Introduction

Chronic Obstructive Pulmonary Disease (COPD) is a progressive chronic disease characterized by irreversible, fixed airways obstruction, progressive destruction of lung parenchyma and airways inflammation.1 Mucus hypersecretion and narrowing of the airways2 contribute to symptoms including excessive sputum production, dyspnoea and chronic cough3 punctuated by episodes of acute worsening of symptoms known as exacerbations.4 The Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2023 guidelines recommend that the mainstay of treatment for COPD patients includes long-acting muscarinic antagonists (LAMA) and long-acting beta agonists (LABA).5,6 These long-acting bronchodilators can be prescribed alone, as a dual therapy with LABA/LAMA, or in combination with inhaled corticosteroids (ICS) as a triple therapy as LABA/LAMA/ICS to relieve symptoms and prevent exacerbations of COPD.7

In accordance with the GOLD guidelines, only symptomatic COPD patients with a blood eosinophil count (BEC) of ≥300 cells/µL and with ≥2 exacerbations per year, who are inadequately controlled by LABA/LAMA therapy, should be given ICS therapy.6,8 Patients with raised BECs have a better response to ICS therapy than patients with low BECs.9,10 Despite this guidance, many patients with a diagnosis of COPD, without a history of frequent exacerbations and mild or moderate airflow limitation continue to be prescribed ICS therapy, in spite of the lack of evidence of efficacy.11 Up to 70% of newly diagnosed COPD patients are prescribed ICS therapy from initiation of inhaled treatment.12 Overprescription of ICS therapy poses a burden for patients and the healthcare system as their use increases the likelihood of adverse effects including glaucoma, cataracts, pneumonia and osteoporosis.13

Despite the increasing evidence for the safety and feasibility of ICS withdrawal and its prominence in clinical guidelines,9,12,14 a number of recent studies suggest that the intervention may lead to a deterioration in clinical outcomes.15,16 In addition, little is known of the participants who fail a trial of withdrawal. The primary aim of this systematic review was to examine the effect of ICS withdrawal on the exacerbation frequency and change in lung function (FEV1) of COPD patients. The secondary aim was to determine the prevalence of resumption of ICS therapy among COPD patients who had undergone ICS withdrawal. The review seeks to assist in the identification of COPD patients eligible for a trial of ICS withdrawal and to improve patient safety in the withdrawal process.

Methods

This systematic review aimed to evaluate the effect of ICS withdrawal on the exacerbation frequency and lung function of COPD patients and to determine the proportion of patients who resumed ICS therapy following withdrawal. The search strategy, structure, and conduct of this review followed the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) checklist.17

Eligibility Criteria

Randomised controlled trials (RCTs) and non-randomised observational studies were included in this review. The RCTs of ICS withdrawal randomised patients into ICS withdrawal and ICS continuation arms. Included studies reported one or more of the outcomes of this review (Table 1). Exacerbations were defined as moderate where antibiotics and/or oral corticosteroids were prescribed for the treatment of COPD symptoms, and severe where hospital admission was required for the treatment of COPD symptoms.18 Included inhaled corticosteroids were mometasone, ciclesonide, flunisolide, beclometasone, budesonide, triamcinolone and fluticasone. Exclusion criteria were all review articles, commentary articles or editorials. Studies that were not in English were also excluded. A full table of inclusion/exclusion criteria can be found in the Supplementary File and Supplementary Table S1.

Table 1 PICO Framework

Search Strategy

The PICO (population, intervention, comparison and outcome) framework was followed.

The electronic databases Cochrane Central, Web of Science, CINHAL, Embase and OVID Medline were searched from inception to 01/08/2023. Medical subject headings (MeSH) search terms were used and searches were conducted using free text, partial abbreviations, truncation, explosion and Boolean operators, such as “OR” and “AND”.19 The web-based software Covidence was used for the screening process and to facilitate the selection of studies. The first author (AG) conducted the database searches and screened retrieved papers by title and abstract with respect to the eligibility criteria. Duplicates were removed automatically by Covidence, or manually by the first author. The remaining full-text articles were screened independently by two reviewers (AG and RR), with any disagreements being resolved by discussion. A third reviewer (TH) moderated the decision where consensus was not reached. Reasons for exclusion of full-text articles were clearly recorded. Quality appraisal of the included studies was conducted independently by two reviewers (AG & TH), with the final quality appraisal being reached by consensus.

