of secondary prophylaxis for cryptococcal meningitis in human immunodeficiency virus-infected patients treated with highly active antiretroviral therapy: a prospective, multicenter, randomized study. Clin Infect Dis 2003; 36(10):1329–31. doi: 10.1086/374849. Vilien M, Dahlerup JF, Munck LK, Nørregaard P, Grønbaek K, Fallingborg J. Randomized controlled azathioprine withdrawal after more than two years treatment in Crohn's disease: increased relapse rate the following year. Aliment Pharmacol Ther 2004; 19(11):1147–52. doi: 10.1111/j.1365-2036.2004.01944.x. Walma EP, Hoes AW, van Dooren C, Prins A, van der Does E. Withdrawal of long-term diuretic medication in elderly patients: a double blind randomised trial. BMJ 1997; 315(7106):464–8. doi: 10.1136/bmj.315.7106.464. Wenzl HH, Primas C, Novacek G, Teml A, Öfferlbauer-Ernst A, Högenauer C et al. Withdrawal of long-term maintenance treatment with azathioprine tends to increase relapse risk in patients with Crohn's disease. Dig Dis Sci 2015; 60(5):1414–23. doi: 10.1007/S10620-014-3419-5. Wistedt B. A depot neuroleptic withdrawal study. A controlled study of the clinical effects of the withdrawal of depot fluphenazine decanoate and depot flupenthixol decanoate in chronic schizophrenic patients. Acta Psychiatr Scand 1981; 64(1):65–84. doi: 10.1111/j.1600-0447.1981.tb00761.x. Wolde S ten, Breedveld FC, Hermans J, Vandenbroucke JP, van de Laar MA, Markusse HM et al. Randomised placebo-controlled study of stopping second-line drugs in rheumatoid arthritis. Lancet 1996; 347(8998):347–52. doi: 10.1016/s0140-6736(96)90535-8. Wunderink L, Nienhuis FJ, Sytema S, Slooff CJ, Knegtering R, Wiersma D. Guided discontinuation versus maintenance treatment in remitted first-episode psychosis: relapse rates and functional outcome. J Clin Psychiatry 2007; 68(5):654–61. doi: 10.4088/jcp.v68n0502. Zhu Q, Zhao Y, Liu W, Luo H, Qiu Y, Gao Z. Two-year observation of a randomized trial on tacrolimus-based therapy with withdrawal of steroids or mycophenolate mofetil after renal transplantation. Chin Med Sci J 2008; 23(4):244–8. doi: 10.1016/S1001-9294(09)60047-X. Additional Declarations Competing interest reported. NK, NG, IS, AB and AV declare that they have no competing interests NDB is co-chairman of Gesellschaft für Patientenzentrierte Kommunikation, a non-profit organization developing and distributing the decision-support software arriba, which among others includes a module for drug discontinuation. Supplementary Files SupplementaryTable1CharacteristicsTrials.docx PRISMAScRChecklistv2.pdf Cite Share Download PDF Status: Published Journal Publication published 27 May, 2025 Read the published version in BMC Medical Research Methodology → Version 1 posted Editorial decision: Accepted 15 May, 2025 Reviews received at journal 14 May, 2025 Reviewers agreed at journal 27 Apr, 2025 Reviewers agreed at journal 20 Apr, 2025 Reviews received at journal 18 Apr, 2025 Reviewers agreed at journal 18 Apr, 2025 Reviewers invited by journal 18 Apr, 2025 Submission checks completed at journal 17 Apr, 2025 First submitted to journal 17 Apr, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-5929100","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":445003288,"identity":"70dbbcd8-a970-4cd2-a275-2a39373211d8","order_by":0,"name":"Nele 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1","display":"","copyAsset":false,"role":"figure","size":208527,"visible":true,"origin":"","legend":"\u003cp\u003ePRISMA flow diagram (15)\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-5929100/v1/26a4587aa9c09fdb47ffc911.png"},{"id":83782721,"identity":"544839ae-a768-4de5-89ac-dbaeeab492e5","added_by":"auto","created_at":"2025-06-02 16:01:45","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2061406,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5929100/v1/84c53b23-2a8f-495b-81d8-71a116f51666.pdf"},{"id":81693885,"identity":"6137fe47-4b0d-4754-a5a8-740660e38ffd","added_by":"auto","created_at":"2025-04-30 11:50:24","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":286900,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementaryTable1CharacteristicsTrials.docx","url":"https://assets-eu.researchsquare.com/files/rs-5929100/v1/2cfd3fc9ec6a0028ad6fcc68.docx"},{"id":81692498,"identity":"3be85211-ac77-40d4-85b7-6b5c7c0b0962","added_by":"auto","created_at":"2025-04-30 11:42:24","extension":"pdf","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":509364,"visible":true,"origin":"","legend":"","description":"","filename":"PRISMAScRChecklistv2.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5929100/v1/f0f0afd18aa4db7da5b179ef.pdf"}],"financialInterests":"Competing interest reported. NK, NG, IS, AB and AV declare that they have no competing interests\nNDB is co-chairman of Gesellschaft für Patientenzentrierte Kommunikation, a non-profit organization developing and distributing the decision-support software arriba, which among others includes a module for drug discontinuation.","formattedTitle":"Trials evaluating drug discontinuation: a scoping review sub-analysis focusing on outcomes and research questions","fulltext":[{"header":"Introduction","content":"\u003cdiv id=\"Sec2\" class=\"Section2\"\u003e \u003ch2\u003eRationale\u003c/h2\u003e \u003cp\u003eMany chronic conditions that were once treatable only symptomatically are now amenable to long-term pharmacological therapy, improving patients\u0026rsquo; long-term prognosis. Randomized controlled trials (RCTs) have established a robust evidence base for the safe and effective treatment of chronic diseases, such as heart failure (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e), asthma(\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e) or rheumatoid arthritis (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e). Nevertheless, these improvements have contributed to a growing concern: polypharmacy. Since the prevalence of most chronic conditions increases with age (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e), older persons are particularly affected, often receiving multiple concurrent prescriptions (\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e). Even when each drug is evidence-based and appropriate on its own, their combination may lead to adverse effects, drug interactions, and an increased risk of medication errors (\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e). Indeed, adverse drug reactions represent a major cause of hospital admissions (\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e). Polypharmacy has become an urgent topic for health policy, practice and research (\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eDiscontinuing drugs that no longer offer a favorable benefit\u0026ndash;risk ratio for the individual patient appears to be a logical response to this dilemma.\u003c/p\u003e \u003cp\u003eHowever, scientific evidence supporting this approach remains limited\u0026mdash;especially when compared to the extensive research on initial drug prescribing. Concerns about potential harms, such as withdrawal symptoms or disease recurrence, further contribute to uncertainty and may impede the discontinuation of drugs in practice (\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eClinicians considering drug discontinuation and researchers studying this process face two main challenges: 1) treating the underlying condition for which the drug was prescribed, and 2) addressing the potential disadvantages of the treatment. While the latter motivates critical evaluation of the drug, the former must be carefully considered to avoid harm from under-treatment. Achieving a high drug discontinuation rate, whether in clinical practice or research, is not a success in itself. For instance, if patients experience harmful consequences such as disease flare-ups after discontinuation, the results of such studies may be ambiguous, and the implications for future care may be unclear. Thus, drug discontinuation studies often raise complex questions that extend beyond those typically addressed in studies of drug safety and efficacy.\u003c/p\u003e \u003cp\u003eTo gain a deeper understanding of the complexities of discontinuation studies, our research group has developed a typology that categorizes the different scientific questions related to drug discontinuation and offers type-specific methodological recommendations(\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e). Among these, type 1 research questions, which concern doubts about the effectiveness and/or safety of a drug, are the focus of this paper.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eObjectives\u003c/h2\u003e \u003cp\u003eThe selection of appropriate outcomes is crucial in this context, as it must align with the motivations for discontinuation while addressing both the challenges of treating the condition and evaluating the potential disadvantages of the treatment. Based on a systematic review of studies evaluating drug discontinuation (\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e), we analysed a subset of RCTs included in this paper. Our objectives were to: 1) assess the authors' motivations for conducting drug discontinuation studies, 2) examine how they addressed the dual challenges of treatment efficacy and discontinuation disadvantages, and 3) explore the outcomes they selected to evaluate these issues. Throughout the paper, we use the terms \u0026ldquo;drug withdrawal\u0026rdquo; and \u0026ldquo;drug discontinuation\u0026rdquo; interchangeably.\u003c/p\u003e \u003c/div\u003e"},{"header":"Methods","content":"\u003ch3\u003eEligibility Criteria\u003c/h3\u003e\n\u003cp\u003eIn this scoping review, we identified studies on drug discontinuation, irrespective of the specific drug, disease, or outcome. For this analysis, we used a subset of the review by Grede et al. (13), consisting exclusively of RCTs\u0026nbsp;classified as type 1 drug discontinuation studies, according to Viniol et al.\u0026nbsp;(12). These studies focus on discontinuation due to concerns about the efficacy or safety of continued drug therapy.\u003c/p\u003e\n\u003cp\u003eWe included only original studies with a prospective RCT design. RCTs provide the highest level of evidence for evaluating the effects of drug discontinuation in clinical practice and represent the methodological standard that future discontinuation studies should adhere to. Eligible studies examined the discontinuation of at least one drug, focusing either on a single agent or one from the same pharmacological class. Type 2 and type 3 studies, which evaluate structured discontinuation procedures or complex discontinuation strategies, were excluded.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eWe also excluded case reports with only one participant, studies that did not involve humans, and studies that have not been published in English, German, Spanish, or French. Retrospective studies were not included to ensure methodological consistency and avoid bias related to data collection and confounding variables. Observational studies, including cohort and case-control studies, were excluded to maintain comparability across trials.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eFurthermore, studies investigating on-demand medications were not considered, as these do not reflect continuous pharmacological treatment. Trials in which a drug was introduced and then discontinued as part of the study to demonstrate efficacy were also excluded, as these studies do not align with the aim of evaluating the discontinuation of established long-term therapies. Finally, we excluded studies focused on substitution therapies in the context of substance abuse or addiction due to their distinct clinical and methodological nature.\u0026nbsp;\u003c/p\u003e\n\u003ch3\u003eInformation Sources and Search Strategy\u003c/h3\u003e\n\u003cp\u003eThe dataset was obtained following the systematic search strategy developed by Grede et al (13). The search encompassed multiple databases, including Medline (PubMed), The Cochrane Library, EMBASE, CINAHL, Web of Science, and PsycINFO. The original search was conducted in January 2016 and subsequently updated in March 2021 to include all references published up to the end of 2020. Search terms comprised \u0026ldquo;discontinuation\u0026rdquo; along with relevant synonyms, as well as the MeSH terms \u0026ldquo;Safety-Based Drug Withdrawals\u0026rdquo; and \u0026ldquo;Drug Therapy.\u0026rdquo; A comprehensive description of the search methodology, including detailed examples for Medline, is available in the Supplementary Material of our previous publication (13). \u0026nbsp;\u003c/p\u003e\n\u003ch3\u003eData Charting Process\u003c/h3\u003e\n\u003cp\u003eTo describe the sample, we extracted bibliographic data, including funding information, from all included studies (see Table 1). The investigated drugs were classified into distinct pharmacological groups (see Table 1). \u0026nbsp;A pharmacological group was then redefined when medications from at least two studies could be assigned to it. This led to the creation of the category \u0026quot;Other drugs for chronic conditions\u0026quot;, which includes pharmacological subclasses that appeared only once in the sample. An overview of the subclasses can be found in Table 1.