International Journal of Chronic Obstructive Pulmonary Disease Dovepress open access to scientific and medical research Open Access Full Text Article E X P E RT O P I N I O N International Journal of Chronic Obstructive Pulmonary Disease downloaded from https://www.dovepress.com/ by 158.109.88.164 on 26-Apr-2021 Withdrawal of inhaled corticosteroids in COPD patients: rationale and algorithms This article was published in the following Dove Press journal: International Journal of Chronic Obstructive Pulmonary Disease Sergey Avdeev 1,2 Abstract: Observational studies indicate that overutilization of inhaled corticosteroids (ICS) Zaurbek Aisanov 3 is common in patients with chronic obstructive pulmonary disease (COPD). Overprescription Vladimir Arkhipov 4 and the high risk of serious ICS-related adverse events make withdrawal of this treatment Andrey Belevskiy 3 necessary in patients for whom the treatment-related risks outweigh the expected benefits. Igor Leshchenko 5 Elaboration of an optimal, universal, user-friendly algorithm for withdrawal of ICS therapy 6 has been identified as an important clinical need. This article reviews the available evidence Svetlana Ovcharenko For personal use only. on the efficacy, risks, and indications of ICS in COPD, as well as the benefits of ICS Evgeny Shmelev 7 treatment withdrawal in patients for whom its use is not recommended by current guidelines. Marc Miravitlles 8 After discussing proposed approaches to ICS withdrawal published by professional associa- 1 Department of Pulmonology, I.M. tions and individual authors, we present a new algorithm developed by consensus of an Sechenov First Moscow State Medical international group of experts in the field of COPD. This relatively simple algorithm is based University, Moscow, Russian Federation; 2 Clinical Department, Federal on consideration and integrated assessment of the most relevant factors (markers) influencing Pulmonology Research Institute, Federal decision-making, such a history of exacerbations, peripheral blood eosinophil count, pre- Medical and Biological Agency of Russia, Moscow, Russian Federation; sence of infection, and risk of community-acquired pneumonia. 3 Department of Pulmonology, N.I. Keywords: COPD, exacerbation, inhaled corticosteroid, patient follow-up, guideline Pirogov Russian State National Research adherence, treatment algorithm Medical University, Moscow, Russian Federation; 4Department of Clinical Pharmacology and Therapy, Russian Medical Academy of Continuous Professional Education, Moscow, Russian Introduction Federation; 5Department of Phthisiology, Chronic obstructive pulmonary disease (COPD) is a progressive chronic disease Pulmonology and Thoracic Surgery, Ural State Medical University, Ekaterinburg, characterized by persistent bronchial obstruction and respiratory symptoms such as Russian Federation; 6Department of dyspnea, chronic cough, and sputum production.1 Chronic airway inflammation Internal Diseases No.1, I.M. Sechenov First Moscow State Medical University, plays a key role in the pathogenesis of COPD, causing narrowing of the small Moscow, Russian Federation; 7 airways, mucus hypersecretion, and destruction of the lung parenchyma.2 Department of Differential Diagnostics, Federal Central Research Institute of At present, there are considerable changes in approaches to prescription of inhaled Tuberculosis, Moscow, Russian corticosteroids (ICS) in COPD.3 As has been shown in clinical trials, an ICS, usually Federation; 8Pneumology Department, University Hospital Vall d’Hebron/Vall prescribed in a fixed-dose combination with a long-acting β2-agonist (LABA), reduces d’Hebron Research Institute (VHIR), the frequency of COPD exacerbations by an average of 25%,4 and may delay COPD Ciber de Enfermedades Respiratorias (CIBERES), Barcelona, Spain progression5 and improve disease prognosis in certain subgroups of patients.6 However, it is important to note that a significant proportion of COPD patients will not benefit from ICS therapy. For example, Lee et al7 tested the hypothesis that Correspondence: Sergey Avdeev different COPD subtypes respond differently to ICS/LABA therapy, and they found Department of Pulmonology, I.M. Sechenov First Moscow State Medical that ICS/LABA therapy provides no significant functional or clinical benefits in University, Healthcare Ministry of Russia, comparison with LABA alone in emphysema-dominant subtype patients. Airway Trubetskaya str., 8, Moscow 119991, Russian Federation inflammation in COPD is primarily neutrophil-driven,8,9 and does not respond to Tel +7 495 708 3576 ICS. Moreover, the combination of neutrophil-driven inflammation, bacterial infec- Fax +7 495 395 6393 Email serg_avdeev@list.ru tion, and ICS use can lead to adverse consequences.10,11 submit your manuscript | www.dovepress.com International Journal of Chronic Obstructive Pulmonary Disease 2019:14 1267–1280 1267 DovePress © 2019 Avdeev et al. This work is published and licensed by Dove Medical Press Limited. 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Powered by TCPDF (www.tcpdf.org) Avdeev et al Dovepress In agreement with current evidence, the Global Efficacy of ICS in COPD – what is Initiative for Chronic Obstructive Lung Disease (GOLD) the evidence? strategy reserves ICS use as part of initial treatment for Early studies on ICS therapy in COPD patients failed to International Journal of Chronic Obstructive Pulmonary Disease downloaded from https://www.dovepress.com/ by 158.109.88.164 on 26-Apr-2021 COPD group D patients with two or more moderate demonstrate any beneficial effects on lung function and exacerbations or one exacerbation leading to hospitaliza- symptom severity.15 However, an assessment of secondary tion in the preceding year and a blood eosinophil count endpoints in the ISOLDE study16 showed that fluticasone greater than 300 cells/µL, or as part of follow-up treatment propionate did reduce the number of exacerbations in in COPD patients with persistent exacerbations on long- COPD patients with severe airflow limitation (forced acting bronchodilator monotherapy or LABA/LAMA expiratory volume in 1 second (FEV1) of less than 50% combination therapy and a blood eosinophil count greater predicted).17 Subsequently, this ability to prevent COPD than 100 cells/µL.1 exacerbations was demonstrated for a number of other In the real-world environment, doctors frequently ICS,18 and it was found that these drugs were effective ignore clinical guidelines and, as shown in a number of not only in high doses, as believed initially, but also in observational studies conducted in different countries, moderate doses.19 overutilization of ICS is common, with up to 70% of all A number of studies were conducted to test the hypoth- COPD patients receiving ICS therapy, including patients in esis that ICS therapy not only decreases the number of GOLD groups A and B (up to 35% of COPD patients).12 exacerbations, but can also reduce mortality and delay The recent SUPPORT study conducted in Russia also COPD progression. Despite a considerable body of data For personal use only. found that the number of ICS prescriptions in real-life accumulated over up to 3 years of follow-up, no statisti- practice is too high, with 33% of ICS users among cally significant results have been obtained in favor of the GOLD group B patients.13 hypothesis, although the studies revealed a slight tendency The observation that ICS are overprescribed in COPD for increased survival in ICS (combined with LABA) has led to the suggestion that ICS therapy should be with- vs placebo.20,21 drawn in certain patients in order to decrease the risk of As ICS do not have the bronchodilator properties that adverse effects while also reducing treatment costs.3,11,14 are necessary to alleviate COPD symptoms, further stu- In this article, we provide a rationale for the withdrawal of dies evaluated fixed-dose ICS/LABA combinations. This unnecessary ICS treatment, and suggest an algorithm to treatment combination was assumed to have a good achieve this objective. bronchodilator effect and to be superior to bronchodila- In this paper we present a new algorithm developed by tor therapy alone in terms of exacerbation prevention. consensus of an international group of experts. Expert selec- However, evidence in favor of this assumption has not tion for the inclusion into consensus panel was based on their been demonstrated in all studies. For example, in the research activities in COPD and their previous publications 3-year TORCH study, the combination of fluticasone in peer reviewed journals. First of all, an expert group iden- propionate and salmeterol was superior to salmeterol tified areas of uncertainty about the efficacy of ICS, possible alone (risk ratio [RR]=0.88) in preventing moderate adverse effects associated with their use, and criteria for the and severe exacerbations in COPD patients (with withdrawal of ICS. The meeting of the expert group was held a prebronchodilator FEV1 of less than 60% predicted), three times in a 6 -month period to discuss different publica- but provided no benefit when only severe exacerbations tions on ICS withdrawal that were considered by all members were included in the analysis.20 Furthermore, in the of the committee, in order to evaluate whether these pub- INSTEAD trial, no difference in the number of exacer- lished data could have an impact on the development of the bations was found between fluticasone/salmeterol and algorithm. Then the expert group reached a consensus on indacaterol in COPD patients with moderate airflow whether to take into account the appropriate approach or if limitation and a history of no exacerbations in the the data presented in the analyzed article could serve as previous year.22 Finally, another fixed combination a reference supporting this approach. In the absence of con- (budesonide/formoterol) significantly decreased the num- sensus it was agreed to make a final solution by a simple ber of exacerbations compared to formoterol, but the majority. Finally, the expert group summarized the available effect of formoterol on the risk of exacerbations differed evidence in response to the aforementioned questions. little compared to placebo in these studies (all patients submit your manuscript | www.dovepress.com International Journal of Chronic Obstructive Pulmonary Disease 2019:14 1268 DovePress Powered by TCPDF (www.tcpdf.org) Dovepress Avdeev et al had a FEV1 of less than 50% predicted and ≥1 exacer- demonstrated. First, ICS are more effective in patients with bation within 2–12 months before the study).23,24 more severe lung function impairment. Second, the efficacy A meta-analysis of 18 randomized clinical trials found of ICS in reducing the risk of exacerbations is higher on International Journal of Chronic Obstructive Pulmonary Disease downloaded from https://www.dovepress.com/ by 158.109.88.164 on 26-Apr-2021 no significant superiority of ICS/LABA combinations a pro rata basis as mucus secretion and blood eosinophil over treatment with LABA alone in reducing the risk count increase and, although ICS-containing combinations of severe exacerbations.25 more effectively prevent exacerbations requiring ICS pre- Fewer clinical studies have compared the efficacy of scription, these are a priori inferior to bronchodilator thera- ICS/LABA combinations and long-acting muscarinic ago- pies in preventing exacerbations associated with nists (LAMA). Once again, no difference was found in a respiratory infection.26 exacerbation rates between patients who received flutica- sone/salmeterol and those who were treated with tiotro- pium bromide over a 2-year period (COPD patients had Risks associated with ICS therapy in FEV1 of less than 50% predicted and a clinical history of COPD patients COPD exacerbations).26 However, significantly more Use of ICS in COPD patients is associated with a number of exacerbations related to an acute respiratory infection adverse events.32 Important adverse effects of ICS therapy were observed in the fluticasone/salmeterol group. include increased risks of pneumonia,33 tuberculosis (TB), Two possible explanations may be suggested for the and non-tuberculous mycobacterial infections,34 osteoporo- inconsistent results of direct comparisons