Data Extraction

The data extracted from the articles included author/year, methods, treatment arms, participants (characteristics, disease severity, prior exacerbation history, trial run-in period, length of prior use of ICS therapy and exacerbation description), and outcomes (change in exacerbation frequency, change in lung function, resumption of ICS use).

Quality Assessment

The risk of bias of the randomised controlled trials was assessed using the Cochrane RoB2 tool,20 whilst the quality assessment of the observational studies was assessed using the Newcastle-Ottawa Scale.21 The grading of recommendations assessment, development, and evaluation approach (GRADE) was used to determine the quality of evidence for each outcome of the included RCTs.22

The risk of bias assessment was conducted independently by two reviewers, with any disagreements being resolved by discussion. The GRADE assessment was similarly conducted by two reviewers independently, with any disagreements being resolved by discussion. The quality of evidence from RCTs was deemed moderate for both outcome measures.

Meta Analysis

A post-hoc meta-analysis was undertaken to summarise the effect of ICS withdrawal on the exacerbation frequency and lung function of COPD patients stratified by blood eosinophil count thresholds of <300 cells/µL and ≥300 cells/µL. Cochran’s Q test was used to assess between-study heterogeneity, where the true underlying effect varies between trials. We used the I2 statistic to quantify this to give the proportion of overall variation accounted for by between-study heterogeneity. The assessment of clinical and methodological heterogeneity was conducted via discussion between authors. A random effects analysis was used where important heterogeneity was identified. Otherwise, a fixed-effects model was used which assumed each study measured the same underlying effect. The STATA version 17 was used for the statistical analysis.

Results

A total of 6729 papers were screened by title and abstract, after 1548 duplicates were removed. The reference list of included studies was also searched by title and abstract against the eligibility criteria to determine relevance to the review. One hundred and forty-nine papers were then screened by full text. Sixteen studies were included in the review (Figure 1); 10 RCTs and 6 observational studies. Search strategies are included in Supplementary Tables S2–S6.

Figure 1 Withdrawal of inhaled corticosteroids from patients with COPD: effect on exacerbation frequency of withdrawal and proportion who resumes treatment.

Effect on Exacerbation Frequency

The earliest RCTs of ICS withdrawal (Table 2) reported either no difference in the frequency of moderate/severe exacerbations,23 or an increased risk of exacerbations in the ICS withdrawal (placebo inhaler) vs ICS continuation arm.24,25 More recent trials (Table 2) demonstrated that when bronchodilation (LABA or LABA+LAMA) was maintained after ICS withdrawal there was no difference in the exacerbation frequency between the trial arms.11,26–30 Within the RCTs in which bronchodilation was maintained after ICS withdrawal, the annual mean exacerbation rate ranged from 0.15 to 1.6 exacerbations per patient-year in the ICS withdrawal arms and from 0.05 to 1.3 exacerbations per patient-year in the ICS continuation arms.11,26,28–30 WISDOM, the largest ICS withdrawal trial, found no significant difference in the rate of moderate/severe exacerbations between the two arms.28

Table 2 Outcomes of RCTs

The evidence for stability in exacerbation frequency following ICS withdrawal was judged to be of moderate quality (Table S7). The trials were judged ineligible for meta-analysis due to their heterogeneity. Comparison showed clinical heterogeneity in the types of maintenance therapies provided to the patients in the ICS withdrawal arms of the RCTs, and variation in the definition of exacerbations between the studies (Table S7). In addition, there was marked variability in the prior exacerbation histories and degree of airflow limitation (FEV1% predicted) among the patients of the RCTs. Prior exacerbation histories of patients across the trials ranged from zero29 to at least two exacerbations30 per patient-year (Table 3). The FEV1% predicted values ranged from 34.3% (±10.8%)28 to 73.53% (±14.12%)11 and from 34.2% (±11.2%) to 72.79% (±14.12%) in the ICS withdrawal and continuation arms, respectively (Table 3). The duration of follow-up varied between trials. One was for 6 weeks,23 two for 3 months,27,31 four for 6 months11,25,26,29 and three for 1 year.24,28,30

Table 3 Characteristics of the RCTs

Risk of bias assessment found some concerns of bias arising from the randomisation process due to unclear allocation concealment in four trials;11,23,25,30 some concerns of bias due to missing outcome data due to unclear risk of attrition bias in one trial;23 and some concerns of bias in measurement of the outcome due to unclear risk of detection bias in five trials11,23–25,30 (Figure 2).