\u003c/p\u003e\n\u003cp\u003eWe extracted information regarding the motivation for drug discontinuation, primary outcomes, and study hypotheses. Initially, the original wording was documented and then summarized and categorized. Categories were iteratively developed and validated by the study team. Data extraction was performed by IS, with ambiguous cases discussed with NDB, AV, and NK. \u0026nbsp;\u003c/p\u003e\n\u003ch3\u003eKey Data Items and Synthesis of Results\u003c/h3\u003e\n\u003cp\u003eWe extracted and analyzed key aspects of each included study to understand how drug discontinuation was conceptualized and evaluated.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMotivation for evaluating drug discontinuation\u003c/strong\u003e: We first identified the \u0026ldquo;initial therapeutic objective\u0026rdquo; of each drug, as specified by the authors (e.g., cure, prophylaxis). Subsequently, we grouped the reported reasons for drug discontinuation into predefined categories, such as \u0026ldquo;side effects\u0026rdquo; and \u0026ldquo;doubts about the benefits of the drug.\u0026rdquo; A complete list of these categories and their definitions is provided in Table 2.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePrimary outcomes:\u0026nbsp;\u003c/strong\u003eWe recorded whether the primary outcome was explicitly defined, could be inferred from contextual information (e.g., sample size calculation), or was not discernible. The category \u0026ldquo;structure of primary outcome(s)\u0026rdquo; differentiates between single outcomes, composite outcomes (i.e., the endpoint occurs if any of several events occur, such as death, myocardial infarction, or stroke), co-primary outcomes (i.e., two or more distinct endpoints must be met), and multiple outcomes (neither co-primary nor composite) (see Table 3).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe category \u0026ldquo;type of outcome\u0026rdquo; classifies primary outcomes as either clinical (e.g., symptoms, quality of life, mortality), subclinical (e.g., biochemical test results, imaging findings), or a combination of both. In addition, the discontinuation rate was included in this category. The discontinuation rate is defined as the proportion of patients who resumed medication following an initial discontinuation. We also categorized the primary outcome based on the clinical challenge it addresses: whether it aims to justify continued treatment (Justification of Treatment, JT), justify withdrawal (Justification of Withdrawal, JW), or both. Finally, we categorized the role of \u0026quot;time\u0026quot; in defining the endpoint (e.g., number of events during follow-up or time to event). Further details and definitions of the categories of interest can be found in Table 3.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStudy hypotheses:\u003c/strong\u003e In the first step, we mapped the study hypotheses\u0026mdash;when explicitly stated by the authors\u0026mdash;to current definitions of \u0026ldquo;superiority\u0026rdquo; or \u0026ldquo;non-inferiority\u0026rdquo; designs\n \u003c!--[if supportFields]\u003e\u003cspan style='mso-element:field-begin'\u003e\u003c/span\u003eADDIN CitaviPlaceholder{{"$id":"1","$type":"SwissAcademic.Citavi.Citations.WordPlaceholder, SwissAcademic.Citavi","Entries":[{"$id":"2","$type":"SwissAcademic.Citavi.Citations.WordPlaceholderEntry, SwissAcademic.Citavi","Id":"9043d52d-3dd9-45cc-94ab-4250ed6baa4c","RangeLength":4,"ReferenceId":"7d3cec0c-81e9-40b1-a851-edaec3acf23d","PageRange":{"$id":"3","$type":"SwissAcademic.PageRange, SwissAcademic","EndPage":{"$id":"4","$type":"SwissAcademic.PageNumber, 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Trials","Translators":[],"Volume":"29","Year":"2017","YearResolved":"2017","CreatedBy":"_Korndern_h","CreatedOn":"2024-12-12T20:21:05","ModifiedBy":"_Korndern_h","Id":"7d3cec0c-81e9-40b1-a851-edaec3acf23d","ModifiedOn":"2025-04-17T13:37:20","Project":{"$ref":"8"}},"UseNumberingTypeOfParentDocument":false}],"FormattedText":{"$id":"22","Count":1,"TextUnits":[{"$id":"23","FontStyle":{"$id":"24","Neutral":true},"ReadingOrder":1,"Text":"(14)"}]},"Tag":"CitaviPlaceholder#69da39c4-b6e8-4f65-adea-58a394447515","Text":"(14)","WAIVersion":"6.19.0.0"}}\u003cspan style='mso-element:field-separator'\u003e\u003c/span\u003e\u003c![endif]--\u003e(14)\n \u003c!--[if supportFields]\u003e\u003cspan style='mso-element:field-end'\u003e\u003c/span\u003e\u003c![endif]--\u003e. This classification was only possible when the hypothesis was clearly stated, which was not always the case. Therefore, we created the category \u0026ldquo;no specification in the text\u0026rdquo; for studies in which the hypothesis was either not identifiable or not mentioned. In the second step, we evaluated the hypotheses or research questions based on their context and clinical relevance, which led to the category \u0026ldquo;appropriate hypotheses according to us.\u0026rdquo; For this classification, two authors (IS, NDB) independently assessed and categorized the hypotheses of the included studies as either superiority or non-inferiority. Each author conducted the classification independently. In cases of agreement, the categorization was accepted; in cases of disagreement, a third author (AV) reviewed the study and made the final decision (see Table 4).\u003c/p\u003e\n\u003ch3\u003eStatistical Analysis\u003c/h3\u003e\n\u003cp\u003eWe calculated descriptive statistics (frequencies and percentages) for each extracted category. All statistical analyses were performed with SPSS software (v 22.0; IBM Corporation, Armonk, NY, USA).\u003c/p\u003e"},{"header":"Results","content":"\u003ch3\u003eStudy Selection\u003c/h3\u003e\n\u003cp\u003eThe scoping review by Grede et al. (13) identified 581 discontinuation studies. Among them were 189 RCTs, of which 103 were type-1 drug discontinuation studies. Finally, 111 articles were selected for analysis, eight of which are associated with one of five studies that published multiple papers contributing to the analysis presented here (see Figure 1). The numbers of records identified, screened, excluded, and included are shown in the PRISMA\u0026mdash;ScR flow diagram (15) (Fig. 1).\u003c/p\u003e\n\u003ch3\u003eCharacteristics of Included Studies\u003c/h3\u003e\n\u003cp\u003eThe majority of the studies we investigated were from Europe (62.1%) and the USA (21.4%). These studies have been published since the late 1970s, with a peak between 1990 and 2009 (61.1%) (see Table 1). In total, we identified and grouped the discontinued substances into 12 distinct drug classes. The 103 included trials evaluated drugs from a range of pharmacological classes, with the most common being immunosuppressants (18.4%) and antipsychotics (20.4%). An overview of the drug classes can be found in Table 1.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eIn 58 studies (56.3%), the discontinuation of a single, prespecified drug was investigated (e.g., \u0026nbsp;lithium for the treatment of depression (16)). In 39 studies (37.9%), the discontinued medication was selected from a drug class\u0026mdash;such as antiepileptic drugs (AEDs), including carbamazepine, valproate, phenytoin, phenobarbital, or lamotrigine (17). 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\u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eno. (%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"5\" valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ePublication year\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 302px;\"\u003e\n \u003cp\u003e1976-79\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003e1 (1.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 302px;\"\u003e\n \u003cp\u003e1980-89\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003e21 (20.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 302px;\"\u003e\n \u003cp\u003e1990-99\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003e23 (22.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 302px;\"\u003e\n \u003cp\u003e2000-09\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003e40 (38,8)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 302px;\"\u003e\n \u003cp\u003e2010-20\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003e18 (17.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"6\" valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eRegion\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 302px;\"\u003e\n \u003cp\u003eUSA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003e22 (21.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 302px;\"\u003e\n \u003cp\u003eSouth America\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003e2 (1.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 302px;\"\u003e\n \u003cp\u003eAfrica\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003e2 (1.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 302px;\"\u003e\n \u003cp\u003eEurope\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003e64 (62.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 302px;\"\u003e\n \u003cp\u003eAsia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003e11 (10.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 302px;\"\u003e\n \u003cp\u003eOceania\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003e2 (1.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"12\" valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eEvaluated (discontinued) active substances\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 302px;\"\u003e\n \u003cp\u003eImmunosuppressants\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003e19 (18.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 302px;\"\u003e\n \u003cp\u003eSteroids\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003e11 (10.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 302px;\"\u003e\n \u003cp\u003eAntiepileptic drugs\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003e6 (5.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 302px;\"\u003e\n \u003cp\u003eAntidepressants\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003e10 (9,7)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 302px;\"\u003e\n \u003cp\u003eAntipsychotics\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003e21 (20.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 302px;\"\u003e\n \u003cp\u003eInfection prophylaxis in chronic diseases\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003e6 (5.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 302px;\"\u003e\n \u003cp\u003eAntihypertensive agents\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003e9 (8.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 302px;\"\u003e\n \u003cp\u003eSedatives and Anxiolytics\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003e5 (4.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 302px;\"\u003e\n \u003cp\u003eCardiac glycosides\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003e2 (1.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 302px;\"\u003e\n \u003cp\u003eAntiviral agents\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003e2 (1.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 302px;\"\u003e\n \u003cp\u003eAcid suppressive agents\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003e2 (1.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 302px;\"\u003e\n \u003cp\u003eOther drugs for chronic conditions (e.g.\u0026nbsp;Alendronate for the treatment of osteoporosis or Theophylline for the treatment of\u0026nbsp;Chronic Obstructive Pulmonary Disease)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003e10 (9.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"4\" valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eFollow up time\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e(Period after the medication has been discontinued / phased out in a study participant)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 302px;\"\u003e\n \u003cp\u003e\u0026le;\u0026nbsp;6 months\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003e40 (38.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 302px;\"\u003e\n \u003col start=\"7\"\u003e\n \u003cli\u003emonth\u003c/li\u003e\n \u003c/ol\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003e18 (17.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 302px;\"\u003e\n \u003cp\u003e\u0026gt; 1 year\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003e18 (17.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 302px;\"\u003e\n \u003cp\u003eNot specified\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003e27 (26.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"4\" valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eFunding by\u0026nbsp;\u003c/strong\u003e(n=113)\u003c/p\u003e\n \u003cp\u003e(more than one funding source in 9 studies)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 302px;\"\u003e\n \u003cp\u003ePharmaceutical industries\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003e14 (12.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 302px;\"\u003e\n \u003cp\u003eGovernmental institutions\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003e24 (21.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 302px;\"\u003e\n \u003cp\u003eVoluntary Foundations\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003e19 (16.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 302px;\"\u003e\n \u003cp\u003eNot specified\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003e56 (49.