of ICS/LABA sis and bone fracture,35 as well as poor diabetes control36 For personal use only. with bronchodilator monotherapies. First, some COPD and local reactions (such as oral candidiasis, hoarse voice, patients may develop resistance to ICS,27 and, second, cough, etc.) (Table 1). ICS efficacy may be strongly influenced by the nature of Pneumonia is the most frequently reported problem in inflammation in the airways. A post-hoc analysis of data both randomized controlled trials (RCTs) and observa- obtained in a number of studies revealed a correlation tional studies. In a meta-analysis, Horita et al37 reported between the efficacy of ICS and eosinophil count in the a 43% increased risk of pneumonia in COPD patients mucus and blood of COPD patients.28 In particular, it treated with an ICS/LABA combination compared to was found that efficacy of the fluticasone furoate/vilan- LABA/LAMA (hazard ratio [HR]=0.57; 95% confidence terol combination was no different from that of vilan- interval [CI]=0.42–0.79). The increased risk of pneumonia terol therapy alone when eosinophil count is low and in patients treated with an ICS, such as fluticasone and increases on a pro rata basis as the blood eosinophil budesonide, has attracted the attention of regulatory autho- count rises.28 A similar tendency was observed when rities on both sides of the Atlantic. the extrafine beclamethasone dipropionate/formoterol In May 2015, the European Medicines Agency (EMA) combination was compared to formoterol issued a statement declaring that a thorough analysis of the 29 monotherapy. The FLAME study, which compared risk of pneumonia in ICS-treated COPD patients needed to the number of exacerbations in COPD patients receiving be performed based on recent studies and meta-analyses of either fluticasone/salmeterol or glycopirronium/indaca- earlier trials.38 This task was assigned to the terol for 1 year, showed that the combination of two Pharmacovigilance Risk Assessment Committee (PRAC). bronchodilator drugs was generally more effective in In March 2016, the PRAC published its report, stating that decreasing the number of exacerbations (RR=0.88, inten- COPD patients on ICS treatment are indeed at increased risk tion-to-treat analysis).30 However, a post hoc analysis of pneumonia.39 However, the PRAC experts noted that the based on blood eosinophil count found that the effect benefits of ICS outweighed the related risks. Furthermore, of the ICS-containing combination on the number of the PRAC did not find conclusive evidence of different risks exacerbations was no different from that of the combina- of pneumonia associated with different types of ICS.39 tion of two bronchodilator drugs in patients with high It is generally accepted that long-term therapy with ICS eosinophilia (≥3% or ≥150 cells/μL).31 leads to suppression of the cellular component of the Although ICS have been shown conclusively in many immune system and increases susceptibility to intracellular studies to reduce the number of exacerbations compared to infections of all types. Therefore, it is interesting to assess placebo, the advantage of ICS/LABA combinations over whether ICS use is associated with an increased risk of non- bronchodilator drugs used as monotherapy cannot be easily tuberculous mycobacterial pulmonary disease (NTM-PD) submit your manuscript | www.dovepress.com International Journal of Chronic Obstructive Pulmonary Disease 2019:14 1269 DovePress Powered by TCPDF (www.tcpdf.org) Avdeev et al Dovepress Table 1 Side-effects of ICS in COPD and the type of studies Side-effect Cohort Population-based case- Randomized con- Systematic reviews studies control studies trolled trials and meta-analysis International Journal of Chronic Obstructive Pulmonary Disease downloaded from https://www.dovepress.com/ by 158.109.88.164 on 26-Apr-2021 Pneumonia + + + + Tuberculosis + + + Non-tuberculous mycobacterial pulmon- + ary diseases Diabetes + + + Bone fracture + + + Cataract + + + Peptic ulcer hemorrhages + Local reactions (oral candidiasis, dysphonia) + + + + Skin bruising + + + Abbreviations: COPD, chronic obstructive pulmonary disease; ICS, inhaled corticosteroids. or tuberculosis. Brode et al34 showed that the use of ICS at mind that elderly patients can suffer from vision, hearing, moderate and high daily doses for 1 year was associated and/or coordination disturbances that may preclude proper with an increased risk of NTM-PD, but not TB. However, use of ICS-containing inhalation devices.44 Therefore, other studies have found a significant association between a benefit-risk analysis is strongly recommended prior to For personal use only. ICS use and TB.34 prescribing ICS to COPD patients, especially in those who Prospective studies on the impact of ICS on bone have risk factors for ICS-related complications. mineral density in COPD patients have yielded inconsis- tent results. A meta-analysis by Yang et al40 failed to demonstrate any difference in bone fracture rate in patients Effects of ICS withdrawal in COPD treated with ICS compared to placebo. In an earlier meta- patients: evidence from clinical analysis, Loke et al35showed that ICS use led to a 19% trials increased risk of bone fracture compared to placebo; how- Overprescription of ICS to COPD patients and the high ever, this difference was not statistically significant. risk of serious ICS-related adverse events makes withdra- In a large cohort study, ICS therapy was associated wal of this treatment necessary in patients for whom the with an increased risk of diabetes mellitus (HR=1.34; treatment-related risks overweigh expected benefits. The 95% CI=1.29–1.39) and of diabetes progression effects of ICS withdrawal have been studied in several (HR=1.34; 95% CI=1.17–1.53).36 The risk increased in randomized and non-randomized trials (Table 2). a dose-dependent manner and was highest in patients In two randomized controlled trials (COPE and WISP), who received ICS doses equivalent to fluticasone doses withdrawal of fluticasone propionate led to an increase in of 1,000 μg/day or higher. exacerbation risk by approximately 50% compared to The existence