Overuse of long-acting β₂-agonist/inhaled corticosteroids in patients with chronic obstructive pulmonary disease: time to rethink prescribing patterns

Figures & data

Figure 1. A summary of the characteristics of COPD (adapted from [15]).

COPD, chronic obstructive pulmonary disease; FEV₁, forced expiratory volume in 1 s; FVC, forced vital capacity; GERD, gastroesophageal reflux disease; ICS, inhaled corticosteroids.

Figure 2. ICS initiation in COPD [1].

CAT, COPD Assessment Test; COPD, chronic obstructive pulmonary disease; GOLD, Global Initiative for Chronic Obstructive Lung Disease; ICS, inhaled corticosteroids; mMRC, modified Medical Research Council.

^aDespite appropriate long-acting bronchodilator maintenance therapy.

For patients with asthma, pharmacotherapy should primarily follow asthma guidelines.

Figure 3. Assessments to guide treatment choice for patients with COPD [1].

COPD, chronic obstructive pulmonary disease; CAT, COPD Assessment Test; FEV₁, forced expiratory volume in 1 s; FVC, forced vital capacity; GOLD, Global Initiative for Chronic Obstructive Lung Disease; mMRC, modified Medical Research Council.

Table 1. Current guidelines for initiating and maintaining therapy for COPD.

Recommendation	American College of Physicians, American College of Chest Physicians, American Thoracic Society, and European Respiratory Society Joint Guideline Update (2011) [60]	American Thoracic Society (2020) [57]	Department of Veterans Affairs and Department of Defense Evidence-Based Practice Work Group (2021) [58]	Global Initiative for Chronic Obstructive Lung Disease (2023) [1]	National Institute for Health and Care Excellence [61]
Monotherapy (LAMA or LABA)	LAMA or LABA for symptomatic patients with COPD and predicted FEV1 <60% (strong recommendation, moderate-quality evidence)	-	LAMA as first-line therapy and against the use of LABA among patients with symptomatic COPD (strong recommendation, existing evidence updated)	Short- or long-acting Bronchodilator: Patients with 0 or 1 moderate exacerbations not leading to hospitalization mMRC 0–1 and CAT < 10	-
Combination therapy (LAMA/LABA)	-	LABA/LAMA combination therapy over LABA or LAMA monotherapy in patients with COPD and dyspnea or exercise intolerance (strong recommendation, moderate-quality evidence)	Patients with moderate-to-severe airflow obstruction who continue to report significant dyspnea or decreased QoL despite using a LAMA (weak recommendation, existing evidence updated)	Patients with 0 or 1 moderate exacerbations not leading to hospital admission mMRC ≥2 and CAT ≥ 10 Patients with ≥ 2 moderate exacerbations or ≥ 1 leading to hospitalization and blood eosinophil < 300 cells/µL	Compared with other dual therapy combinations and monotherapy, LAMA/LABA provides the greatest benefit to overall QoL for patients with COPD is better than other inhaled treatments for reducing the risk of moderate-to-severe exacerbations is the most cost-effective option
Triple therapy (ICS/LAMA/LABA)	-	ICS/LAMA/LABA over dual therapy with LABA/LAMA is advocated for patients with COPD and dyspnea or exercise intolerance who have experienced ≥ 1 exacerbation in the previous year (conditional recommendation, moderate-quality evidence)	Addition of ICS is suggested to patients on LAMA/LABA who continue to experience exacerbations (weak recommendation, existing evidence updated)	Initial: Patients with ≥ 2 moderate exacerbations or ≥ 1 leading to hospitalization mMRC ≥2 and CAT ≥ 10 and blood eosinophil count ≥ 300 cells/µL Follow-up: Escalate to ICS/LAMA/LABA in patients on LABA/LAMA if exacerbations not controlled on LAMA/LABA and eosinophils > 100 cells/µL.	Not all patients with COPD benefit from triple therapy and NICE recommends a clinical review (through a conversation with the patient inquiring about their symptoms rather than relying on tools such as the CAT score or MRC breathlessness score in isolation) to ensure that only those patients who would benefit from triple therapy receive it
ICS withdrawal	-	Recommended for patients with COPD receiving triple therapy (ICS/LAMA/LABA) if the patient has had no exacerbations in the previous year (conditional recommendation, moderate-quality evidence)	Withdrawal of ICS is only recommended if patients have not reported moderate-to-severe exacerbations in the previous 2 years (weak recommendation, existing evidence updated)	Can be considered if there are adverse effects such as pneumonia or a reported lack of efficacy. However, a blood eosinophil count ≥ 300 cells/µL identifies patients with the greatest likelihood of experiencing more exacerbations after ICS withdrawal and who subsequently should be followed closely for relapse of exacerbations.	-

CAT, COPD Assessment Test; COPD, chronic obstructive pulmonary disease; FEV₁, forced expiratory volume in 1 s; ICS, inhaled corticosteroids; LABA, long-acting β₂-agonist; LAMA, long-acting muscarinic antagonist; MRC, Medical Research Council; mMRC, modified Medical Research Council; NICE, National Institute for Health and Care Excellence; QoL, quality of life.