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cem\u003eTable 1: This table summarizes the characteristics of the 103 drug discontinuation trials, including publication year, region, active substances evaluated, follow-up time after discontinuation, and funding sources\u003c/em\u003e\u003c/p\u003e\n\u003ch3\u003eMotivation for Treatment and Drug Discontinuation\u003c/h3\u003e\n\u003cp\u003eNearly two-thirds (62.1%) of the drugs analyzed were initially prescribed to improve the prognosis of a chronic disease, such as statins for coronary heart disease (see Table 2). \u003cstrong\u003eApproximately one-third (31.1 %) was administered for symptom control.\u0026nbsp;\u003c/strong\u003eDiscontinuation studies involving drugs originally prescribed for curative (2.9 %) or prophylactic (4.9 %) purposes were comparatively rare.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eIn nearly 40% of the studies, side effects were the primary reason for investigating drug discontinuation.\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003eThis was particularly relevant in patients with stable disease, where long-term treatment caused frequent or severe adverse effects. Common examples include antiepileptics, antipsychotics, diuretics, glucocorticoids, and other immunosuppressants.\u003c/p\u003e\n\u003cp\u003eIn more than half of the studies (53.4%) discontinuation was motivated by uncertainty regarding the clinical benefit of the drug or used as an indirect method of evaluating its efficacy (see Table 2).\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003eThis was especially relevant for antidepressants and antipsychotics. For instance, the DESEP study examined dementia patients receiving long-term antidepressants and monitored depressive symptoms following discontinuation\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;\n \u003c!--[if supportFields]\u003e\u003cspan style='mso-element:field-begin'\u003e\u003c/span\u003e\u003cb\u003eADDIN 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style='mso-element:field-separator'\u003e\u003c/span\u003e\u003c![endif]--\u003e\u003cstrong\u003e(21)\u003c/strong\u003e\n \u003c!--[if supportFields]\u003e\u003cspan style='mso-element:field-end'\u003e\u003c/span\u003e\u003c![endif]--\u003e\u003c/strong\u003e\u003cstrong\u003e.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA smaller proportion of studies (4.9%) investigated drugs that had entered clinical use prior to the implementation of rigorous trial requirements. In these cases, discontinuation served as a means to assess real-world effectiveness\u0026mdash;such as in studies on long-term nitrate therapy for angina (22).\u003c/p\u003e\n\u003cp\u003eIn a few cases (2.9%), discontinuation was part of an intentional therapy adjustment, typically after a predefined treatment target had been reached \u003cstrong\u003e(see Table 2).\u003c/strong\u003e One example is the RCT by Lee et al. (23), in which statins were discontinued after achieving a target LDL cholesterol level.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 2: Overview of drugs under study in the included trials (n = 103)\u003c/strong\u003e\u003c/p\u003e\n\u003ctable style=\"width: 4.5e+2pt;\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd\u003e\u0026nbsp;\u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\u0026nbsp;\u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eno. (%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"4\"\u003e\n \u003cp\u003e\u003cstrong\u003eInitial therapeutic objective\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eSymptom control\u003c/strong\u003e - alleviation of discomfort, but no effect on the underlying disease (for example: Analgesic for pain syndromes or Metoclopramid or nausea)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e32 (31.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eCure\u003c/strong\u003e - causal treatment of the disease; with the aim of cure (for example: H2-receptor antagonist for duodenal ulcer)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e2 (1.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003ePrognostic improvement\u003c/strong\u003e - disease modification (for example: ACE inhibitor for heart failure or statin for coronary heart disease)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e64 (62.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eProphylaxis\u003c/strong\u003e - currently non-existent but impending problem is to be prevented (for example: Antifungal drug to prevent mycosis in HIV)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e5 (4.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"4\"\u003e\n \u003cp\u003e\u003cstrong\u003eMotive for investigating drug discontinuation from the author\u0026rsquo;s perspective\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eSide effects of drug\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e40 (38.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eDoubts about the benefit of drug (unclear/low/absent benefit) or indirectly proof of efficacy by discontinuation\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e55 (53.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eEstablished therapy despite low evidence level\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e5 (4.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eModified therapy regime in course of time\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e3 (2.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eTable 2: This table summarizes the initial therapeutic objectives and the motivations for investigating drug discontinuation in the 103 included trials.\u003c/em\u003e\u003c/strong\u003e\u003cem\u003e\u0026nbsp;\u003c/em\u003e\u003c/p\u003e\n\u003ch3\u003ePrimary Outcome Definitions\u0026nbsp;\u003c/h3\u003e\n\u003cp\u003eIn 66% of the studies primary outcomes were explicitly defined. In approximately one-third, the outcome was not directly stated but could be inferred from contextual information such as the sample size calculation. In a small proportion of studies (4.9%), no primary outcome could be discerned (see Table 3).\u003c/p\u003e\n\u003cp\u003eMost studies used a single primary outcome; composite and co-primary outcomes were relatively uncommon. Clinical endpoints were employed in the majority of trials (59.2%), while subclinical or mixed outcomes were used less frequently. Only a small subset of studies (5%) included discontinuation rates as part of the primary outcome\u003cstrong\u003e\u0026nbsp;(see Table 3).\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe majority of trials (65.0 %) focused on outcomes related to the condition for which the drug had originally been prescribed (JT). In these cases, researchers typically monitored symptom deterioration, relapse, or adverse events following discontinuation. Demonstrating that the discontinuation of therapy does not lead to clinical worsening is highly relevant. Thus, such studies are ideally based on a non-inferiority design, including a clearly defined non-inferiority margin and appropriate sample size calculation.\u003c/p\u003e\n\u003cp\u003eIn 20.4% of studies, outcomes were selected to assess the disadvantages of ongoing therapy (JW) such as side effects, costs, or patient burden. Here, superiority hypotheses are generally more appropriate, as they test whether discontinuation leads to measurable improvements compared to continuation.\u003c/p\u003e\n\u003cp\u003eBoth JT and JW challenges were reflected in 10 out of 103 studies. For instance, Curran et al. (24) investigated benzodiazepine withdrawal. Improvements in cognitive function and psychomotor performance supported discontinuation (JW), while outcomes such as mood, sleep, and quality of life reflected the original treatment intent (JT).\u003c/p\u003e\n\u003cp\u003eRegarding temporal orientation, the majority of primary outcomes (66%) were based on the number of events occurring during follow-up. Fewer studies employed time-to-event or pre-post comparisons (see Table 3).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 3: Overview of primary outcome definitions and challenges (n = 103)\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"606\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 133px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 330px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 144px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eno. (%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"3\" valign=\"top\" style=\"width: 133px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ePresentation of primary outcome\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 330px;\"\u003e\n \u003cp\u003ePrimary Outcome(s) explicitly defined in article\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 144px;\"\u003e\n \u003cp\u003e68 (66.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 330px;\"\u003e\n \u003cp\u003ePrimary Outcome(s) not explicitly described, but can be assumed from context or the section on sample size calculation\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 144px;\"\u003e\n \u003cp\u003e30 (29.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 330px;\"\u003e\n \u003cp\u003eNo primary outcome(s) discernible\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 144px;\"\u003e\n \u003cp\u003e5 (4.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"5\" valign=\"top\" style=\"width: 133px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eStructure of primary\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003eoutcome(s)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 330px;\"\u003e\n \u003cp\u003eSingle\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 144px;\"\u003e\n \u003cp\u003e69 (67)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 330px;\"\u003e\n \u003cp\u003eComposite outcome\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 144px;\"\u003e\n \u003cp\u003e11 (10.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 330px;\"\u003e\n \u003cp\u003eCo-primary outcome\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 144px;\"\u003e\n \u003cp\u003e5 (4.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 330px;\"\u003e\n \u003cp\u003eMultiple outcomes, neither composite nor co-primary\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 144px;\"\u003e\n \u003cp\u003e13 (12.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 330px;\"\u003e\n \u003cp\u003eNo primary outcome(s) discernible\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 144px;\"\u003e\n \u003cp\u003e5 (4.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"5\" valign=\"top\" style=\"width: 133px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eType of primary outcome\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 330px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eDiscontinuation rate\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 144px;\"\u003e\n \u003cp\u003e5 (4.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 330px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eSubclinical\u0026nbsp;\u003c/strong\u003e- endpoint not noticeable to the patient\u0026nbsp;\u003cbr\u003e(e.g. laboratory values, imaging findings)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 144px;\"\u003e\n \u003cp\u003e26 (25.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 330px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eClinical\u003c/strong\u003e \u0026ndash; endpoints noticeable for the patient\u0026nbsp;\u003cbr\u003e(e.g. symptoms, quality of life, morbidity, death)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 144px;\"\u003e\n \u003cp\u003e61 (59.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 330px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eCombination of subclinical and clinical endpoint\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 144px;\"\u003e\n \u003cp\u003e6 (5.8)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 330px;\"\u003e\n \u003cp\u003eNo primary outcome(s) discernible\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 144px;\"\u003e\n \u003cp\u003e5 (4.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"4\" valign=\"top\" style=\"width: 133px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eChallenges\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 330px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eJustification of treatment\u003c/strong\u003e \u0026ndash; Outcome selection focus is on the disease and its course for which the medication was originally prescribed\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 144px;\"\u003e\n \u003cp\u003e67 (65.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 330px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eJustification of withdrawal\u003c/strong\u003e - Outcome selection focuses on disadvantages of drugs\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 144px;\"\u003e\n \u003cp\u003e21 (20.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 330px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eBoth\u0026nbsp;\u003c/strong\u003e(more than one outcome referring to justification of treatment and withdrawal)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 144px;\"\u003e\n \u003cp\u003e10 (9.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 330px;\"\u003e\n \u003cp\u003eNo primary outcome(s) discernible\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 144px;\"\u003e\n \u003cp\u003e5 (4.