Figure 2 Risk of bias (ROB) summary of randomised controlled trials I for outcome measure change in exacerbation frequency.

Many of the observational studies described variability in the patient characteristics and treatment regimens (Table 4). All but one of the eligible observational studies reported no difference or a protective effect of ICS withdrawal with respect to change in exacerbation frequency (Table 5).32–34 Neches Garcia et al found an increase in the annual exacerbation rate within the ICS withdrawal in comparison to the ICS continuation group.15 The results of the quality assessment of the observational studies are presented in Table S8. Five of the six studies were of high quality.15,16,33–35 One study was of fair quality due to concerns of bias regarding its selection of controls, ascertainment of exposure and non-response rate.32

Table 4 Characteristics of the Observational Studies

Table 5 Outcomes of Observational Studies

Effect on Lung Function

The RCTs which compared continuation of ICS therapy with use of placebo found either no difference24,25 in change in lung function or an increased decline in lung function23 among those participants who withdrew from ICS therapy (Table 2). The INSTEAD trial compared ICS continuation therapy with LABA monotherapy and reported no difference in change in lung function between the arms.29 All but one of the trials which compared continuation of ICS therapy with use of dual-bronchodilation LABA/LAMA therapy reported either no difference in the change in lung function between the trial arms or an improvement favouring the ICS withdrawal arm.11,26,27,31 Across the eligible trials, the difference in the change in mean FEV1 between the trial arms ranged from 0.014L (95% CI −0.046 to 0.019)29 to 0.38L (−0.79 to 0.016).25

The COSMIC30 and the WISDOM28 trials, which compared ICS continuation with LABA monotherapy and LABA/LAMA dual therapies, respectively, did report a significantly increased decline in lung function among the ICS withdrawal compared to the ICS continuation arms. The differences in change in lung function between the trial arms were 0.05L (95% CI: 0.01 to 0.1) in the COSMIC trial and 0.043L (p = 0.001) in the WISDOM trial. In both trials, the difference between the arms did not meet the threshold for the minimal clinically important difference (MCID) in change in lung function of 0.1L.36

The evidence for stability in lung function following ICS withdrawal was judged to be of moderate quality (Table S9). Risk of bias assessment found some concerns of bias arising from the randomisation process due to unclear allocation concealment in five trials;11,23,25,30,31 some concerns of bias due to missing outcome data due to unclear risk of attrition bias in two trials;23,31 and some concerns of bias in measurement of the outcome due to unclear risk of detection bias in six trials11,23–25,30,31 (Figure 3).

Figure 3 Risk of bias (ROB) summary of randomised controlled trials II for outcome measure change in lung function.

The observational studies found no significant difference in the change in lung function between patients who withdrew from and those who continued using ICS therapy (Table 5).16,34

Resumption of ICS Treatment

Few of the studies included in this review reported on the proportion of patients who resumed ICS therapy following a trial of withdrawal. Only two of the RCTs11,24 and three of the observational studies reported this finding.33–35 The reported range of patients resuming ICS therapy following withdrawal was from 21% to 74%.11,35

Impact on Outcomes of the Stratification by Blood Eosinophil Count

Two RCTs, the SUNSET26 and WISDOM28 trials reported an association between blood eosinophil count and the impact of ICS withdrawal on exacerbation frequency and change in lung function among COPD patients. Both were post-hoc analyses and, in the case of the WISDOM trial, the findings were included in a later publication.37 These post-hoc analyses were eligible for meta-analysis. Both trials included treatment arms of triple therapy vs dual-bronchodilation therapy. They both described the annualised exacerbation rate among participants. Among patients with COPD with a BEC ≥300 cells/µL, ICS withdrawal was associated with an increased exacerbation risk of 63% (RR, 1.63; 1.24–2.14) (Figure S1) and a decline in FEV1 of 0.05L (RR, 0.05; 0.01–0.10) (Figure S2). ICS withdrawal was not associated with a change in exacerbation risk or a change in lung function in COPD patients with a BEC <300 cells/µL (Figures S3 and S4).