of a moderate risk for cataract has been COPD patients continuing ICS treatment.45,46 However, shown in open-label studies in patients treated with ICS, it should be noted that in these studies patients only especially at high doses and for a long time.41 A meta- received placebo following ICS withdrawal. In all subse- analysis showed that the number needed to harm is 16, that quent studies, COPD patients were switched to long-acting is to say that 16 patients need to be treated with ICS to bronchodilator drugs post-ICS withdrawal. cause this adverse event in one patient [95% CI=13–19].42 In the COSMIC trial, the effects of ICS withdrawal were Also of note is an increased risk of recurrent peptic ulcer studied in 373 patients with moderate-to-severe COPD with hemorrhages in COPD patients on ICS therapy.43 frequent exacerbations (two or more over the Special caution should be taken when prescribing ICS preceding year). Following treatment with fluticasone/sal- to older COPD patients. The expected benefits should be meterol for 3 months, one group of patients continued the carefully weighed against the increased risk of adverse treatment while the second group was switched to salme- events such as cataract, diabetes, pneumonia, osteoporosis, terol alone.47 For 1 year, no significant difference in the and bone fracture.44 Furthermore, it should be kept in number of moderate-to-severe exacerbations was observed submit your manuscript | www.dovepress.com International Journal of Chronic Obstructive Pulmonary Disease 2019:14 1270 DovePress Powered by TCPDF (www.tcpdf.org) International Journal of Chronic Obstructive Pulmonary Disease downloaded from https://www.dovepress.com/ by 158.109.88.164 on 26-Apr-2021 For personal use only. Powered by TCPDF (www.tcpdf.org) Table 2 Trials investigating the effects of ICS in COPD patients Dovepress Trial Design N Characteristics of the study Study groups Duration Withdrawal Main effects population of ICS therapy Randomized controlled trials COPE (van 6-month, rando- 244 ● Moderate-to-severe COPD (pre- FP vs placebo FP for Immediate withdra- Early exacerbations with placebo treatment der Valk mized, double- bronchodilation FEV1 25–80% 4-month run- wal during (RR 1.5; 95% CI 1.05–2.1) et al, 2002)45 blind, parallel- predicted) in period randomisation group ● No exacerbation during 1 month prior to enrolment COSMIC 52-week, rando- 373 ● Moderate-to-severe COPD (FEV1 SAL/FP vs SAL SAL/FP for Immediate withdra- A greater FEV1 decrease in the SAL group (Wouters mized, double- 30–70% predicted) 3-month run- wal during (4.1%; 95% CI 1.6–6.6) et al, 2005)47 blind, parallel- ● ≥2 exacerbations during preceding year in period randomisation group WISP 52-week, rando- 260 • Moderate-to-very-severe COPD (FEV1 FP vs placebo On average, ICS therapy with- An increase of the risk of exacerbations with International Journal of Chronic Obstructive Pulmonary Disease 2019:14 (Choudhury mized, double- <80% predicted) 8 years prior drawn at the start placebo treatment (RR 1.48; 95% CI 1.17–1.86) et al, 2007)46 blind, parallel- to enrolment of the trial and FP group or placebo prescribed INSTEAD 26-week, rando- 581 ● Moderate COPD (FEV1 50–80% SAL/FP vs IND SAL/FP ≥3 Immediate withdra- No difference in trough FEV1 after 12 weeks (Rossi et al, mized, double- predicted) months wal during (mean difference −9 mL; 95% CI −45–26) 2014)22 blind, parallel- ● No exacerbation during preceding year randomisation group WISDOM 52-week, rando- 2,485 ● Severe-to-very severe COPD (FEV1 TIO+FP+SAL Triple ther- Stepwise FP dose No difference between groups in time to first (Magnussen mized, double- <50% predicted) vs TIO+SAL apy for reduction every 6 moderate or severe exacerbation (RR 1.06; et al, 2014)50 blind, parallel- ● 1 exacerbation during preceding year 6-week run- weeks up to com- 95% CI 0.94–1.19); a greater decrease of FEV1 group in period plete withdrawal in the withdrawal group (−38 mL) CRYSTAL 12-week, rando- 4,389 ● Moderate COPD, on ICS/LABA, Switching to Pre-study Immediate Improvement of FEV1 (by 71 mL) and decrease (Vogelmeier mized, open, paral- LABA, or LAMA therapy GLY or IND/GLY therapy ≥3 withdrawal of dyspnoea (improvement of TDI score 1.101 et al, 2017)53 lel-group ● ≤1 exacerbation during preceding year vs continuation months units) after switching from ICS/LABA to IND/ of pre-study GLY therapy DovePress submit your manuscript | www.dovepress.com (Continued) 1271 Avdeev et al International Journal of Chronic Obstructive Pulmonary Disease downloaded from https://www.dovepress.com/ by 158.109.88.164 on 26-Apr-2021 For personal use only. Powered by TCPDF (www.tcpdf.org) 1272 Table 2 (Continued). Avdeev et al DovePress Trial Design N Characteristics of the study Study groups Duration Withdrawal Main effects population of ICS therapy SUNSET 26-week, rando- 1,053 ● COPD (FEV1 40–80% predicted), on TIO/SAL/FP Triple ther- Immediate withdra- No difference between groups in number of (Chapman mized, double- triple therapy vs apy for at wal during exacerbations (RR 1.08), a greater FEV1 et al, 2018)54 blind, parallel- ● 0–1 exacerbation during IND/GLY least 6 randomisation decrease in the withdrawal group (−26 mL) submit your manuscript | www.dovepress.com group preceding year months FLASH 12-week, rando- 502 ● Moderate-to-severe COPD SAL/FP SAL/FP ther- Immediate withdra- In IND/GLY group improvement of pre-dose (Frith et al, mized, double- ● up to 1 exacerbation in previous year vs apy at least 3 wal during trough FEV1 (45 mL) and pre-dose trough FVC 2018)55 blind, parallel- IND/GLY months randomisation (102 mL), improvements in dyspnoea (TDI). group No differences between groups in rescue medication use and CAT scores. Observational trials OPTIMO 6-month, prospec- 914 ● Mild-to-moderate COPD (FEV1> 50%), ICS/LABA vs ICS therapy Immediate No difference between groups in the number (Rossi et al, tive, real-world on ICS/LABA therapy LABD on a regular withdrawal of exacerbations, symptom severity and lung 2014)48 environment, fol- ● <2 exacerbations during basis during function decline low-up duration 6 preceding year previous year months Suissa