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"4\" valign=\"top\" style=\"width: 133px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eThe role of \u0026quot;time\u0026quot; in endpoint definition\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 330px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eNumber of events during follow-up time\u003c/strong\u003e (frequency of events, e.g., number of myocardial infarctions)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 144px;\"\u003e\n \u003cp\u003e68 (66.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 330px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eTime to event\u003c/strong\u003e, typically in weeks or month\u0026nbsp;\u003cbr\u003e(definition can be clinical, biochemical, imaging etc.)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 144px;\"\u003e\n \u003cp\u003e2 (1.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 330px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eDifference of a metric endpoint between study start and end\u0026nbsp;\u003c/strong\u003e(e.g., cognitive function after six weeks of follow-up)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 144px;\"\u003e\n \u003cp\u003e28 (27.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 330px;\"\u003e\n \u003cp\u003eNo primary outcome(s) discernible\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 144px;\"\u003e\n \u003cp\u003e5 (4.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cem\u003eTable 3: This table summarizes the presentation, type, and challenges of primary outcomes, as well as the role of time in endpoint definition in the included trials.\u003c/em\u003e\u003c/p\u003e\n\u003ch3\u003eHypotheses Evaluated\u003c/h3\u003e\n\u003cp\u003eIn 43 (41.7 %) of the included studies, the hypothesis being investigated was explicitly stated. Specifically, 10 studies described a non-inferiority hypothesis, and 32 studies presented a superiority hypothesis (see Table 4). However, in more than half of the studies (58.3%), the hypothesis type was not explicitly mentioned.\u003c/p\u003e\n\u003cp\u003eTable 4 shows the cross-classification of hypothesis types as reported by study authors and as assessed by us. We categorized all studies according to the most relevant research question, taking into account the study topic and clinical context. Based on our assessment, a non-inferiority hypothesis would have been appropriate in nearly half of all studies (48.5%).\u003c/p\u003e\n\u003cp\u003eAmong the 32 studies classified as superiority trials by the original authors, 16 (50.0%) were also categorized as superiority trials in our assessment, while 12 (37.5%) were categorized as non-inferiority trials and 4 (12.5%) as addressing both. Of the 10 studies described as non-inferiority trials, 9 (90.0%) were confirmed as such in our assessment, and 1 (10.0%) was assigned to both. Among the 60 studies without a stated hypothesis type, we assessed 29 (48.3%) as non-inferiority trials, 15 (25.0%) as superiority trials, and 16 (26.7%) as addressing both (see Table 4). For additional details, please refer to Supplementary Table 1, which provides further breakdowns and specific data points.\u003c/p\u003e\n\u003cp\u003eOur findings suggest that several studies might have been more appropriately conceptualized as non-inferiority trials, although they were not presented as such. One example is the study by Chen et al. (25), which examined quetiapine discontinuation in patients with a first remitted psychotic episode. While the authors expected higher relapse rates in the discontinuation group, from a clinical perspective, a non-inferiority design would have been more suitable to assess whether discontinuation leads to recurrence within an acceptable margin, particularly considering the potential side effects of quetiapine.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 4: Underlying hypotheses: Authors\u0026apos; perspective and our interpretation (n = 103)\u003c/strong\u003e\u003c/p\u003e\n\u003ctable\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd\u003e\u0026nbsp;\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"3\"\u003e\n \u003cp\u003e\u003cstrong\u003eAppropriate hypotheses according to us\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eTotal (study authors)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eHypotheses according to the study authors\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eSuperiority\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eNon-inferiority\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eboth\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\u0026nbsp;\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eSuperiority\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e16\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e32\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eNon-inferiority\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eboth\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eNo specification\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e15\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e29\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e16\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e60\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eTotal (us)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e31\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e50\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e22\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e103\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cem\u003eTable 4: This table compares the hypotheses specified by the study authors (e.g., superiority, non-inferiority) with our interpretation\u003c/em\u003e\u0026nbsp;\u003c/p\u003e\n\u003ch3\u003eHypotheses and the JW/JT Challenges\u003c/h3\u003e\n\u003cp\u003eIn our analysis of 67 studies with a primary outcome addressing JT, 41 studies aimed to investigate non-inferiority. In six of these studies, however, a non-inferiority hypothesis was not explicitly stated. Instead, outcomes related to JW were used, although the research question appeared more closely aligned with a non-inferiority framework focused on JT. Concrete examples of such cases are presented and discussed below.\u003c/p\u003e\n\u003cp\u003eIn 13 studies, a JW outcome was investigated, and we considered a superiority design to be appropriate for these. Conversely, 18 studies employed a superiority design while addressing outcomes related to JT. For instance, McMillan et al. (26) used a statistical approach consistent with superiority testing (t-test or Mann\u0026ndash;Whitney U test) to examine the discontinuation of growth hormone substitution and its effect on psychological well-being (JT) in patients with severe hormone deficiency. This suggests that their primary motivation was to demonstrate effectiveness, which seems plausible given the state of the evidence.\u003c/p\u003e\n\u003cp\u003eOverall, we observed two recurring patterns: (1) a shift in the selected outcome type (between JT and JW) and (2) the use of a superiority design where a non-inferiority design may have been more appropriate. In several cases, an outcome switch from JT to JW was observed, which potentially avoided the methodological requirements of a non-inferiority trial, such as a larger sample size.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cdiv id=\"Sec18\" class=\"Section2\"\u003e \u003ch2\u003eSummary of our findings\u003c/h2\u003e \u003cp\u003eOur review of discontinuation studies (type 1 according to Viniol et al. (\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e)) reveals the complexity of this kind of research, especially in selecting the primary outcome and formulating study hypotheses. We explored the motivations, challenges, and consequences of discontinuation studies regarding primary outcome selection.\u003c/p\u003e \u003cp\u003eIn most studies, primary outcomes were clearly defined, with a majority using a single primary outcome and some using either composite or co-primary outcomes. Clinically relevant endpoints such as symptoms, quality of life, and death were frequently used, while subclinical measurements were less common. Discontinuation rates were considered in only a small fraction of the studies. However, our evaluation also highlights that discontinuation studies pose substantial methodological challenges—particularly regarding outcome specification, hypothesis formulation, and study design.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec19\" class=\"Section2\"\u003e \u003ch2\u003eChoice of outcomes and formulation of hypotheses\u003c/h2\u003e \u003cp\u003eDiscontinuation studies must address two distinct perspectives: the justification for continuing treatment (JT) and for withdrawing it (JW). While JT outcomes assess disease control and typically necessitate non-inferiority designs, JW outcomes highlight drawbacks of ongoing treatment and are best addressed using superiority designs.\u003c/p\u003e \u003cp\u003eAlthough most studies aligned broadly with these principles, several cases revealed inconsistencies between stated goals and methodological choices. For example, Höcker et al. (\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e) investigated steroid withdrawal in pediatric kidney transplant recipients and chose longitudinal growth (JW) as the primary endpoint. However, the clinically critical outcome—graft function (JT)—was only analyzed descriptively as a secondary endpoint. A non-inferiority design focused on graft survival would have been more appropriate, though it would have required a substantially larger sample size (see Table\u0026nbsp;\u003cspan refid=\"Tab5\" class=\"InternalRef\"\u003e5\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e\u003cdiv class=\"gridtable\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003ctable float=\"Yes\" id=\"Tab5\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 5\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003e\u003cb\u003eStudy Example – Steroid discontinuation in Pediatric Kidney Transplantation\u003c/b\u003e\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e\u003ccolgroup cols=\"2\"\u003e\u003c/colgroup\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eStudy description\u003c/p\u003e \u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cem\u003e42 low-immunologic risk pediatric kidney transplant recipients on cyclosporine micro-emulsion, mycophenolate mofetil, and corticosteroids were randomly assigned to either continue steroids or withdraw them over 3 months. The primary outcome was longitudinal growth.\u003c/em\u003e\u003c/p\u003e \u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eProblem Statement\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eThe key issue with steroid withdrawal is the safety of graft function. Theoretically, safety should be the primary endpoint and adequately powered to show at least non-inferiority of the proposed regimen.\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eSample Size Considerations\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eA non-inferiority study would require at least 196 patients per treatment arm to detect a ≤ 5% difference in glomerular filtration rate (GFR) with 90% power and a 15% coefficient of variation. Due to the limited number of pediatric renal transplant patients, such a study would not be feasible.\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eReference\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eHöcker B, Weber LT, Feneberg R, Drube J, John U, Fehrenbach H et al. \u003cem\u003eNephrol Dial Transplant\u003c/em\u003e 2010; 25(\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e):617–24. doi: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1093/ndt/gfp506\u003c/span\u003e\u003cspan address=\"10.1093/ndt/gfp506\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/table\u003e\u003c/div\u003e \u003cp\u003e\u003c/p\u003e \u003cp\u003eTable\u0026nbsp;\u003cspan refid=\"Tab5\" class=\"InternalRef\"\u003e5\u003c/span\u003e: \u003cem\u003eThis table presents a typical study example that illustrates the challenges involved in hypothesis formulation and outcome selection.\u003c/em\u003e\u003c/p\u003e \u003cp\u003eA similar issue arises in the study by Kendrick et al. (\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e), which prioritized cognitive function (JW) after antiepileptic withdrawal, while seizure frequency (JT) was a secondary outcome and not part of the sample size calculation. These examples illustrate that, while both perspectives are often acknowledged, they are rarely addressed equally in study design and statistical planning.\u003c/p\u003e \u003cp\u003eThis imbalance poses a problem. As shown in the study by Höcker et al. (\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e), the omission of an adequately powered primary endpoint for a rare but severe outcome—such as graft failure—limits interpretability. Severe outcomes not only require narrow non-inferiority margins but also demand ethical scrutiny, as they cannot be dismissed as rare side effects. Statistical parameters like alpha, beta, and acceptable risk thresholds must therefore be clinically and ethically justified, not treated as formalities.