Discussion

This systematic review has identified a substantial number of studies which examined the impact of ICS withdrawal from patients with COPD. The earliest withdrawal studies, in which patients substituted ICS therapy for a placebo, did describe a worsening in the exacerbation frequency and a deterioration in lung function among patients withdrawn from ICS therapy compared with those who continued it. Newer studies in which participants maintained mono- or dual-bronchodilation therapy after ICS withdrawal did not report a deterioration in health outcomes for COPD patients with respect to change in exacerbation frequency or lung function. This included the WISDOM trial which enrolled COPD patients with severe and very severe airflow limitation, historically those candidates for whom ICS therapy would have been recommended.28 In two of the trials in which bronchodilation therapy was maintained following ICS withdrawal a statistically significant increased decline in lung function within the ICS withdrawal group was reported.28,30 The decline in lung function may not be of clinical significance, as the change in FEV1 was beneath the threshold for the minimal clinically important difference of 0.1L.36 The effects on change in lung function and exacerbation frequency of withdrawal of ICS therapy, when bronchodilation was maintained, from COPD patients were minor. These findings were consistent across the majority of the RCTs and observational studies and the evidence was judged to be of high to moderate quality.

Few studies have reported the prevalence of resumption of ICS therapy after a trial of withdrawal, an important consideration for all clinicians who attempt ICS withdrawal in clinical practice.

In the RCTs and observational studies which did report this outcome, the analyses of rates were unclear and inconsistent between studies. The studies varied with regard to the types of replacement inhalers provided to those who withdrew from ICS therapy, the degree of airflow limitation among participants, differences in their prior exacerbation histories and the length of follow-up per study. An accurate estimate would best be derived from a prospective trial. The paucity of data reported on the resumption of ICS therapy and the wide range in prevalence among those studies that reported this finding, makes it difficult to provide a firm estimate by which to guide clinical practice.

The findings from the majority of the studies included in this review were not appropriate for meta-analysis due to major differences in study populations and methodology. Many withdrawal studies had different treatment arms, preventing statistical comparison. There was heterogeneity between trials in terms of sample size, differing inclusion criteria, definition of exacerbation and type of replacement therapies following ICS withdrawal. Participants in many studies had substantial differences in age, lung function, and exacerbation histories. Many studies included different types and dosages of steroid therapies, with variation in the treatment strategies, run-in periods, and types of ICS therapy used by the participants prior to study enrolment.

The meta-analysis, obtained from post-hoc analyses of the WISDOM and SUNSET trials,26,37 provides evidence of lung function decline and an increased risk of exacerbations among those patients with COPD with BEC ≥300 cells/µL who withdrew from ICS therapy. The findings suggest that in COPD patients without a history of frequent prior exacerbations (<2 exacerbations per year) and with a BEC <300 cells/µL, ICS withdrawal is safe and feasible, provided patients also receive maintenance therapy with either mono- or dual-bronchodilation. This supports the GOLD recommendations for ICS prescription within this group.6 The follow-up periods after ICS withdrawal included in the post-hoc analyses varied between the two included trials.26,37 In the WISDOM trial,37 the 9-month period after complete withdrawal of ICS was included, while a 6-month period was included in the SUNSET trial.26 The demographic characteristics of the participants of the two trials differed. The participants included in the analysis of the WISDOM trial had a mean FEV1% predicted of 34.2% ± 11.0 and all had experienced at least one moderate or severe exacerbation in the year prior to the trial. The participants included in the analysis of the SUNSET trial had a mean FEV1% predicted of 56.6% ± 9.97 and 34% of the participants had experienced one moderate or severe exacerbation in the past year.

Our findings are supported by those of previous systematic reviews. Nadeem et al looked at the effects of withdrawal of ICS therapy from patients with COPD in RCTs that compared ICS withdrawal with continuation. The review included four RCTs (WISP, COPE, COSMIC, O’Brien et al, 2001).13 They found no statistically significant difference in exacerbation frequency. Change in lung function was only found to be statistically significant in the COSMIC trial (but did not reach the threshold of the MCID).13 In 2020, a review by Chalmers et al reported similar findings from a broader range of trials.9 Again, no statistically significant difference was found in exacerbation frequency between ICS continuation and ICS withdrawal and, whilst the change in lung function was statistically significant, this did not meet the threshold for the MCID.36 A recent scoping review of ICS withdrawal suggested that adverse effects of withdrawal were more common following abrupt withdrawal in comparison to gradual withdrawal.38