Table 2. Summary of some key studies comparing LABA/ICS vs LAMA/LABA therapy.

			Key efficacy endpoints
Authors, publication year (study design)	Patient characteristics	Intervention, number of patients (treatment duration)	Lung function	Exacerbations	Symptoms	Safety	Key findings
Donohue et al [78] (2015) (multicenter, randomized, double-blind, parallel-group, double-dummy trials) (DB2114930/NCT01817764; DB2114951/NCT01879410)	Patients with symptomatic (dyspnea score ≥ 2, mMRC Dyspnea Scale), moderate-to-severe COPD (FEV1 ≥ 30% and ≤ 70%) without a documented history of an exacerbation (COPD symptoms requiring treatment with either oral corticosteroids, antibiotics, and/or hospitalization) in the year before screening.	Once-daily UMEC/VI 62.5/25 μg (delivered doses 55/22 μg, morning) via the ELLIPTA® DPI and twice-daily placebo (DISKUS®) (n = 702) Twice-daily FP/SAL 250/50 µg via the DISKUS® and once-daily placebo (ELLIPTA® DPI) (n = 701) (12 weeks)	UMEC/VI demonstrated statistically significant, clinically meaningful improvements in lung function measures vs FP/SAL. For 0–24 h, wmFEV1 (Day 84), improvements with UMEC/VI vs FP/SAL were 74 mL (95% CI: 38–110; DB2114930) and 101 mL (63–139; DB2114951) (both p < 0.001). Trough FEV1 improvements were 82 mL (45–119) and 98 mL (59–137) (both p < 0.001) for UMEC/VI vs FP/SAL, respectively.	UMEC/VI vs FP/SAL: 3% vs 3%	UMEC/VI and FP/SAL demonstrated similar clinically meaningful improvements from baseline in dyspnea (TDI focal score > 1 unit) and QoL (SGRQ total score > 4-unit decrease) in both studies with no statistical differences between treatments.	Adverse event rates UMEC/VI vs FP/SAL: 26%–30% vs 27%–31%; the most frequent adverse events were headache and nasopharyngitis.	Once-daily UMEC/VI 62.5/25 μg over 12 weeks resulted in statistically significant, clinically meaningful improvements in lung function vs twice-daily FP/SAL 250/50 μg in patients with moderate-to-severe COPD with infrequent exacerbations. Both treatments improved dyspnea and QoL.
Singh et al [79] (2015) (phase IIIb, multicenter, double-blind, parallel-group, double-dummy study) (NCT01822899)	Current/former smokers (≥ 10 pack-years), ≥ 40 years old, post-bronchodilator FEV1/FVC < 0.70, 30% ≤ post-bronchodilator FEV1 ≤ 70% of predicted, and an mMRC score ≥ 2	Treatment with UMEC/VI OD (n = 358) Treatment with FP/SAL BID (n = 358) (12 weeks)	UMEC/VI OD significantly improved all lung function endpoints compared with FP/SAL BID	A statistical imbalance in the number of COPD exacerbations was observed between treatment groups (UMEC/VI: 8 [2%] patients vs FP/SAL: 3 [<1%] patients).	There was a clinically significant improvement in symptoms with both treatments (TDI score ≥ 1-unit focal score) and QoL (SGRQ Total score ≥ 4 unit decrease from baseline).	The incidence of adverse events was comparable between both treatment groups (UMEC/VI: 28% vs FP/SAL: 29%); the most frequent adverse events were headache and nasopharyngitis.	Patients with moderate-to-severe COPD and no exacerbations in the year prior to enrollment experienced significant and persistent improvements in lung function with UMEC/VI OD over the course of 12 weeks compared with FP/SAL BID.
Zhong et al [80] (2015) (multicenter, randomized, double-blind, double-dummy, parallel-group study) (NCT01709903)	Male and female patients aged ≥ 40 years with moderate-to-severe COPD (stage II and III, as defined in the GOLD 2010 criteria). All patients had a mMRC grade ≥ 2 at screening.	IND/GLY (110/50 µg) OD (n = 372) SFC (50/500 µg) BID (n = 372) (26 weeks)	IND/GLY demonstrated statistically significant superiority to SFC for trough FEV1 (treatment difference [Δ] = 75 mL; p < 0.001). IND/GLY demonstrated a statistically significant improvement in standardized AUC from 0 to 4 h for FEV1 (FEV1 AUC0–4 h) at week 26 vs SFC (Δ = 122 mL; P < 0.001).	IND/GLY significantly reduced the rate of moderate or severe exacerbations by 31% (p = 0.048) over SFC.	IND/GLY and SFC had similar improvements in TDI focal score, SGRQ total score, and rescue medication use.	The incidence of adverse events was comparable between IND/GLY (40.1%) and SFC (47.4%). The incidence of pneumonia was three-fold lower with IND/GLY (0.8%) vs SFC (2.7%).	The findings from this study support the use of LABA/LAMA as an alternative treatment, over LABA/ICS in the management of patients with moderate-to-severe COPD (GOLD B and GOLD D) with a history of ≤ 1 exacerbation in the previous year.