\u003c/p\u003e \u003cp\u003eBorm et al. (\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e) emphasized that a study's evidential strength should be judged by its overall success, not just by the power of isolated results. They further developed this concept, stressing that the selection of endpoints should not be based solely on statistical properties—clinical relevance must always take precedence (\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e). In this light, a trial that shows improved growth (JW) after discontinuing immunosuppressive therapy but cannot rule out an increased risk of graft rejection (JT) remains inconclusive. A more meaningful design would enable conclusions on both dimensions—treatment safety and benefit of withdrawal—even if this increases the complexity and resource demands of the study.\u003c/p\u003e \u003cp\u003eDespite this, none of the 103 studies we reviewed explicitly defined both JT and JW as co-primary endpoints. Most studies chose a single primary outcome, and only five included co-primary outcomes. The likely reason is feasibility: powering a study for both hypotheses often requires much larger sample sizes. Nevertheless, integrating both perspectives is essential to ensure that drug discontinuation studies are methodologically sound and clinically meaningful.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec20\" class=\"Section2\"\u003e \u003ch2\u003eClinical Relevance\u003c/h2\u003e \u003cp\u003eIn clinical studies, researchers choose between clinical endpoints and surrogate markers based on the study goals, constraints, and disease characteristics. Clinical endpoints, which assess a patient's well-being, function, or survival, provide the most reliable measure of an intervention's impact but often require long follow-ups or large samples. Surrogate markers are useful in phase 2 trials to assess feasibility but become problematic in definitive phase 3 trials (\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eThe validity of a surrogate depends on how well it captures the causal pathways between the intervention and the outcome. For example, Thyroid Stimulating Hormone (TSH) is a justified surrogate when discontinuing thyroid hormones, as regular monitoring helps prevent overt hypothyroidism and its associated harms. In contrast, Low-Density Lipoprotein cholesterol (LDL-C), as used by Lee et al. (\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e), is an inadequate surrogate for cardiovascular events. While cholesterol levels correlate with cardiovascular disease, they do not reliably predict individual risk (\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e, \u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eThus, monitoring TSH to prevent overt hypothyroidism is appropriate when discontinuing thyroid hormones. However, using LDL-C instead of clinical events to assess statin discontinuation in older adults is inappropriate.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec21\" class=\"Section2\"\u003e \u003ch2\u003eDiscontinuation Rate and follow-up\u003c/h2\u003e \u003cp\u003eDiscontinuation rates can be a key outcome in drug discontinuation studies (\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e). When a drug is stopped as part of the study protocol, reinstitution rates can indicate \"failed discontinuation\" and offer valuable insights. Disease flares or symptom recurrence are common reasons for resuming treatment, reflecting JT. For example, restarting antipsychotics due to neuropsychiatric symptoms or reintroducing thyroxine when TSH levels rise are both instances of JT. In these cases, TSH could also serve as a safety measure.\u003c/p\u003e \u003cp\u003eHowever, in patients who tolerate increased disease activity after discontinuation, a mechanism justifying withdrawal can be identified. For instance, in the treatment of autoimmune diseases, glucocorticoids are often discontinued due to metabolic side effects, such as weight gain (\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e).\u003c/p\u003e \u003cp\u003ePsychological factors, like patient or clinician reactions, may also influence the decision to reinstitute treatment, particularly in blinded trials. For example, statin discontinuation could reveal unmasked treatment arms due to rising LDL-cholesterol levels, leading to concerns and, consequently, treatment resumption.\u003c/p\u003e \u003cp\u003eThus, the discontinuation rate is a complex measure that reflects JT, JW, and psychological factors. Additional outcomes may be needed to assess the reasons behind treatment reinstitution, depending on the drug and its indication. The follow-up period must also be considered when evaluating discontinuation rates. For diseases with long-term clinical consequences, such as statin use in cardiovascular prevention, longer follow-up is necessary to capture adverse events, like stroke. If a strong surrogate marker exists, such as HBV DNA levels after discontinuing tenofovir, a shorter follow-up period may be justified (\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec22\" class=\"Section2\"\u003e \u003ch2\u003eWhat do others say?\u003c/h2\u003e \u003cp\u003eIn 2022, the US Deprescribing Research Network (USDeN) published recommendations on outcome selection in discontinuation studies (\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e). A year later, Nizet et al. compared their systematic review of deprescribing implementation trials with these recommendations (\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e). Unlike our approach, they did not distinguish between the three types of discontinuation studies (\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e) and instead analyzed studies of all three types together. In contrast, we focused specifically on Type 1 studies. Given the differing goals and design requirements, we advocate for considering these study types separately. Additionally, the authors did not address the key challenge of discontinuation studies—balancing JT and JW—and its implications for study design and hypothesis formulation. However, they underscored the importance of clinically relevant outcomes, adequate power, and sufficient follow-up time.\u003c/p\u003e \u003cdiv id=\"Sec23\" class=\"Section3\"\u003e \u003ch2\u003eStrength and Limitations of our review\u003c/h2\u003e \u003cp\u003eThis scoping review provides a comprehensive analysis of studies on drug discontinuation, examining motivations, challenges, outcomes, and hypotheses. Based on an extensive literature search, it also proposes a systematic framework to categorize key research questions and guide future studies.\u003c/p\u003e \u003cp\u003eOur review specifically focused on randomized controlled trials (RCTs) of type 1 drug discontinuation studies. Although we may have overlooked relevant findings from other study types, we believe this limitation is justified given the higher risk of bias associated with non-RCT designs. Therefore, we chose to focus solely on RCTs to ensure the reliability of our analysis.\u003c/p\u003e \u003cp\u003eThe studies included in our review were limited to those examined by Grede et al., who published a scoping review in 2023 covering publications up to 2020. Since our study aims to develop a structured synthesis rather than provide a fully up-to-date systematic review of the drug discontinuation literature, we do not believe extending the time frame would have substantially altered our findings. While the field of drug discontinuation is evolving rapidly, the 103 studies included in our analysis provide a solid and comprehensive foundation for this work. The primary objective of this study is to synthesize and conceptualize existing knowledge, and the patterns, barriers, and facilitators of drug withdrawal identified in these studies form the basis of our model.\u003c/p\u003e \u003cp\u003eAlthough two authors independently interpreted the hypotheses, some subjectivity inevitably remains in the interpretation process. This subjectivity may have influenced of our conclusions regarding study designs and hypotheses to some extent.\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e "},{"header":"Conclusion: Recommendations of outcome selection in drug discontinuation studies","content":"\u003cp\u003eIn conclusion, drug discontinuation studies must address both key clinical and methodological challenges. The selection of endpoints should prioritize clinical relevance, emphasizing meaningful outcomes or appropriate surrogate markers over purely statistical considerations. This approach should inform the formulation of hypotheses, carefully balancing non-inferiority and superiority designs. Such studies typically require large sample sizes and extended follow-up periods.\u003c/p\u003e\u003cp\u003eThe field of drug discontinuation research is rapidly evolving, with many questions still to be answered. These include the comparative valuation of outcomes, the definition of error margins, and strategies for determining sample sizes. Securing funding remains a significant challenge due to the lack of commercial incentives, and public or independent funding sources are often insufficient to support the scale of these studies. Governments must play a central role in addressing this funding gap by supporting research that aligns with public health priorities.\u003c/p\u003e\u003cp\u003eThe example of Canada, with initiatives like the Canadian Institutes of Health Research (CIHR) and the Canadian Deprescribing Network (CaDeN), highlights how national networks can drive research on drug discontinuation and the development of specific guidelines. Similar efforts, along with international collaboration, are essential to advancing evidence-based approaches to medication discontinuation and ensuring the safe reduction of unnecessary or potentially harmful drugs (\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e).\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003e\u003cstrong\u003eACE\u003c/strong\u003e: Angiotensin-Converting Enzyme\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAED:\u003c/strong\u003e Antiepileptic Drugs\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCIHR:\u003c/strong\u003e Canadian Institutes of Health Research\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDNA:\u003c/strong\u003e Deoxyribonucleic Acid\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eGFR:\u003c/strong\u003e Glomerular Filtration Rate\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eHBV\u003c/strong\u003e: Hepatitis B Virus\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eHIV:\u003c/strong\u003e Human Immunodeficiency Virus\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eJT:\u003c/strong\u003e Justification of Treatment\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eJW:\u003c/strong\u003e Justification of Withdrawal\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eLDL-C:\u003c/strong\u003e Low-Density Lipoprotein Cholesterol\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePPI:\u003c/strong\u003e Proton Pump Inhibitor\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePRISMA:\u003c/strong\u003e Preferred Reporting Items for Systematic Reviews and Meta-Analyses\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eRCT:\u003c/strong\u003e Randomized Controlled Trial\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSPSS\u003c/strong\u003e: Statistical Package for the Social Sciences\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTNF:\u003c/strong\u003e Tumor Necrosis Factor\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTSH\u003c/strong\u003e: Thyroid-Stimulating Hormone\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eUS:\u003c/strong\u003e United States\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eUSA:\u003c/strong\u003e United States of America\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eUSDeN\u003c/strong\u003e: US Deprescribing Research Network\u003c/p\u003e"},{"header":"Declarations","content":"\u003ch3\u003eEthics approval and consent to participate\u0026nbsp;\u003c/h3\u003e\n\u003cp\u003eNot applicable.\u0026nbsp;\u003c/p\u003e\n\u003ch3\u003eConsent for publication\u003c/h3\u003e\n\u003cp\u003eNot applicable.\u0026nbsp;\u003c/p\u003e\n\u003ch3\u003eAvailability of data and materials\u0026nbsp;\u003c/h3\u003e\n\u003cp\u003eThe datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.\u0026nbsp;\u003c/p\u003e\n\u003ch3\u003eCompeting interests\u0026nbsp;\u003c/h3\u003e\n\u003cp\u003eNK, NG, IS, AB and AV declare that they have no competing interests\u003c/p\u003e\n\u003cp\u003eNDB is co-chairman of Gesellschaft f\u0026uuml;r Patientenzentrierte Kommunikation, a non-profit organization developing and distributing the decision-support software arriba, which among others includes a module for drug discontinuation.\u0026nbsp;\u003c/p\u003e\n\u003ch3\u003eFunding\u0026nbsp;\u003c/h3\u003e\n\u003cp\u003eThis work was funded by the Federal Ministry of Education and Research (BMBF, Bundesministerium f\u0026uuml;r Bildung und Forschung) as part of the project \u0026ldquo;DRUG-STOP\u0026rdquo; (Grant Number: 01KG1507). The funders had no role in the design of the study, analysis and interpretation of data, or in writing the manuscript.\u0026nbsp;\u003c/p\u003e\n\u003ch3\u003eAuthors\u0026apos; contributions\u0026nbsp;\u003c/h3\u003e\n\u003cp\u003eAV and NDB conceptualized and supervised this scoping review. IS, NG, NK and AB contributed significantly to the development of the study. IS, NDB and NK screened the abstracts and full-texts, \u0026nbsp; extracted and analyzed the data. NDB, NK and AV prepared this manuscript. All authors read and approved the final manuscript.