The current systematic review is the first to compare randomised controlled trials and observational studies of ICS withdrawal in COPD. The meta-analysis of the impact of withdrawal of ICS therapy with respect to exacerbation frequency and change in lung function among patients with COPD stratified by blood eosinophil count is novel. Heterogeneity between the ICS withdrawal studies in participant characteristics, factors that may influence the impact of ICS withdrawal, prevented inclusion of most studies in the meta-analysis. Another limitation of the review was that follow-up times were not compared between the studies to understand whether time since ICS withdrawal modified the relationship between withdrawal and the outcome measures. Confounding is a possible limitation in the interpretation of the results of the observational studies. However, in most of the observational studies the ICS withdrawal group had either similar32,35 or poorer baseline morbidity,33,34 with respect to symptom severity33 or prior exacerbation history,34 but showed no adverse outcome in comparison to the continuation group. One observational study did report a worsening in exacerbation rate among those who withdrew from ICS therapy.15 These participants had less severe airflow limitation at baseline and fewer prior exacerbations compared to those in the continuation group.

Conclusions

Withdrawal of ICS from COPD patients is safe and feasible without a detrimental impact on exacerbation frequency and decline in lung function among the majority of COPD patients. Withdrawal of ICS therapy should be accompanied by maintenance of bronchodilation therapy for optimal outcomes. Patients with frequent exacerbations (≥2 per year) and a BEC ≥300 cells/µL may benefit from continued ICS use. These findings provide clinicians with the confidence to withdraw ICS therapy from COPD patients for whom it has been inappropriately prescribed. There is a need for prospective trials, both RCTs and observational studies using routinely collected data, which identify the characteristics of those in whom ICS withdrawal should not be attempted. Details such as the patient’s exacerbation history, lung function, exercise capacity, physical activity and health status could all possibly be used to determine whether withdrawing ICS from these patients with COPD is feasible. Further research may outline more clearly the criteria that a patient needs to fulfil to increase clinicians’ confidence that withdrawal of ICS will be safe.

Abbreviations

COPD, chronic obstructive pulmonary disease; ICS, inhaled corticosteroids; FEV1, forced expiratory volume in 1 second; OCSs, observational cohort studies; RCTs, randomised controlled trials; LAMA, long-acting muscarinic antagonists; LABA, long-acting beta agonists; MCID, minimal clinically important difference.

Data Sharing Statement

All data generated or analysed during this study are included in this published article [and its Supplementary Information Files].

Disclosure

THH and PW were co-authors of the study Harries TH, Gilworth G, Corrigan CJ, et al. Withdrawal of inhaled corticosteroids from patients with COPD with mild or moderate airflow limitation in primary care: a feasibility randomised trial. BMJ Open Respir Res. 2022;9(1):e001311. doi:10.1136/bmjresp-2022-001311. They have recused themselves from any involvement in the assessment of the risk of bias in this study. The authors report no other conflicts of interest in this work.

References

1. Hogg JC, Timens W. The pathology of chronic obstructive pulmonary disease. Annu Rev Pathol. 2009;4:435–459. doi:10.1146/annurev.pathol.4.110807.092145

2. Avdeev S, Aisanov Z, Arkhipov V, et al. Withdrawal of inhaled corticosteroids in COPD patients: rationale and algorithms. Int J Chron Obstruct Pulmon Dis. 2019;14:1267–1280. doi:10.2147/COPD.S207775

3. Nielsen AO, Hilberg O, Jensen JUS, et al. Withdrawal of inhaled corticosteroids in patients with COPD - A prospective observational study. Int J Chron Obstruct Pulmon Dis. 2021;16:807–815. doi:10.2147/COPD.S294217

4. Vogelmeier CF, Román-Rodríguez M, Singh D, Han MK, Rodríguez-Roisin R, Ferguson GT. Goals of COPD treatment: focus on symptoms and exacerbations. Respir Med. 2020;166:105938. doi:10.1016/j.rmed.2020.105938

5. 2023 GOLD Report. Global initiative for chronic obstructive lung disease - GOLD. Available from: https://goldcopd.org/2023-gold-report-2/. Accessed April26, 2023.