Beeh et al [81] 2016 (phase IIIb, multicenter, multinational, randomized, double-blind, double-dummy, active-controlled, four-treatment, complete crossover study) (NCT01969721)	A diagnosis of COPD; moderate-to-severe pulmonary impairment (post-bronchodilator FEV1 ≥ 30% and < 80% of predicted normal); post-bronchodilator FEV1/FVC < 70% at screening visit; age ≥ 40 years; current or ex-smoker with a smoking history of > 10 pack-years; able to perform technically acceptable PFT and maintain paper diaries as required; and able to competently inhale medication from the Respimat® inhaler (a metered-dose inhaler) and the Accuhaler®.	Tiotropium/olodaterol (5/5 µg and 2.5/5 µg) OD Salmeterol/fluticasone propionate (50/500 µg and 50/250 µg) BID (6 weeks)	Tiotropium/olodaterol 5/5 μg and 2.5/5 μg demonstrated statistically significant improvements in FEV1 AUC0–12 compared with salmeterol/fluticasone propionate (improvements from baseline were 317 mL and 295 mL with tiotropium/olodaterol 5/5 μg and 2.5/5 μg, and 188 mL and 192 mL with salmeterol/fluticasone propionate 50/500 μg and 50/250 μg, respectively). Tiotropium/olodaterol was superior to SAL/fluticasone propionate in lung function secondary endpoints, including FEV1 AUC0–24.	Not available	Not available	The frequency of adverse events was similar between all treatment groups: tiotropium/olodaterol (33.9%–34.4%) vs SAL/fluticasone propionate (29.7%–37.0%); the most frequent adverse events were COPD worsening and nasopharyngitis.	Once-daily tiotropium/olodaterol in patients with moderate-to-severe COPD provided superior lung function improvements to twice-daily SAL/fluticasone propionate.
Vogelmeier et al [82] (2016) (double-blind, double-dummy, active-controlled, randomized, multicenter, phase 3b study) AFFIRM COPD (NCT01908140)	Age ≥ 40 years, with a smoking history of ≥ 10 pack-years and diagnosed with moderate-to-severe COPD; CAT score ≥ 10 at the screening and baseline visits; post-bronchodilator FEV1/FVC < 70% and FEV1 < 80% predicted.	ITT population: Treatment with aclidinium/formoterol 400/12 µg BID (n = 468) Treatment with SFC 50/500 µg BID (n = 463) (24 weeks)	Aclidinium/formoterol was superior to SFC in peak FEV1.	The incidence of exacerbations did not differ significantly between the aclidinium/formoterol and SFC groups.	Similar clinically relevant improvements in the mean TDI focal score at week 24 and at all prior visits were seen with aclidinium/formoterol and SFC. At week 24, clinically significant differences from baseline in CAT total scores of ≥ 2 units were seen with both aclidinium/formoterol and SFC.	Pneumonia occurred less frequently with aclidinium/formoterol than with SFC, and both therapies were well tolerated.	Aclidinium/formoterol treatment was superior to SFC in peak FEV1. The therapy groups showed equivalent reduction in dyspnea and symptom control. Adverse ICS-related events were less frequent with aclidinium/formoterol. Exacerbation rates were comparable in both groups, although the study was not powered for exacerbations.
Wedzicha et al [40] (2016) (multicenter, randomized, double-blind, double-dummy, parallel-group, noninferiority study) FLAME (NCT01782326)	Adults aged ≥ 40 years, post-bronchodilator FEV1/FVC < 0.70, 25% ≤ post-bronchodilator FEV1 < 60% of predicted, a mMRC score ≥ 2, and a documented history of at least one exacerbation in the previous year.	Treatment with IND/GLY OD N = 1,680 Treatment with SFC BID N = 1,682 (52 weeks)	In comparison to the SFC group, the IND/GLY group had improved lung function	Compared with the SFC group, the IND/GLY group demonstrated an 11% (p < 0.003) lower annual rate of exacerbations and a longer duration to the first exacerbation (16% lower risk; p < 0.001).	Use of rescue medication was significantly reduced and health condition was improved in the IND/GLY group (decrease in SGRQ-C score).	The incidence of adverse events and deaths was similar in the two groups. Pneumonia occurred in 3.2% of the IND/GLY group and 4.8% of the SFC group (p = 0.02).	In patients with a history of an exacerbation during the past year, IND/GLY was more effective than SFC at preventing COPD exacerbations. In both the subgroup of patients with blood eosinophil counts < 2% and the subgroup of patients with counts of ≥ 2%, the rates of moderate or severe exacerbations and of all exacerbations were significantly lower in the indacaterol–glycopyrronium group than in the salmeterol–fluticasone group, a finding that suggests that the LABA/ LAMA regimen was more effective in reducing the rate of exacerbations than the LABA/ICS regimen in both eosinophil subgroups.