\u0026nbsp;\u003c/p\u003e\n\u003ch3\u003eAcknowledgements\u003c/h3\u003e\n\u003cp\u003eWe would like to thank Kiana Rafat for her valuable support in preparing various materials for this manuscript.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eZhang H, Huang T, Shen W, Xu X, Yang P, Zhu D et al. Efficacy and safety of sacubitril-valsartan in heart failure: a meta-analysis of randomized controlled trials. ESC Heart Fail 2020; 7(6):3841\u0026ndash;50. doi: 10.1002/ehf2.12974.\u003c/li\u003e\n\u003cli\u003eWalters EH, Gibson PG, Lasserson TJ, Walters JAE. Long-acting beta2-agonists for chronic asthma in adults and children where background therapy contains varied or no inhaled corticosteroid. Cochrane Database Syst Rev 2007; 2007(1):CD001385. doi: 10.1002/14651858.CD001385.pub2.\u003c/li\u003e\n\u003cli\u003eKerschbaumer A, Sepriano A, Smolen JS, van der Heijde D, Dougados M, van Vollenhoven R et al. Efficacy of pharmacological treatment in rheumatoid arthritis: a systematic literature research informing the 2019 update of the EULAR recommendations for management of rheumatoid arthritis. Ann Rheum Dis 2020; 79(6):744\u0026ndash;59. doi: 10.1136/annrheumdis-2019-216656.\u003c/li\u003e\n\u003cli\u003eWolff JL, Starfield B, Anderson G. Prevalence, expenditures, and complications of multiple chronic conditions in the elderly. Arch Intern Med 2002; 162(20):2269\u0026ndash;76. doi: 10.1001/archinte.162.20.2269.\u003c/li\u003e\n\u003cli\u003eMoore KL, Boscardin WJ, Steinman MA, Schwartz JB. Age and sex variation in prevalence of chronic medical conditions in older residents of U.S. nursing homes. J Am Geriatr Soc 2012; 60(4):756\u0026ndash;64. doi: 10.1111/j.1532-5415.2012.03909.x.\u003c/li\u003e\n\u003cli\u003eLiu Q, Schwartz JB, Slattum PW, Lau SWJ, Guinn D, Madabushi R et al. Roadmap to 2030 for Drug Evaluation in Older Adults. Clin Pharmacol Ther 2022; 112(2):210\u0026ndash;23. doi: 10.1002/cpt.2452.\u003c/li\u003e\n\u003cli\u003eDavies LE, Spiers G, Kingston A, Todd A, Adamson J, Hanratty B. Adverse Outcomes of Polypharmacy in Older People: Systematic Review of Reviews. J Am Med Dir Assoc 2020; 21(2):181\u0026ndash;7. doi: 10.1016/j.jamda.2019.10.022.\u003c/li\u003e\n\u003cli\u003eSchurig AM, B\u0026ouml;hme M, Just KS, Scholl C, Dormann H, Plank-Kiegele B et al. Adverse Drug Reactions (ADR) and Emergencies. Dtsch Arztebl Int 2018; 115(15):251\u0026ndash;8. doi: 10.3238/arztebl.2018.0251.\u003c/li\u003e\n\u003cli\u003eOsanlou R, Walker L, Hughes DA, Burnside G, Pirmohamed M. Adverse drug reactions, multimorbidity and polypharmacy: a prospective analysis of 1 month of medical admissions. BMJ Open 2022; 12(7):e055551. doi: 10.1136/bmjopen-2021-055551.\u003c/li\u003e\n\u003cli\u003eDepartment of Health \u0026amp; Social Care (UK). Good for you, good for us, good for everybody: A plan to reduce overprescribing to make patient care better and safer, support the NHS, and reduce carbon emissions; 2021. In:.\u003c/li\u003e\n\u003cli\u003eReeve E, Moriarty F, Nahas R, Turner JP, Kouladjian O\u0026apos;Donnell L, Hilmer SN. A narrative review of the safety concerns of deprescribing in older adults and strategies to mitigate potential harms. Expert Opin Drug Saf 2018; 17(1):39\u0026ndash;49. doi: 10.1080/14740338.2018.1397625.\u003c/li\u003e\n\u003cli\u003eViniol A, Haasenritter J, Grede N, Wegscheider K, Becker A, Sitter H et al. Typology of drug discontinuation trials - Methodological recommendations. J Clin Epidemiol 2021; 137:23\u0026ndash;30. doi: 10.1016/j.jclinepi.2021.03.017.\u003c/li\u003e\n\u003cli\u003eGrede N, Kuss K, Staudt I, Donner-Banzhoff N, Viniol A. Mapping the methodological diversity of published drug discontinuation studies-a scoping review of study topics, objectives, and designs. Trials 2023; 24(1):58. doi: 10.1186/s13063-023-07105-6.\u003c/li\u003e\n\u003cli\u003eWang B, Wang H, Tu XM, Feng C. Comparisons of Superiority, Non-inferiority, and Equivalence Trials. Shanghai Arch Psychiatry 2017; 29(6):385\u0026ndash;8. doi: 10.11919/j.issn.1002-0829.217163.\u003c/li\u003e\n\u003cli\u003eTricco AC, Lillie E, Zarin W, O\u0026apos;Brien KK, Colquhoun H, Levac D et al. PRISMA Extension for Scoping Reviews (PRISMA-ScR): Checklist and Explanation. Ann Intern Med 2018; 169(7):467\u0026ndash;73. doi: 10.7326/M18-0850.\u003c/li\u003e\n\u003cli\u003eHardy BG, Shulman KI, Zucchero C. Gradual discontinuation of lithium augmentation in elderly patients with unipolar depression. J Clin Psychopharmacol 1997; 17(1):22\u0026ndash;6. doi: 10.1097/00004714-199702000-00005.\u003c/li\u003e\n\u003cli\u003eHessen E, Lossius MI, Reinvang I, Gjerstad L. Influence of major antiepileptic drugs on attention, reaction time, and speed of information processing: results from a randomized, double-blind, placebo-controlled withdrawal study of seizure-free epilepsy patients receiving monotherapy. Epilepsia 2006; 47(12):2038\u0026ndash;45. doi: 10.1111/j.1528-1167.2006.00805.x.\u003c/li\u003e\n\u003cli\u003eMiro JM, Lopez JC, Podzamczer D, Pe\u0026ntilde;a JM, Alberdi JC, Mart\u0026iacute;nez E et al. Discontinuation of primary and secondary Toxoplasma gondii prophylaxis is safe in HIV-infected patients after immunological restoration with highly active antiretroviral therapy: results of an open, randomized, multicenter clinical trial. Clin Infect Dis 2006; 43(1):79\u0026ndash;89. doi: 10.1086/504872.\u003c/li\u003e\n\u003cli\u003eSrivanichakorn W, Sriwijitkamol A, Kongchoo A, Sriussadaporn S, Plengvidhya N, Lertwattanarak R et al. Withdrawal of sulfonylureas from patients with type 2 diabetes receiving long-term sulfonylurea and insulin combination therapy results in deterioration of glycemic control: a randomized controlled trial. Diabetes Metab Syndr Obes 2015; 8:137\u0026ndash;45. doi: 10.2147/DMSO.S78008.\u003c/li\u003e\n\u003cli\u003eReimer C, Bytzer P. Discontinuation of long-term proton pump inhibitor therapy in primary care patients: a randomized placebo-controlled trial in patients with symptom relapse. Eur J Gastroenterol Hepatol 2010; 22(10):1182\u0026ndash;8. doi: 10.1097/MEG.0b013e32833d56d1.\u003c/li\u003e\n\u003cli\u003eBergh S, Selb\u0026aelig;k G, Engedal K. Discontinuation of antidepressants in people with dementia and neuropsychiatric symptoms (DESEP study): double blind, randomised, parallel group, placebo controlled trial. BMJ 2012; 344:e1566. doi: 10.1136/bmj.e1566.\u003c/li\u003e\n\u003cli\u003eLemos KF, Rabelo-Silva ER, Ribeiro LW, Cruz LN, Polanczyk CA. Effect of nitrate withdrawal on quality of life and adherence to treatment in patients with stable angina: evidence from a randomized clinical trial. Coron Artery Dis 2014; 25(3):215\u0026ndash;23. doi: 10.1097/MCA.0000000000000083.\u003c/li\u003e\n\u003cli\u003eLee S-H, Kwon H-S, Park Y-M, Ko S-H, Choi Y-H, Yoon K-H et al. Statin Discontinuation after Achieving a Target Low Density Lipoprotein Cholesterol Level in Type 2 Diabetic Patients without Cardiovascular Disease: A Randomized Controlled Study. Diabetes Metab J 2014; 38(1):64\u0026ndash;73. doi: 10.4093/dmj.2014.38.1.64.\u003c/li\u003e\n\u003cli\u003eCurran HV, Collins R, Fletcher S, Kee SCY, Woods B, Iliffe S. Older adults and withdrawal from benzodiazepine hypnotics in general practice: effects on cognitive function, sleep, mood and quality of life. Psychol Med 2003; 33(7):1223\u0026ndash;37. doi: 10.1017/s0033291703008213.\u003c/li\u003e\n\u003cli\u003eChen EYH, Hui CLM, Lam MML, Chiu CPY, Law CW, Chung DWS et al. Maintenance treatment with quetiapine versus discontinuation after one year of treatment in patients with remitted first episode psychosis: randomised controlled trial. BMJ 2010; 341:c4024. doi: 10.1136/bmj.c4024.\u003c/li\u003e\n\u003cli\u003eMcMillan CV, Bradley C, Gibney J, Healy ML, Russell-Jones DL, S\u0026ouml;nksen PH. Psychological effects of withdrawal of growth hormone therapy from adults with growth hormone deficiency. Clin Endocrinol (Oxf) 2003; 59(4):467\u0026ndash;75. doi: 10.1046/j.1365-2265.2003.01870.x.\u003c/li\u003e\n\u003cli\u003eH\u0026ouml;cker B, Weber LT, Feneberg R, Drube J, John U, Fehrenbach H et al. Improved growth and cardiovascular risk after late steroid withdrawal: 2-year results of a prospective, randomised trial in paediatric renal transplantation. Nephrol Dial Transplant 2010; 25(2):617\u0026ndash;24. doi: 10.1093/ndt/gfp506.\u003c/li\u003e\n\u003cli\u003eKendrick AM, Duncan JS, Trimble MR. Effects of discontinuation of individual antiepileptic drugs on mood. Human Psychopharmacology 1993; 8(4):263\u0026ndash;70. doi: 10.1002/hup.470080405.\u003c/li\u003e\n\u003cli\u003eBorm GF, van der Wilt GJ, Kremer JAM, Zielhuis GA. A generalized concept of power helped to choose optimal endpoints in clinical trials. J Clin Epidemiol 2007; 60(4):375\u0026ndash;81. doi: 10.1016/j.jclinepi.2006.06.015.\u003c/li\u003e\n\u003cli\u003eBorm GF, Teerenstra S, Zielhuis GA. Objective and perspective determine the choice of composite endpoint. J Clin Epidemiol 2008; 61(2):99\u0026ndash;101. doi: 10.1016/j.jclinepi.2007.10.001.\u003c/li\u003e\n\u003cli\u003eFleming TR, DeMets DL. Surrogate end points in clinical trials: are we being misled? Ann Intern Med 1996; 125(7):605\u0026ndash;13. doi: 10.7326/0003-4819-125-7-199610010-00011.\u003c/li\u003e\n\u003cli\u003eDonner-Banzhoff N, S\u0026ouml;nnichsen A. Strategies for prescribing statins. BMJ 2008; 336(7639):288\u0026ndash;9. doi: 10.1136/bmj.39387.573947.80.\u003c/li\u003e\n\u003cli\u003eHeart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebo-controlled trial. Lancet 2002; 360(9326):7\u0026ndash;22. doi: 10.1016/S0140-6736(02)09327-3.\u003c/li\u003e\n\u003cli\u003eKulkarni S, Durham H, Glover L, Ather O, Phillips V, Nemes S et al. Metabolic adverse events associated with systemic corticosteroid therapy-a systematic review and meta-analysis. BMJ Open 2022; 12(12):e061476. doi: 10.1136/bmjopen-2022-061476.\u003c/li\u003e\n\u003cli\u003eButi M, Casillas R, Riveiro-Barciela M, Homs M, Tabernero D, Salcedo MT et al. Tenofovir discontinuation after long-term viral suppression in HBeAg negative chronic hepatitis B. Can HBsAg levels be useful? J Clin Virol 2015; 68:61\u0026ndash;8. doi: 10.1016/j.jcv.2015.05.002.\u003c/li\u003e\n\u003cli\u003eBayliss EA, Albers K, Gleason K, Pieper LE, Boyd CM, Campbell NL et al. Recommendations for outcome measurement for deprescribing intervention studies. J Am Geriatr Soc 2022; 70(9):2487\u0026ndash;97. doi: 10.1111/jgs.17894.\u003c/li\u003e\n\u003cli\u003eNizet P, Evin A, Brociero E, Vigneau CV, Huon J-F. Outcomes in deprescribing implementation trials and compliance with expert recommendations: a systematic review. BMC Geriatr 2023; 23(1):428. doi: 10.1186/s12877-023-04155-y.\u003c/li\u003e\n\u003cli\u003eDeprescribing.org. Deprescribing guidelines and algorithms. Verf\u0026uuml;gbar unter: https://deprescribing.org/resources/deprescribing-guidelines-algorithms/.\u003c/li\u003e\n\u003cli\u003eAbramowicz D, Manas D, Lao M, Vanrenterghem Y, Del Castillo D, Wijngaard P et al. Cyclosporine withdrawal from a mycophenolate mofetil-containing immunosuppressive regimen in stable kidney transplant recipients: a randomized, controlled study. Transplantation 2002; 74(12):1725\u0026ndash;34. doi: 10.1097/00007890-200212270-00015.\u003c/li\u003e\n\u003cli\u003eAndrews P, Hall JN, Snaith RP. A controlled trial of phenothiazine withdrawal in chronic schizophrenic patients. Br J Psychiatry 1976; 128:451\u0026ndash;5. doi: 10.1192/bjp.128.5.451.\u003c/li\u003e\n\u003cli\u003eBaker LA, Cheng LY, Amara IB. The withdrawal of benztropine mesylate in chronic schizophrenic patients. Br J Psychiatry 1983; 143:584\u0026ndash;90. doi: 10.1192/bjp.143.6.584.\u003c/li\u003e\n\u003cli\u003eBallard C, Lana MM, Theodoulou M, Douglas S, McShane R, Jacoby R et al. A randomised, blinded, placebo-controlled trial in dementia patients continuing or stopping neuroleptics (the DART-AD trial). PLoS Med 2008; 5(4):e76. doi: 10.1371/journal.pmed.0050076.\u003c/li\u003e\n\u003cli\u003eBykerk V., Sampalis J., Esdaile J.M., Choquette D., Senecal J.-L., Danoff D. et al. A randomized study of the effect of withdrawing hydroxychloroquine sulfate in systemic lupus erythematosus. N Engl J Med 1991; 324(3):150\u0026ndash;4. doi: 10.1056/NEJM199101173240303.\u003c/li\u003e\n\u003cli\u003eCampbell AJ, Robertson MC, Gardner MM, Norton RN, Buchner DM. Psychotropic medication withdrawal and a home-based exercise program to prevent falls: a randomized, controlled trial. J Am Geriatr Soc 1999; 47(7):850\u0026ndash;3. doi: 10.1111/j.1532-5415.1999.tb03843.x.\u003c/li\u003e\n\u003cli\u003eCampbell JD, Moore D, Degerman R, Kaharuza F, Were W, Muramuzi E et al. HIV-infected ugandan adults taking antiretroviral therapy with CD4 counts 200 cells/\u0026mu;L who discontinue cotrimoxazole prophylaxis have increased risk of malaria and diarrhea. Clin Infect Dis 2012; 54(8):1204\u0026ndash;11. doi: 10.1093/cid/cis013.\u003c/li\u003e\n\u003cli\u003eChaiwarith R, Praparattanapan J, Nuntachit N, Kotarathitithum W, Supparatpinyo K. Discontinuation of primary and secondary prophylaxis for opportunistic infections in HIV-infected patients who had CD4+ cell count \u0026lt;200 cells/mm(3) but undetectable plasma HIV-1 RNA: an open-label randomized controlled trial. AIDS Patient Care STDS 2013; 27(2):71\u0026ndash;6. doi: 10.1089/apc.2012.0303.