6. Agustí A, Celli BR, Criner GJ, et al. Global initiative for chronic obstructive lung disease 2023 report: GOLD executive summary. Eur Respir J. 2023;61(4):2300239. doi:10.1183/13993003.00239-2023

7. Patel S, Dickinson S, Morris K, Ashdown HF, Chalmers JD. A descriptive cohort study of withdrawal from inhaled corticosteroids in COPD patients. NPJ Prim Care Respir Med. 2022;32(1):25. doi:10.1038/s41533-022-00288-6

8. Yawn BP, Suissa S, Rossi A. Appropriate use of inhaled corticosteroids in COPD: the candidates for safe withdrawal. NPJ Prim Care Respir Med. 2016;26:16068. doi:10.1038/npjpcrm.2016.68

9. Chalmers JD, Laska IF, Franssen FME, et al. Withdrawal of inhaled corticosteroids in COPD: a European respiratory society guideline. Eur Respir J. 2020;55(6):2000351. doi:10.1183/13993003.00351-2020

10. Harries TH, Rowland V, Corrigan CJ, et al. Blood eosinophil count, a marker of inhaled corticosteroid effectiveness in preventing COPD exacerbations in post-hoc RCT and observational studies: systematic review and meta-analysis. Respir Res. 2020;21(1):3. doi:10.1186/s12931-019-1268-7

11. Harries TH, Gilworth G, Corrigan CJ, et al. Withdrawal of inhaled corticosteroids from patients with COPD with mild or moderate airflow limitation in primary care: a feasibility randomised trial. BMJ Open Respir Res. 2022;9(1):e001311. doi:10.1136/bmjresp-2022-001311

12. Cataldo D, Derom E, Liistro G, et al. Overuse of inhaled corticosteroids in COPD: five questions for withdrawal in daily practice. Int J Chron Obstruct Pulmon Dis. 2018;13:2089–2099. doi:10.2147/COPD.S164259

13. Nadeem NJ, Taylor SJC, Eldridge SM. Withdrawal of inhaled corticosteroids in individuals with COPD--A systematic review and comment on trial methodology. Respir Res. 2011;12(1):107. doi:10.1186/1465-9921-12-107

14. Calzetta L, Matera MG, Braido F, et al. Withdrawal of inhaled corticosteroids in COPD: a meta-analysis. Pulm Pharmacol Ther. 2017;45:148–158. doi:10.1016/j.pupt.2017.06.002

15. Neches García V, Vallejo-Aparicio LA, Ismaila AS, et al. Clinical and economic impact of long-term inhaled corticosteroid withdrawal in patients with chronic obstructive pulmonary disease treated with triple therapy in Spain. Int J Chron Obstruct Pulmon Dis. 2022;17:2161–2174. doi:10.2147/COPD.S367708

16. Whittaker HR, Wing K, Douglas I, Kiddle SJ, Quint JK. Inhaled corticosteroid withdrawal and change in lung function in primary care patients with chronic obstructive pulmonary disease in England. Ann Am Thorac Soc. 2022;19(11):1834–1841. doi:10.1513/AnnalsATS.202111-1238OC

17. Moher D, Liberati A, Tetzlaff J, Altman DG, PRISMA Group. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. BMJ. 2009;339:b2535. doi:10.1136/bmj.b2535

18. Wedzicha JA, Seemungal TAR. COPD exacerbations: defining their cause and prevention. Lancet. 2007;370(9589):786–796. doi:10.1016/S0140-6736(07)61382-8

19. Bramer WM, de Jonge GB, Rethlefsen ML, Mast F, Kleijnen J. A systematic approach to searching: an efficient and complete method to develop literature searches. J Med Libr Assoc JMLA. 2018;106(4):531–541. doi:10.5195/jmla.2018.283

20. Sterne JAC, Savović J, Page MJ, et al. RoB 2: a revised tool for assessing risk of bias in randomised trials. BMJ. 2019;366:l4898. doi:10.1136/bmj.l4898

21. Wells G, Shea B, O’Connell D, et al. The Newcastle-Ottawa Scale (NOS) for assessing the quality if nonrandomized studies in meta-analyses. 2012. Available from: http://www.ohri.ca/programs/clinical_epidemiology/oxford.htm. Accessed June4, 2024.