et al, Population-based, 103,386 ● COPD patients treated with ICS prior ICS withdrawal ICS prescrip- – Reduction of the risk of pneumonia by 20% at 1 201556 observational to enrolment tion accord- month and by 37% during subsequent 3 years study, follow-up ing to duration 4.9 years prescription registry DACCORD Prospective, real- 1,258 ● COPD patients treated with ICS prior ICS withdrawal ICS therapy Immediate No difference in number of exacerbations and (Vogelmeier world environ- to enrolment vs continuation withdrawal symptom severity (CAT score) et al, 2017)49 ment, follow-up of pre-study duration 24 therapy months Abbreviations: COPD, chronic obstructive pulmonary disease; GLY, glycopyrronium bromide; ICS, inhaled corticosteroids; IND, indacaterol; LABA, long-acting β2-agonists; LABD, long-acting bronchodilator drugs; FP, fluticasone propionate; RR, risk ratio; SAL, salmeterol; TDI, transition dyspnoea index; TIO, tiotropium bromide. Dovepress International Journal of Chronic Obstructive Pulmonary Disease 2019:14 Dovepress Avdeev et al between the study groups. However, lung function was significant deterioration of lung function (mean FEV1 found to be better in the ICS group (FEV1 difference=4.1%, difference=38 mL), but this was not clinically relevant. 95% CI=1.6–6.6%).47 A subsequent post-hoc analysis of WISDOM data showed International Journal of Chronic Obstructive Pulmonary Disease downloaded from https://www.dovepress.com/ by 158.109.88.164 on 26-Apr-2021 The INSTEAD trial included COPD patients with no that the rate of decline of lung function in COPD patients indication for ICS prescription, ie, having no severe air- who discontinued ICS was no different from that in flow limitation (FEV1>50% predicted) and without patients who continued ICS use.51 The post-hoc analysis a history of exacerbations.22 Included patients must have of the WISDOM trial found that patients with higher blood been on treatment with fluticasone/salmeterol for at least 3 eosinophil counts at screening were more likely to develop months before ramdomization. Patients were randomized exacerbations after ICS treatment was withdrawn.52 to two groups and received either continuation with fluti- Continuation of ICS was associated with a reduced rate casone/salmeterol or indacaterol for 26 weeks. The study of moderate or severe exacerbations in the smaller sub- failed to find any difference in the number of COPD groups of patients with eosinophil counts of 300 cells/μL exacerbations (RR=0.86; 95% CI=0.62–1.20) or FEV1 or more or 4% or greater, whereas there was no difference (the difference was 9 mL) between the groups.22 in exacerbation rate after discontinuation of ICS in patients Interestingly, no deterioration in quality-of-life or symp- with counts of less than 4% or less than 300 cells/μL. tom aggravation was seen in COPD patients following ICS In the open-label, randomized CRYSTAL trial, patients withdrawal. with moderate COPD and pronounced symptoms (mMRC The INSTEAD results were reproduced in the OPTIMO dyspnea score ≥1) were switched from ICS/LABA to For personal use only. and DACCORD trials, which were conducted in the real- a fixed-dose combination of indacaterol/glycopyrronium world environment. The OPTIMO trial included COPD for 12 weeks. This resulted in an improvement of FEV1 patients with FEV1>50%, and with a history of less than (by 71 mL, 95% CI=36–107 mL) and a decrease in dys- two exacerbations over the preceding year.48 The decision pnea severity (improvement of TDI score=1.10 units, 95% to discontinue ICS therapy was made by the treating physi- CI=0.65–1.55 units).53 cian at enrolment. No difference was found between the The 26-week, randomized SUNSET trial, which study groups in the number of exacerbations, symptom involved 1,053 COPD patients, studied the effects of ICS severity, or decline of lung function after 6 months. withdrawal in COPD patients who received triple therapy In DACCORD, which included 1,258 COPD patients for at least 6 months.53 COPD patients (FEV1 50–80% (mean FEV1 60% predicted), the decision to discontinue predicted) with a history of at least one exacerbation over ICS therapy was also made by the treating doctor at study the preceding year were randomly assigned to either tio- enrolment. ICS was discontinued in 19% of the study popu- tropium plus salmeterol/fluticasone or indacaterol/glyco- lation. The study failed to show any difference between ICS pyrronium. Over the study period, no difference was users and non-users in the number of exacerbations and seen between study groups in the number of exacerbations symptom severity over 2 years of observation.49 (RR=1.08; 95% CI=0.83–1.40), with a minor, clinically Moreover, by the end of the 2-year period, the risk of irrelevant reduction of FEV1 (−26 mL; 95% CI= exacerbations was found to be lower in ICS non-users −53–1 mL) observed in the ICS withdrawal group. In compared to patients who were still on ICS therapy.49 a subgroup of COPD patients with peripheral blood eosi- The largest trial conducted thus far, WISDOM, which nophil count ≥300 cells/μL (approximately 25%), the included 2,485 COPD patients, compared a continued number of moderate and severe COPD exacerbations was treatment regimen with tiotropium, salmeterol, and fluti- significantly higher following ICS withdrawal (RR=1.86; casone propionate to a treatment regimen which included 95% CI=1.06–3.29), which is consistent with earlier data tiotropium, salmeterol, and a stepwise ICS dose de- indicative of a higher ICS efficacy in this patient category. escalation (every 6 weeks) up to full withdrawal.50 All A recently published study on the efficacy and safety COPD patients had severe airflow limitation (FEV1<50% of the direct switch to indacaterol/glycopyrronium from predicted) and a history of at least one exacerbation during salmeterol/fluticasone in non-frequently exacerbating the year prior to enrolment. ICS withdrawal did not lead to COPD patients (the FLASH trial) provided additional evi- an increased number of COPD exacerbations compared to dence on abrupt withdrawal of ICS therapy in COPD continued ICS users (RR=1.06; 95% CI=0.94–1.19). patients.55 In this 12-week double-blind study of 502 Nevertheless, ICS withdrawal led to a statistically COPD patients it has been observed that a direct switch submit your manuscript | www.dovepress.com International Journal of Chronic Obstructive Pulmonary Disease 2019:14 1273 DovePress Powered by TCPDF (www.tcpdf.org) Avdeev et al Dovepress from ICS/LABA to LAMA/LABA, without a washout clinical characteristics, spirometry, sputum/blood period, improved lung function (pre-dose FEV1 and eosinophil, and FeNO levels for answering the ques- FVC) in patients with moderate-to-severe COPD with up tions about presence of ACO, frequent exacerbations, International Journal of Chronic Obstructive Pulmonary Disease downloaded from https://www.dovepress.com/ by 158.109.88.164 on 26-Apr-2021 to one exacerbation in the previous year, without new and markers of eosinophilic inflammation; safety signals. These results add new evidence that dual ● initiating stepwise ICS withdrawal based on the bronchodilation is a preferable way of treatment compared patient’s current ICS dose; with ICS/LABA in symptomatic COPD patients with low ● optimization of bronchodilation with LABA/LAMA risk of exacerbations. combination; and ICS withdrawal can also result in a reduction in the risk ● following-up patient every 3 months during the of adverse events, particularly pneumonia. In a population- first year and then annually if COPD stable and based cohort trial, ICS withdrawal was associated with exacerbation free. a reduction of the risk of clinically relevant pneumonia by 20% at 1 month and by 37% during the subsequent 3 The discussion and proposition of differential stepwise, years.56 Reduction of the risk of pneumonia was higher in “hit hard”, step-up, and ICS withdrawal therapeutic patients treated with fluticasone as compared to budeso- approaches for COPD patients based on their GOLD cate- nide-treated patients.54 These data show that beneficial gory and sub-categories was made by a group of effects on selected outcomes (eg, pneumonia) can be Portuguese experts.58 They concluded that all approaches expected soon after ICS withdrawal. are feasible and the choice of the best approach should be For personal use only. Based on the results of the studies described above based on patient careful selection and sub-categorizing, (see Table 2), it can be concluded that ICS withdrawal taking into account different characteristics: initial FEV1 does not lead to a significant increase in the risk of and worsening of FEV1 in annual assessment for category exacerbations in COPD patients with no prior history of A (AX1: FEV1>80%; no worsening of FEV1 in annual frequent exacerbations, regardless of their lung function assessment; AX2: 50%50% and <50% predicted). FEV1 in annual assessment); lung function, mMRC-score, Moreover, ICS withdrawal results in a reduction of the and cardiovascular comorbidities (category B); lung func- risk of adverse events, particularly pneumonia, in the tion and exacerbation risk for categories C and D. short-term. However, ICS withdrawal can have unfavor- This approach is based to a certain extent on WISDOM able effects in COPD patients who suffer from frequent study and seems to be complicated for practical use. exacerbations and who have elevated eosinophil levels in Moreover, the authors emphasized that the proposed algorithm the peripheral blood. will need to be validated, particularly in the real-life setting. Another strategy has been proposed by a group of Spanish authors.59 The first and essential condition for its Algorithms for ICS withdrawal in implementation is an established COPD diagnosis (criteria COPD patients for COPD diagnosis: age ≥35 years, current or past smok- As a result of overutilization of ICS in real-world practice ing history ≥10 pack-years, post-bronchodilation FEV1 and with the advent of effective combined bronchodilator /FVC <0.7) with or without asthma. A concomitant diag- therapies to treat COPD, elaboration of an optimal, uni- nosis of asthma and COPD is made when the key diag- versal, user-friendly algorithm for withdrawal of ICS ther- nostic criteria for both diseases are met. Asthma–COPD apy appears to be important. overlap can also be diagnosed in patients without diagnos- In recent years, some professional associations and tic criteria for asthma, but who have a positive broncho- individual authors have designed approaches to discon- dilation test ≥400 mL and 15% FEV1 improvement and/or tinue ICS. One of the first approaches for stepwise ICS eosinophil count ≥300 cells/μL.60 Patients with non-fully withdrawal was proposed by Kaplan.57 The proposed algo- reversible airflow obstruction, but with a smoking history rithm was built on five steps and took into account: of fewer than 10 pack-years are classified and treated as asthma patients. ● reviewing current management of COPD; The proposed algorithm distinguishes two categories ● evaluating the risk-benefit profile of continuing ICS on opposite ends of the spectrum: patients without asthma, therapy, which needs considering patient history and with preserved lung function (FEV1>50% predicted) and submit your manuscript | www.dovepress.com International Journal of Chronic Obstructive Pulmonary Disease 2019:14 1274 DovePress Powered by TCPDF (www.tcpdf.org) Dovepress Avdeev et al no history of exacerbation; and patients with concomitant ● who have no history of exacerbations. asthma and a history of exacerbations. ICS therapy should 3. ICS withdrawal can be considered in patients who definitely be discontinued in the first group and continued had no apparent indication for ICS therapy in the International Journal of Chronic Obstructive Pulmonary Disease downloaded from https://www.dovepress.com/ by 158.109.88.164 on 26-Apr-2021 in the second. Intermediate categories, which include past. Generally, these are patients whose treatment patients without asthma, with FEV1>50% and exacerba- was initiated prior to the publication of the current tions, and patients with FEV1<50%, concomitant asthma, guidelines and before the advent of fixed-dose and no history of exacerbations, require close follow-up LABA/LAMA combinations. and the use of a differentiated approach to ICS withdrawal. 