\u003c/li\u003e\n\u003cli\u003eCheng C-Y, Chen M-Y, Hsieh S-M, Sheng W-H, Sun H-Y, Lo Y-C et al. Risk of pneumocystosis after early discontinuation of prophylaxis among HIV-infected patients receiving highly active antiretroviral therapy. BMC Infect Dis 2010; 10:126. doi: 10.1186/1471-2334-10-126.\u003c/li\u003e\n\u003cli\u003eChoudhury AB, Dawson CM, Kilvington HE, Eldridge S, James W-Y, Wedzicha JA et al. Withdrawal of inhaled corticosteroids in people with COPD in primary care: a randomised controlled trial. Respir Res 2007; 8(1):93. doi: 10.1186/1465-9921-8-93.\u003c/li\u003e\n\u003cli\u003eCook BL, Helms PM, Smith RE, Tsai M. Unipolar depression in the elderly. Reoccurrence on discontinuation of tricyclic antidepressants. J Affect Disord 1986; 10(2):91\u0026ndash;4. doi: 10.1016/0165-0327(86)90031-5.\u003c/li\u003e\n\u003cli\u003eCoulter DL. Withdrawal of barbiturate anticonvulsant drugs: prospective controlled study. Am J Ment Retard 1988; 93(3):320\u0026ndash;7.\u003c/li\u003e\n\u003cli\u003eJonge JW de, Knottnerus JA, van Zutphen WM, Bruijne GA de, Struijker Boudier HA. Short term effect of withdrawal of diuretic drugs prescribed for ankle oedema. BMJ 1994; 308(6927):511\u0026ndash;3. doi: 10.1136/bmj.308.6927.511.\u003c/li\u003e\n\u003cli\u003eFarmer CKT, Hampson G, Abbs IC, Hilton RM, Koffman CG, Fogelman I et al. Late low-dose steroid withdrawal in renal transplant recipients increases bone formation and bone mineral density. Am J Transplant 2006; 6(12):2929\u0026ndash;36. doi: 10.1111/j.1600-6143.2006.01557.x.\u003c/li\u003e\n\u003cli\u003eFindlay DJ, Sharma J, McEwen J, Ballinger BR, MaClennan WJ, McHarg AM. Double‐blind controlled withdrawal of thioridazine treatment in elderly female inpatients with senile dementia. Int J Geriat Psychiatry 1989; 4(2):115\u0026ndash;20. doi: 10.1002/gps.930040210.\u003c/li\u003e\n\u003cli\u003eGeorge J, Kitzis I, Zandorf D, Golovner M, Shapira I, Laniado S et al. Safety of nitrate withdrawal in angina-free and hemodynamically stable patients with coronary artery disease. Chest 2003; 124(5):1652\u0026ndash;7. doi: 10.1016/s0012-3692(15)33392-4.\u003c/li\u003e\n\u003cli\u003eGhaemi SN, Ostacher MM, El-Mallakh RS, Borrelli D, Baldassano CF, Kelley ME et al. Antidepressant discontinuation in bipolar depression: a Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) randomized clinical trial of long-term effectiveness and safety. J Clin Psychiatry 2010; 71(4):372\u0026ndash;80. doi: 10.4088/JCP.08m04909gre.\u003c/li\u003e\n\u003cli\u003eGiller E, Bialos D, Harkness L, Jatlow P, Waldo M. Long-term amitriptyline in chronic depression. Hillside J Clin Psychiatry 1985; 7(1):16\u0026ndash;33.\u003c/li\u003e\n\u003cli\u003eGleissner CA, Doesch A, Ehlermann P, Koch A, Sack FU, Katus HA et al. Cyclosporine withdrawal improves renal function in heart transplant patients on reduced-dose cyclosporine therapy. Am J Transplant 2006; 6(11):2750\u0026ndash;8. doi: 10.1111/j.1600-6143.2006.01527.x.\u003c/li\u003e\n\u003cli\u003eG\u0026oslash;tzsche PC, Hansen M, Stoltenberg M, Svendsen A, Beier J, Faarvang KL et al. Randomized, placebo controlled trial of withdrawal of slow-acting antirheumatic drugs and of observer bias in rheumatoid arthritis. Scand J Rheumatol 1996; 25(4):194\u0026ndash;9. doi: 10.3109/03009749609069987.\u003c/li\u003e\n\u003cli\u003eGreil W, Haag H, Rossnagl G, R\u0026uuml;ther E. Effect of anticholinergics on tardive dyskinesia. A controlled discontinuation study. Br J Psychiatry 1984; 145:304\u0026ndash;10. doi: 10.1192/bjp.145.3.304.\u003c/li\u003e\n\u003cli\u003eHabraken H, Soenen K, Blondeel L, van Elsen J, Bourda J, Coppens E et al. Gradual withdrawal from benzodiazepines in residents of homes for the elderly: experience and suggestions for future research. Eur J Clin Pharmacol 1997; 51(5):355\u0026ndash;8. doi: 10.1007/s002280050213.\u003c/li\u003e\n\u003cli\u003eHausberg M, Lang D, Levers A, Suwelack B, Kisters K, Tokmak F et al. Sympathetic nerve activity in renal transplant patients before and after withdrawal of cyclosporine. J Hypertens 2006; 24(5):957\u0026ndash;64. doi: 10.1097/01.hjh.0000222767.15100.e4.\u003c/li\u003e\n\u003cli\u003eHawthorne AB, Logan RF, Hawkey CJ, Foster PN, Axon AT, Swarbrick ET et al. Randomised controlled trial of azathioprine withdrawal in ulcerative colitis. BMJ 1992; 305(6844):20\u0026ndash;2. doi: 10.1136/bmj.305.6844.20.\u003c/li\u003e\n\u003cli\u003eHessen E, Lossius MI, Reinvang I, Gjerstad L. Slight improvement in mood and irritability after antiepileptic drug withdrawal: a controlled study in patients on monotherapy. Epilepsy Behav 2007; 10(3):449\u0026ndash;55. doi: 10.1016/j.yebeh.2007.01.014.\u003c/li\u003e\n\u003cli\u003eHollander AA, Hene RJ, Hermans J, van Es LA, van der Woude FJ. Late prednisone withdrawal in cyclosporine-treated kidney transplant patients: a randomized study. J Am Soc Nephrol 1997; 8(2):294\u0026ndash;301. doi: 10.1681/ASN.V82294.\u003c/li\u003e\n\u003cli\u003eJellinek T, Gardos G, Cole JO. Adverse effects of antiparkinson drug withdrawal. Am J Psychiatry 1981; 138(12):1567\u0026ndash;71. doi: 10.1176/ajp.138.12.1567.\u003c/li\u003e\n\u003cli\u003eKim MN, Lee CK, Ahn SH, Lee S, Kim SU, Kim DY et al. Maintaining remission in lamivudine-resistant patients with a virological response to adefovir add-on lamivudine after stopping lamivudine therapy. Liver Int 2014; 34(10):1543\u0026ndash;9. doi: 10.1111/liv.12437.\u003c/li\u003e\n\u003cli\u003eKirsten DK, Wegner RE, J\u0026ouml;rres RA, Magnussen H. Effects of theophylline withdrawal in severe chronic obstructive pulmonary disease. Chest 1993; 104(4):1101\u0026ndash;7. doi: 10.1378/chest.104.4.1101.\u003c/li\u003e\n\u003cli\u003eKorman MG, Hetzel DJ, Hansky J, Shearman DJ, Don G. Relapse rate of duodenal ulcer after cessation of long-term cimetidine treatment: a double-blind controlled study. Dig Dis Sci 1980; 25(2):88\u0026ndash;91. doi: 10.1007/BF01308302.\u003c/li\u003e\n\u003cli\u003eKosch M, Hausberg M, Suwelack B. Studies on effects of calcineurin inhibitor withdrawal on arterial distensibility and endothelial function in renal transplant recipients. Transplantation 2003; 76(10):1516\u0026ndash;9. doi: 10.1097/01.TP.0000092521.57633.BD.\u003c/li\u003e\n\u003cli\u003eLe Cesne A, Ray-Coquard I, Bui BN, Adenis A, Rios M, Bertucci F et al. Discontinuation of imatinib in patients with advanced gastrointestinal stromal tumours after 3 years of treatment: an open-label multicentre randomised phase 3 trial. Lancet Oncol 2010; 11(10):942\u0026ndash;9. doi: 10.1016/S1470-2045(10)70222-9.\u003c/li\u003e\n\u003cli\u003eLegendre C, Brault Y, Morales JM, Oberbauer R, Altieri P, Riad H et al. Factors influencing glomerular filtration rate in renal transplantation after cyclosporine withdrawal using sirolimus-based therapy: a multivariate analysis of results at five years. Clin Transplant 2007; 21(3):330\u0026ndash;6. doi: 10.1111/j.1399-0012.2007.00645.x.\u003c/li\u003e\n\u003cli\u003eL\u0026eacute;mann M, Mary J-Y, Colombel J-F, Duclos B, Soule J-C, Lerebours E et al. A randomized, double-blind, controlled withdrawal trial in Crohn\u0026apos;s disease patients in long-term remission on azathioprine. Gastroenterology 2005; 128(7):1812\u0026ndash;8. doi: 10.1053/j.gastro.2005.03.031.\u003c/li\u003e\n\u003cli\u003eLossius MI, Hessen E, Mowinckel P, Stavem K, Erikssen J, Gulbrandsen P et al. Consequences of antiepileptic drug withdrawal: a randomized, double-blind study (Akershus Study). Epilepsia 2008; 49(3):455\u0026ndash;63. doi: 10.1111/j.1528-1167.2007.01323.x.\u003c/li\u003e\n\u003cli\u003eMaland LJ, Lutz LJ, Castle CH. Effects of withdrawing diuretic therapy on blood pressure in mild hypertension. Hypertension 1983; 5(4):539\u0026ndash;44. doi: 10.1161/01.hyp.5.4.539.\u003c/li\u003e\n\u003cli\u003eMargo A, McMahon P. Lithium withdrawal triggers psychosis. Br J Psychiatry 1982; 141:407\u0026ndash;10. doi: 10.1192/bjp.141.4.407.\u003c/li\u003e\n\u003cli\u003eMayur PM, Gangadhar BN, Subbakrishna DK, Janakiramaiah N. Discontinuation of antidepressant drugs during electroconvulsive therapy: a controlled study. J Affect Disord 2000; 58(1):37\u0026ndash;41. doi: 10.1016/s0165-0327(99)00096-8.\u003c/li\u003e\n\u003cli\u003eMcDiarmid SV, Farmer DA, Goldstein LI, Martin P, Vargas J, Tipton JR et al. A randomized prospective trial of steroid withdrawal after liver transplantation. Transplantation 1995; 60(12):1443\u0026ndash;50. doi: 10.1097/00007890-199560120-00013.\u003c/li\u003e\n\u003cli\u003eMcInnis M, Petursson H. Withdrawal of trihexyphenidyl. Acta Psychiatr Scand 1985; 71(3):297\u0026ndash;303. doi: 10.1111/j.1600-0447.1985.tb01287.x.\u003c/li\u003e\n\u003cli\u003eMcLennan J, Findlay DJ, Sharma J, McEwen J, Ballinger BR, MaClennan WJ et al. Prolactin response to withdrawal of thioridazine in dementia. Int J Geriat Psychiatry 1992; 7(10):739\u0026ndash;42. doi: 10.1002/gps.930071009.\u003c/li\u003e\n\u003cli\u003eMellman TA, Uhde TW. Withdrawal syndrome with gradual tapering of alprazolam. Am J Psychiatry 1986; 143(11):1464\u0026ndash;6. doi: 10.1176/ajp.143.11.1464.\u003c/li\u003e\n\u003cli\u003eMichalsk\u0026aacute; D, Stepan JJ, Basson BR, Pavo I. The effect of raloxifene after discontinuation of long-term alendronate treatment of postmenopausal osteoporosis. J Clin Endocrinol Metab 2006; 91(3):870\u0026ndash;7. doi: 10.1210/jc.2004-2212.\u003c/li\u003e\n\u003cli\u003eMussini C, Pezzotti P, Govoni A, Borghi V, Antinori A, d\u0026apos;Arminio Monforte A et al. Discontinuation of primary prophylaxis for Pneumocystis carinii pneumonia and toxoplasmic encephalitis in human immunodeficiency virus type I-infected patients: the changes in opportunistic prophylaxis study. J Infect Dis 2000; 181(5):1635\u0026ndash;42. doi: 10.1086/315471.\u003c/li\u003e\n\u003cli\u003eMussini C, Pezzotti P, Antinori A, Borghi V, Monforte Ad, Govoni A et al. Discontinuation of secondary prophylaxis for Pneumocystis carinii pneumonia in human immunodeficiency virus-infected patients: a randomized trial by the CIOP Study Group. Clin Infect Dis 2003; 36(5):645\u0026ndash;51. doi: 10.1086/367659.\u003c/li\u003e\n\u003cli\u003eOdejide OA, Aderounmu AF. Double-blind placebo substitution: withdrawal of fluphenazine decanoate in schizophrenic patients. J Clin Psychiatry 1982; 43(5):195\u0026ndash;6.\u003c/li\u003e\n\u003cli\u003eOry-Magne F, Corvol J-C, Azulay J-P, Bonnet A-M, Brefel-Courbon C, Damier P et al. Withdrawing amantadine in dyskinetic patients with Parkinson disease: the AMANDYSK trial. Neurology 2014; 82(4):300\u0026ndash;7. doi: 10.1212/WNL.0000000000000050.\u003c/li\u003e\n\u003cli\u003ePacker M, Gheorghiade M, Young JB, Costantini PJ, Adams KF, Cody RJ et al. Withdrawal of digoxin from patients with chronic heart failure treated with angiotensin-converting-enzyme inhibitors. RADIANCE Study. N Engl J Med 1993; 329(1):1\u0026ndash;7. doi: 10.1056/NEJM199307013290101.\u003c/li\u003e\n\u003cli\u003ePato MT, Zohar-Kadouch R, Zohar J, Murphy DL. Return of symptoms after discontinuation of clomipramine in patients with obsessive-compulsive disorder. Am J Psychiatry 1988; 145(12):1521\u0026ndash;5. doi: 10.1176/ajp.145.12.1521.\u003c/li\u003e\n\u003cli\u003ePetursson H, Gudjonsson GH, Lader MH. Psychometric performance during withdrawal from long-term benzodiazepine treatment. Psychopharmacology (Berl) 1983; 81(4):345\u0026ndash;9. doi: 10.1007/BF00427575.\u003c/li\u003e\n\u003cli\u003ePincus T, Swearingen CJ, Luta G, Sokka T. Efficacy of prednisone 1-4 mg/day in patients with rheumatoid arthritis: a randomised, double-blind, placebo controlled withdrawal clinical trial. Ann Rheum Dis 2009; 68(11):1715\u0026ndash;20. doi: 10.1136/ard.2008.095539.\u003c/li\u003e\n\u003cli\u003eRatcliffe PJ, Dudley CR, Higgins RM, Firth JD, Smith B, Morris PJ. Randomised controlled trial of steroid withdrawal in renal transplant recipients receiving triple immunosuppression. Lancet 1996; 348(9028):643\u0026ndash;8. doi: 10.1016/s0140-6736(96)02510-x.\u003c/li\u003e\n\u003cli\u003eRice KL, Rubins JB, Lebahn F, Parenti CM, Duane PG, Kuskowski M et al. Withdrawal of chronic systemic corticosteroids in patients with COPD: a randomized trial. Am J Respir Crit Care Med 2000; 162(1):174\u0026ndash;8. doi: 10.1164/ajrccm.162.1.9909066.\u003c/li\u003e\n\u003cli\u003eRuskin PE, Nyman G. Discontinuation of neuroleptic medication in older, outpatient schizophrenics. A placebo-controlled, double-blind trial. J Nerv Ment Dis 1991; 179(4):212\u0026ndash;4. doi: 10.1097/00005053-199104000-00006.\u003c/li\u003e\n\u003cli\u003eRuths S, Straand J, Nygaard HA, Aarsland D. Stopping antipsychotic drug therapy in demented nursing home patients: a randomized, placebo-controlled study--the Bergen District Nursing Home Study (BEDNURS). Int J Geriat Psychiatry 2008; 23(9):889\u0026ndash;95. doi: 10.1002/gps.1998.\u003c/li\u003e\n\u003cli\u003eRuths S, Straand J, Nygaard HA, Bjorvatn B, Pallesen S. Effect of antipsychotic withdrawal on behavior and sleep/wake activity in nursing home residents with dementia: a randomized, placebo-controlled, double-blinded study. The Bergen District Nursing Home Study. J Am Geriatr Soc 2004; 52(10):1737\u0026ndash;43. doi: 10.1111/j.1532-5415.2004.52470.x.\u003c/li\u003e\n\u003cli\u003eSaksa JR, Baker CB, Woods SW. Mood-stabilizer-maintained, remitted bipolar patients: taper and discontinuation of adjunctive antipsychotic medication. Gen Hosp Psychiatry 2004; 26(3):233\u0026ndash;6. doi: 10.1016/j.genhosppsych.2004.02.002.