22. Guyatt G, Oxman AD, Akl EA, et al. GRADE guidelines: 1. Introduction-GRADE evidence profiles and summary of findings tables. J Clin Epidemiol. 2011;64(4):383–394. doi:10.1016/j.jclinepi.2010.04.026

23. O’brien A, Russo-Magno P, Karki A, et al. Effects of withdrawal of inhaled steroids in men with severe irreversible airflow obstruction. Am J Respir Crit Care Med. 2001;164(3):365–371. doi:10.1164/ajrccm.164.3.2002052

24. Choudhury AB, Dawson CM, Kilvington HE, 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

25. van der Valk P, Monninkhof E, van der Palen J, Zielhuis G, van Herwaarden C. Effect of discontinuation of inhaled corticosteroids in patients with chronic obstructive pulmonary disease: the COPE study. Am J Respir Crit Care Med. 2002;166(10):1358–1363. doi:10.1164/rccm.200206-512OC

26. Chapman KR, Hurst JR, Frent SM, et al. Long-term triple therapy de-escalation to indacaterol/glycopyrronium in patients with chronic obstructive pulmonary disease (SUNSET): a randomized, double-blind, triple-dummy clinical trial. Am J Respir Crit Care Med. 2018;198(3):329–339. doi:10.1164/rccm.201803-0405OC

27. Frith PA, Ashmawi S, Krishnamurthy S, et al. Efficacy and safety of the direct switch to indacaterol/glycopyrronium from salmeterol/fluticasone in non-frequently exacerbating COPD patients: the FLASH randomized controlled trial. Respirol Carlton Vic. 2018;23(12):1152–1159. doi:10.1111/resp.13374

28. Magnussen H, Disse B, Rodriguez-Roisin R, et al. Withdrawal of inhaled glucocorticoids and exacerbations of COPD. N Engl J Med. 2014;371(14):1285–1294. doi:10.1056/NEJMoa1407154

29. Rossi A, van der Molen T, Del Olmo R, et al. INSTEAD: a randomised switch trial of indacaterol versus salmeterol/fluticasone in moderate COPD. Eur Respir J. 2014;44(6):1548–1556. doi:10.1183/09031936.00126814

30. Wouters EFM, Postma DS, Fokkens B, et al. Withdrawal of fluticasone propionate from combined salmeterol/fluticasone treatment in patients with COPD causes immediate and sustained disease deterioration: a randomised controlled trial. Thorax. 2005;60(6):480–487. doi:10.1136/thx.2004.034280

31. Vogelmeier CF, Gaga M, Aalamian-Mattheis M, et al. Efficacy and safety of direct switch to indacaterol/glycopyrronium in patients with moderate COPD: the CRYSTAL open-label randomised trial. Respir Res. 2017;18(1):140. doi:10.1186/s12931-017-0622-x

32. Rossi A, Guerriero M, Corrado A; OPTIMO/AIPO Study Group. Withdrawal of inhaled corticosteroids can be safe in COPD patients at low risk of exacerbation: a real-life study on the appropriateness of treatment in moderate COPD patients (OPTIMO). Respir Res. 2014;15(1):77. doi:10.1186/1465-9921-15-77

33. Vogelmeier C, Worth H, Buhl R, et al. “Real-life” inhaled corticosteroid withdrawal in COPD: a subgroup analysis of DACCORD. Int J Chron Obstruct Pulmon Dis. 2017;12:487–494. doi:10.2147/COPD.S125616

34. Magnussen H, Lucas S, Lapperre T, et al. Withdrawal of inhaled corticosteroids versus continuation of triple therapy in patients with COPD in real life: observational comparative effectiveness study. Respir Res. 2021;22(1):25. doi:10.1186/s12931-021-01615-0

35. Suissa S, Dell’Aniello S, Ernst P. Single-inhaler triple versus dual bronchodilator therapy in COPD: real-world comparative effectiveness and safety. Int J Chron Obstruct Pulmon Dis. 2022;17:1975–1986. doi:10.2147/COPD.S378486

36. Jones PW, Beeh KM, Chapman KR, Decramer M, Mahler DA, Wedzicha JA. Minimal clinically important differences in pharmacological trials. Am J Respir Crit Care Med. 2014;189(3):250–255. doi:10.1164/rccm.201310-1863PP

37. Watz H, Tetzlaff K, Wouters EFM, et al. Blood eosinophil count and exacerbations in severe chronic obstructive pulmonary disease after withdrawal of inhaled corticosteroids: a post-hoc analysis of the WISDOM trial. Lancet Respir Med. 2016;4(5):390–398. doi:10.1016/S2213-2600(16)00100-4

38. Schroeder MN, Sens HM, Shah SK. De-prescribing inhaled corticosteroids in chronic obstructive pulmonary disease: a narrative review. J Pharm Pract. 2022;8971900221144127. doi:10.1177/08971900221144127