4. Current evidence on the topic is limited, and the ICS withdrawal is not indicated for patients with asthma- available studies are heterogeneous in terms of COPD overlap and exacerbations. study designs (randomized, controlled, or observa- A group of authors from the UK proposed a protocol tional) and study populations (variable disease for ICS withdrawal in COPD patients intended for primary severity and exacerbation frequency). care physicians.61 The authors recommend caution in 5. It should be remembered that no substantiated, applying the protocol to patients with a concomitant diag- practical guidelines on the strategy for ICS with- nosis of COPD and asthma. The protocol uses severity of drawal, either immediate or stepwise, are avail- lung function impairment as its starting point. For patients able at present. Instead, there are limited data with relatively preserved lung function (FEV1≥50% pre- indicating systemic symptoms that may develop dicted) and a history of frequent exacerbations (≥2 exacer- as a result of depression of endogenous steroid For personal use only. bations over 1 year), the protocol recommends reducing production, such as those observed after ICS ICS dose, with due consideration for concomitant diseases withdrawal in the run-in period in the ISOLDE (asthma, bronchiectasis), as well as prescription of pul- study.62 On the other hand, the level of patient monary rehabilitation programs and monitoring of inhaler acceptance of ICS therapy is low in the real-world technique. For patients with preserved lung function environment, resulting in poor adherence to the (FEV1≥50% predicted) and less than two exacerbations prescribed treatment.11,61,63 during the past year, an immediate switch to a LAMA/ LABA combination is recommended. Cataldo et al3 proposed a fairly simple algorithm based on In patients with a pronounced decrease of FEV1 (<50% exacerbation history. The authors suggest that patients predicted) and a history of exacerbations, ICS therapy with no history of exacerbations during the should be continued, and a reduction of the ICS dose preceding year (approximately 75% of the DACCORD should be considered. For patients with a 50% decrease study population)64 who are treated with either an ICS/ in lung function and less than two exacerbations during the LABA/LAMA or an ICS/LABA combination may benefit past year, a switch to a fixed-dose bronchodilator drug from ICS withdrawal and a switch to a double bronchodi- combination is recommended. lator therapy. In order to prepare a new algorithm for ICS withdra- A different approach should be applied in patients with wal, the international expert group reviewed a number of a history of exacerbations during the previous 12 months significant issues related to ICS withdrawal in COPD (25% of the DACCORD study population).64 If the patient patients raised by Cataldo et al3 in a recent publication: was on triple therapy, prescription of an add-on therapy and ICS dose correction should be considered. If the 1. Only a minority of COPD patients derive benefit patient was receiving an ICS/LABA combination, modifi- from ICS therapy. These are patients with a high cation of the treatment regimen is recommended by either benefit-to-risk ratio, including patients with adding a LAMA or by switching the patient to a LAMA/ a concomitant diagnosis of COPD and asthma, as LABA combination. well as patients suffering from frequent exacerba- Finally, the new GOLD 2017 classification has not tions despite optimal bronchodilator therapy. included the FEV1 in the initial classification of symptoms 2. ICS therapy is not indicated in COPD patients: and risk, and, therefore, a significant number of patients ● with a newly-diagnosed disease, originally classified as D according to GOLD 2013 will ● who have developed severe adverse reactions as now be classified as B, indicating low level of risk. In this a consequence of ICS therapy, and case, patients newly classified as B according to GOLD 2017 submit your manuscript | www.dovepress.com International Journal of Chronic Obstructive Pulmonary Disease 2019:14 1275 DovePress Powered by TCPDF (www.tcpdf.org) Avdeev et al Dovepress should be discontinued from ICS if they have less than 300 the essential prerequisite for further therapy revision in eosinophils/μL.65 COPD patients without concomitant asthma. Once the This is a selective and far from complete list of approaches above requirement is met, blood eosinophil count is used International Journal of Chronic Obstructive Pulmonary Disease downloaded from https://www.dovepress.com/ by 158.109.88.164 on 26-Apr-2021 to withdrawal of unnecessary ICS, as defined in currently as the main marker to guide decision-making. If the blood available clinical guidelines. The expert group held several eosinophil count is below a cut-off value of 300 cells/μL, working group meetings in order to formulate approaches to ICS withdrawal is appropriate for patients treated with an ICS withdrawal in COPD patients.66–68 The expert team ICS/LABA, ICS/LAMA, or ICS/LABA/LAMA triple reviewed available approaches to (and algorithms for) ICS combination. withdrawal and switching to treatment regimens without ICS. For patients with a blood eosinophil count above a cut- It was emphasized that any attempt to include more factors off value of 300 cells/μL, the treatment strategy should be than are considered in the currently available protocols would based on whether the patient has a history and risk of inevitably lead to an oversophisticated algorithm that would infectious exacerbations and/or community-acquired pneu- be difficult to use in everyday clinical practice. On the other monia, which is indicative of a high risk of occurrence of hand, oversimplification of the approach by minimizing the these conditions in the future.56 Factors associated with number of the factors would not allow for all possible clinical a significant increase in the risk of ICS associated pneumo- situations to be covered. In view