\u003c/li\u003e\n\u003cli\u003eSampath G, Shah A, Krska J, Soni SD. Neuroleptic discontinuation in the very stable schizophrenic patient: Relapse rates and serum neuroleptic levels. Human Psychopharmacology 1992; 7(4):255\u0026ndash;64. doi: 10.1002/hup.470070405.\u003c/li\u003e\n\u003cli\u003eSchnuelle P, van der Heide JH, Tegzess A, Verburgh CA, Paul LC, van der Woude FJ et al. Open randomized trial comparing early withdrawal of either cyclosporine or mycophenolate mofetil in stable renal transplant recipients initially treated with a triple drug regimen. J Am Soc Nephrol 2002; 13(2):536\u0026ndash;43. doi: 10.1681/ASN.V132536.\u003c/li\u003e\n\u003cli\u003eSmak Gregoor PJH, S\u0026eacute;vaux RGL de, Ligtenberg G, Hoitsma AJ, Hen\u0026eacute; RJ, Weimar W et al. Withdrawal of cyclosporine or prednisone six months after kidney transplantation in patients on triple drug therapy: a randomized, prospective, multicenter study. J Am Soc Nephrol 2002; 13(5):1365\u0026ndash;73. doi: 10.1097/01.asn.0000013298.11876.bf.\u003c/li\u003e\n\u003cli\u003eStellon AJ, Keating JJ, Johnson PJ, McFarlane IG, Williams R. Maintenance of remission in autoimmune chronic active hepatitis with azathioprine after corticosteroid withdrawal. Hepatology 1988; 8(4):781\u0026ndash;4. doi: 10.1002/hep.1840080414.\u003c/li\u003e\n\u003cli\u003eStellon AJ, Hegarty JE, Portmann B, Williams R. Randomised controlled trial of azathioprine withdrawal in autoimmune chronic active hepatitis. Lancet 1985; 1(8430):668\u0026ndash;70. doi: 10.1016/s0140-6736(85)91329-7.\u003c/li\u003e\n\u003cli\u003eTakata Y, Yoshizumi T, Ito Y, Ueno M, Tsukashima A, Iwase M et al. Comparison of withdrawing antihypertensive therapy between diuretics and angiotensin converting enzyme inhibitors in essential hypertensives. Am Heart J 1992; 124(6):1574\u0026ndash;80. doi: 10.1016/0002-8703(92)90075-7.\u003c/li\u003e\n\u003cli\u003eTengstrand B, Larsson E, Klareskog L, Hafstr\u0026ouml;m I. Randomized withdrawal of long-term prednisolone treatment in rheumatoid arthritis: effects on inflammation and bone mineral density. Scand J Rheumatol 2007; 36(5):351\u0026ndash;8. doi: 10.1080/03009740701394021.\u003c/li\u003e\n\u003cli\u003eThielen N, van der Holt B, Cornelissen JJ, Verhoef GEG, Gussinklo T, Biemond BJ et al. Imatinib discontinuation in chronic phase myeloid leukaemia patients in sustained complete molecular response: a randomised trial of the Dutch-Belgian Cooperative Trial for Haemato-Oncology (HOVON). Eur J Cancer 2013; 49(15):3242\u0026ndash;6. doi: 10.1016/j.ejca.2013.06.018.\u003c/li\u003e\n\u003cli\u003eTse W, Frisina PG, H\u0026auml;lbig TD, Gracies J-M, Liang L, Tarshish C et al. The effects of withdrawal of dopaminergic medication in nursing home patients with advanced parkinsonism. J Am Med Dir Assoc 2008; 9(9):670\u0026ndash;5. doi: 10.1016/j.jamda.2008.07.001.\u003c/li\u003e\n\u003cli\u003eUlfvarson J, Adami J, Wredling R, Kjellman B, Reilly M, Bahr C von. Controlled withdrawal of selective serotonin reuptake inhibitor drugs in elderly patients in nursing homes with no indication of depression. Eur J Clin Pharmacol 2003; 59(10):735\u0026ndash;40. doi: 10.1007/s00228-003-0687-y.\u003c/li\u003e\n\u003cli\u003eUngvari GS, Chiu HF, Lam LC, Pang AH, Chung DW, Li SW et al. Gradual withdrawal of long-term anticholinergic antiparkinson medication in Chinese patients with chronic schizophrenia. J Clin Psychopharmacol 1999; 19(2):141\u0026ndash;8. doi: 10.1097/00004714-199904000-00009.\u003c/li\u003e\n\u003cli\u003eUretsky BF, Young JB, Shahidi FE, Yellen LG, Harrison MC, Jolly MK. Randomized study assessing the effect of digoxin withdrawal in patients with mild to moderate chronic congestive heart failure: results of the PROVED trial. PROVED Investigative Group. J Am Coll Cardiol 1993; 22(4):955\u0026ndash;62. doi: 10.1016/0735-1097(93)90403-n.\u003c/li\u003e\n\u003cli\u003evan den Ham ECH, Kooman JP, Christiaans ML, van Hooff JP. The influence of early steroid withdrawal on body composition and bone mineral density in renal transplantation patients. Transpl Int 2003; 16(2):82\u0026ndash;7. doi: 10.1007/s00147-002-0488-8.\u003c/li\u003e\n\u003cli\u003evan der Leeden H, Dijkmans BA, Hermans J, Cats A. A double-blind study on the effect of discontinuation of gold therapy in patients with rheumatoid arthritis. Clin Rheumatol 1986; 5(1):56\u0026ndash;61. doi: 10.1007/BF02030968.\u003c/li\u003e\n\u003cli\u003evan Herwaarden N, van der Maas A, Minten MJM, van den Hoogen FHJ, Kievit W, van Vollenhoven RF et al. Disease activity guided dose reduction and withdrawal of adalimumab or etanercept compared with usual care in rheumatoid arthritis: open label, randomised controlled, non-inferiority trial. BMJ 2015; 350:h1389. doi: 10.1136/bmj.h1389.\u003c/li\u003e\n\u003cli\u003evan Kraaij DJ, Jansen RW, Bouwels LH, Gribnau FW, Hoefnagels WH. Furosemide withdrawal in elderly heart failure patients with preserved left ventricular systolic function. Am J Cardiol 2000; 85(12):1461\u0026ndash;6. doi: 10.1016/s0002-9149(00)00795-5.\u003c/li\u003e\n\u003cli\u003evan Kraaij DJ, Jansen RW, Bouwels LH, Hoefnagels WH. Furosemide withdrawal improves postprandial hypotension in elderly patients with heart failure and preserved left ventricular systolic function. Arch Intern Med 1999; 159(14):1599\u0026ndash;605. doi: 10.1001/archinte.159.14.1599.\u003c/li\u003e\n\u003cli\u003evan Kraaij DJW, Jansen RWMM, Sweep FCGJ, Hoefnagels WHL. Neurohormonal effects of furosemide withdrawal in elderly heart failure patients with normal systolic function. Eur J Heart Fail 2003; 5(1):47\u0026ndash;53. doi: 10.1016/s1388-9842(02)00205-2.\u003c/li\u003e\n\u003cli\u003evan Reekum R, Clarke D, Conn D, Herrmann N, Eryavec G, Cohen T et al. A randomized, placebo-controlled trial of the discontinuation of long-term antipsychotics in dementia. Int Psychogeriatr 2002; 14(2):197\u0026ndash;210. doi: 10.1017/s1041610202008396.\u003c/li\u003e\n\u003cli\u003eVibhagool A, Sungkanuparph S, Mootsikapun P, Chetchotisakd P, Tansuphaswaswadikul S, Bowonwatanuwong C et al. Discontinuation of secondary prophylaxis for cryptococcal meningitis in human immunodeficiency virus-infected patients treated with highly active antiretroviral therapy: a prospective, multicenter, randomized study. Clin Infect Dis 2003; 36(10):1329\u0026ndash;31. doi: 10.1086/374849.\u003c/li\u003e\n\u003cli\u003eVilien M, Dahlerup JF, Munck LK, N\u0026oslash;rregaard P, Gr\u0026oslash;nbaek K, Fallingborg J. Randomized controlled azathioprine withdrawal after more than two years treatment in Crohn\u0026apos;s disease: increased relapse rate the following year. Aliment Pharmacol Ther 2004; 19(11):1147\u0026ndash;52. doi: 10.1111/j.1365-2036.2004.01944.x.\u003c/li\u003e\n\u003cli\u003eWalma EP, Hoes AW, van Dooren C, Prins A, van der Does E. Withdrawal of long-term diuretic medication in elderly patients: a double blind randomised trial. BMJ 1997; 315(7106):464\u0026ndash;8. doi: 10.1136/bmj.315.7106.464.\u003c/li\u003e\n\u003cli\u003eWenzl HH, Primas C, Novacek G, Teml A, \u0026Ouml;fferlbauer-Ernst A, H\u0026ouml;genauer C et al. Withdrawal of long-term maintenance treatment with azathioprine tends to increase relapse risk in patients with Crohn\u0026apos;s disease. Dig Dis Sci 2015; 60(5):1414\u0026ndash;23. doi: 10.1007/S10620-014-3419-5.\u003c/li\u003e\n\u003cli\u003eWistedt B. A depot neuroleptic withdrawal study. A controlled study of the clinical effects of the withdrawal of depot fluphenazine decanoate and depot flupenthixol decanoate in chronic schizophrenic patients. Acta Psychiatr Scand 1981; 64(1):65\u0026ndash;84. doi: 10.1111/j.1600-0447.1981.tb00761.x.\u003c/li\u003e\n\u003cli\u003eWolde S ten, Breedveld FC, Hermans J, Vandenbroucke JP, van de Laar MA, Markusse HM et al. Randomised placebo-controlled study of stopping second-line drugs in rheumatoid arthritis. Lancet 1996; 347(8998):347\u0026ndash;52. doi: 10.1016/s0140-6736(96)90535-8.\u003c/li\u003e\n\u003cli\u003eWunderink L, Nienhuis FJ, Sytema S, Slooff CJ, Knegtering R, Wiersma D. Guided discontinuation versus maintenance treatment in remitted first-episode psychosis: relapse rates and functional outcome. J Clin Psychiatry 2007; 68(5):654\u0026ndash;61. doi: 10.4088/jcp.v68n0502.\u003c/li\u003e\n\u003cli\u003eZhu Q, Zhao Y, Liu W, Luo H, Qiu Y, Gao Z. Two-year observation of a randomized trial on tacrolimus-based therapy with withdrawal of steroids or mycophenolate mofetil after renal transplantation. Chin Med Sci J 2008; 23(4):244\u0026ndash;8. doi: 10.1016/S1001-9294(09)60047-X.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-medical-research-methodology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bmrm","sideBox":"Learn more about [BMC Medical Research Methodology](http://bmcmedresmethodol.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bmrm/default.aspx","title":"BMC Medical Research Methodology","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Polypharmacy, Deprescribing; Drug discontinuation, Scoping Review, Outcome Selection ","lastPublishedDoi":"10.21203/rs.3.rs-5929100/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-5929100/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground:\u003c/strong\u003e The widespread use of long-term pharmacological treatments for chronic conditions has led to polypharmacy, raising concerns about adverse effects and interactions. Deprescribing, the discontinuation of drugs with unfavorable benefit-risk ratios, is gaining attention. Studies evaluating the discontinuation of drugs have a broad methodological spectrum. The selection of outcomes poses a particular challenge. This scoping review addresses the methodological challenges of outcome selection in RCTs investigating drug discontinuation.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods:\u003c/strong\u003e The scoping review includes RCTs that investigated the discontinuation of drugs whose efficacy and/or safety was in doubt. Data on study characteristics, the motivation for evaluating drug discontinuation, the number and type of primary endpoints, and the stated hypotheses were extracted and analyzed.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults:\u003c/strong\u003e We included 103 RCTs. Most studies were from Europe and the USA and mainly investigated antipsychotics/antidepressants, immunosuppressants, steroids and antiepileptics. The discontinuation studies were often conducted due to side effects of the treatment and doubts about the benefits of the drug. The primary endpoints reflected either the course of the disease (\"justification of treatment\") or the disadvantages of the drug (\"justification of withdrawal”). Non-inferiority hypotheses were generally prevalent in justification of treatment studies, while superiority hypotheses were more commonly used in justification of withdrawal studies. However, due to methodological and practical challenges this was not always the case.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion:\u003c/strong\u003e We present a framework to choose outcomes and specify hypotheses for discontinuation studies. With regard to this, both key challenges (justification of treatment and justification of withdrawal) must be met.\u003c/p\u003e","manuscriptTitle":"Trials evaluating drug discontinuation: a scoping review sub-analysis focusing on outcomes and research questions","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-04-30 11:42:19","doi":"10.21203/rs.3.rs-5929100/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Accepted","date":"2025-05-15T07:11:56+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-05-14T20:52:15+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"224216286803130717857430115235698203121","date":"2025-04-27T08:10:30+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"85978218148550068158009563447270352405","date":"2025-04-21T03:19:42+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-04-19T01:58:07+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"234772330835733393068242709444180037559","date":"2025-04-18T17:28:25+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-04-18T16:05:04+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-04-17T12:43:56+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Medical Research Methodology","date":"2025-04-17T12:24:00+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-medical-research-methodology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bmrm","sideBox":"Learn more about [BMC Medical Research Methodology](http://bmcmedresmethodol.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bmrm/default.aspx","title":"BMC Medical Research Methodology","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"3bcb0f04-29b0-471a-aeb2-50595ee818dc","owner":[],"postedDate":"April 30th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2025-06-02T15:58:20+00:00","versionOfRecord":{"articleIdentity":"rs-5929100","link":"https://doi.org/10.1186/s12874-025-02597-z","journal":{"identity":"bmc-medical-research-methodology","isVorOnly":false,"title":"BMC Medical Research Methodology"},"publishedOn":"2025-05-27 15:56:55","publishedOnDateReadable":"May 27th, 2025"},"versionCreatedAt":"2025-04-30 11:42:19","video":"","vorDoi":"10.1186/s12874-025-02597-z","vorDoiUrl":"https://doi.org/10.1186/s12874-025-02597-z","workflowStages":[]},"version":"v1","identity":"rs-5929100","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-5929100","identity":"rs-5929100","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}