of the above, the working nia could be defined as: being a current smoker, having prior group tried to use an integrated approach to formulate pneumonia, body mass index <25 kg/m2, and severe airflow a relatively simple algorithm that is based on consideration limitation (FEV1<50%).69 A large population-based cohort For personal use only. and integrated assessment of the most relevant factors (mar- trial demonstrated that reduction of the risk of pneumonia kers) influencing decision-making, such as a history of can be expected soon after ICS withdrawal.56 exacerbations, peripheral blood eosinophil count, presence Patients with persistent exacerbations despite ICS treat- of infection, and risk of community-acquired pneumonia.66–68 ment and features of so called “infective phenotype“ (fre- In the algorithm proposed (see Figure 1), stable COPD, quent bacterial exacerbations, chronic bacterial ie, the absence of exacerbations in the previous 3 months, is colonization, bronchiectasis)70 can also require ICS Figure 1 A proposed algorithm for ICS withdrawal in patients with COPD. Abbreviations: BA, bronchial asthma; CAP, community-acquired pneumonia; COPD, chronic obstructive pulmonary disease; EOS, eosinophils; ICS, inhaled corticosteroid; LABA, long-acting β2-agonist; LAMA, long-acting muscarinic antagonist. submit your manuscript | www.dovepress.com International Journal of Chronic Obstructive Pulmonary Disease 2019:14 1276 DovePress Powered by TCPDF (www.tcpdf.org) Dovepress Avdeev et al reduction or withdrawal, and additional use of long-term Disclosure antibiotics has been advocated in these patients.71 Professor Dr Sergey Avdeev has received speaker/consul- ICS dose reduction as a way of treatment modification tancy fees from Boehringer Ingelheim, AstraZeneca, Chiesi, International Journal of Chronic Obstructive Pulmonary Disease downloaded from https://www.dovepress.com/ by 158.109.88.164 on 26-Apr-2021 (rather than withdrawal) would be a reasonable therapeutic Teva, and Novartis; and research grants from AstraZeneca, option for many COPD patients, for example, with high GlaxoSmithKline, and Novartis, outside the submitted work. eosinophil counts and a history/risk of pneumonia and Professor Dr Zaurbek Aisanov has received speaker/consul- infectious exacerbations. tancy fees from Boehringer Ingelheim, AstraZeneca, Chiesi, This ICS reduction step of the decision-making tree can be Teva, Novartis, and GlaxoSmithKline; and research grants justified by previously shown predominantly anti- from AstraZeneca, GlaxoSmithKline, and Novartis, outside inflammatory effects related to modulation of the humoral the submitted work. Professor Dr Vladimir Arkhipov has components of the innate immune response, which may lead received speaker/consultancy fees from Boehringer to reduced airway bacterial load and lower risk of Ingelheim, AstraZeneca, Chiesi, Teva, and Astrllas; non- pneumonia.10,72 financial support from Boehringer Ingelheim; and research The concept of switching to ICS with lower risk of side- grants from AstraZeneca, outside the submitted work. effects (SE) is based on data which demonstrated substan- Professor Dr Andrey Belevskiy has received speaker/consul- tially increased risk of pneumonia with using of more potent tancy fees from Boehringer Ingelheim, AstraZeneca, Chiesi, and lipophilic ICS such as fluticasone propionate or flutica- and Novartis, outside the submitted work. Professor Dr Igor sone furoate, but not beclometasone dipropionate or Leshchenko has received speaker/consultancy fees from For personal use only. budesonide.73,74 It is possible that the differences observed Boehringer Ingelheim, AstraZeneca, Chiesi, Teva, and in the incidence of pneumonia reflect the dose of ICS used. Novartis, outside the submitted work. Professor Almost all salmeterol/fluticasone trials used fluticasone 500 Dr Svetlana Ovcharenkohas received speaker/consultancy μg bid, whereas all the budesonide/formoterol trials used fees from AstraZeneca, Boehringer Ingelheim, Chiesi, and budesonide 320 μg bid. (Dose equivalences used are beclo- Novartis, outside the submitted work. Professor Dr Evgeny methasone 1,000 μg, budesonide 800 μg, fluticasone propio- Shmelev has received speaker/consultancy fees from nate 500 μg, and fluticasone furoate 100 μg). Boehringer Ingelheim, AstraZeneca, Chiesi, Roche, Teva, So, in COPD patients with history and/or increased risk and Novartis, outside the submitted work. Dr Marc of pneumonia and/or infectious exacerbations, it’s reason- Miravitlles has received speaker fees from Boehringer able to change ICS to a molecule with lower risk of side- Ingelheim, Chiesi, Cipla, Menarini, Rovi, Bial, CSL effects (eg, from fluticasone to budesonide or Behring, Grifols, and Novartis; consultancy fees from beclomethasone).74,75 Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Bial, ICS withdrawal is not recommended for COPD Gebro Pharma, CSL Behring, Laboratories Esteve, Mereo patients with high eosinophil counts without a risk of BioPharm, Verona Pharma, pH Pharma, Novartis, and infectious exacerbations and/or community-acquired Grifols; and research grants from GlaxoSmithKline and pneumonia. Grifols, outside the submitted work. Conclusion Common overutilization and the high risk of serious treatment- References related adverse events make withdrawal of this ICS therapy 1. GOLD. 2019 global strategy for prevention, diagnosis and manage- necessary in COPD patients for whom its use is not recom- ment of COPD. Available from: https://goldcopd.org/gold-reports/ (Accessed December 11, 2018). Fontana, WI, USA: Global Initiative mended by current guidelines. Practical implementation of ICS for Chronic Obstructive Lung Disease, Inc., 2019 withdrawal in everyday clinical practice for clinicians is 2. Barnes PJ. Cellular and molecular mechanisms of chronic obstructive pulmonary disease. Clin Chest Med. 2014;35:71–86. doi:10.1016/j. needed in the management of COPD patients. The ICS with- ccm.2013.10.004 drawal algorithm developed by an expert group provides 3. Cataldo D, Derom E, Liistro G, et al. 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