Kaplan et al [83] (2019) (single-cohort, prospective, multicenter, open-label, interventional study) POWER (NCT02202616)	Patients aged > 40 years, with physician-diagnosed COPD per the GOLD 2011 criteria, a moderate-to-severe airflow limitation indicated by a pre-dose trough FEV1 ≥ 30% and < 80% of predicted, a smoking history of > 10 pack-years, CAT score of > 10, and symptomatic despite tiotropium 18 µg OD or SFC BID (any dose)	Treatment with IND/GLY 110/50 µg OD Tiotropium, n = 248; SFC, n = 87; IND/GLY All patients N = 338 (16 weeks)	At week 16, patients who switched to IND/GLY demonstrated a 175-mL mean increase in trough FEV1. When switching from tiotropium, the change from baseline was 176 mL (95% CI: 135–217), and when switching from SFC FDC, it was 172 mL (95% CI: 85–258)	In SFC initiators, exacerbations occurred more frequently.	At week 16, after switching to IND/GLY medication, a significant improvement was seen in the mean TDI total scores (Δ = 2.5) and CAT scores (Δ = −6.5) (both p < 0.0001).	In patients with moderate-to-severe COPD, IND/GLY was well tolerated. The prevalence of pneumonia was higher among SFC beginners. There were no patient deaths during the study.	A real-life switch from tiotropium monotherapy or SFC FDC to IND/GLY resulted in clinically significant improvements in lung function, dyspnea, and health-related QoL after 16 weeks of treatment in symptomatic individuals with moderate-to-severe COPD. The IND/GLY transition was well tolerated, and the research has not identified any additional safety signals.
Pascoe et al (2019) [46] (phase 3, randomized, double-blind, parallel-group, multicenter study) IMPACT (NCT02164513)	Adults aged ≥ 40 years, CAT score ≥ 10, FEV1 < 50% of predicted and history of at least one moderate or severe exacerbation in the previous year, or FEV1 50%–80% of predicted and at least two moderate or one severe exacerbation in the previous year	Treatment with FF/VI OD N = 4,125 Treatment with UMEC/VI OD N = 2,065 (52 weeks)	At all baseline blood eosinophil counts, the improvement in FEV1 was greater with UMEC/VI than with FF/VI.	In the overall population, exacerbation rates were lower with FF/VI than with UMEC/VI. Only eosinophil counts of approximately > 200 cells/µL in the overall population with FF/VI were associated with treatment benefit.	At lower eosinophil counts, benefits on SGRQ and TDI were numerically greater with UMEC/VI than with FF/VI. UMEC/VI numerically underperformed FF/VI at higher eosinophil counts.	High pneumonia incidence rates were seen in the FF/VI group. Compared with the UMEC/VI group, the FF/VI group displayed higher rates of events when treated with antibiotics alone.	Compared with a dual long-acting non-ICS bronchodilator (UMEC/VI), the extent of the benefit of ICS-based regimens (FF/VI) in reducing rates of moderate and severe exacerbations increased proportionally with the blood eosinophil count.
Suissa et al (2019) [84] (Real-world study using Clinical Practice Research Datalink from the United Kingdom)	The study cohort was formed by first identifying all members of the base cohort (age ≥ 55 years) with the first occurrence of prescriptions for LABA and LAMA (tiotropium) on the same date, but no ICS. For each subject initiating LABA-LAMA treatment, a matched comparator subject initiating LABA-ICS was identified using a time-conditional propensity score-matched approach.	LABA-LAMA initiators (n = 1,977) LABA-ICS initiators (n = 1,977)	Not available	The HR of moderate or severe COPD exacerbation associated with LABA-LAMA initiation, relative to LABA-ICS initiation, was 1.04 (95% CI: 0.90–1.20), whereas for a severe exacerbation, it was 0.94 (95% CI: 0.65–1.36).	Not available	The incidence of severe pneumonia requiring hospitalization was lower with LABA-LAMA initiation (HR, 0.66; 95% CI: 0.41–1.05), particularly in the on-treatment analysis (HR, 0.66; 95% CI: 0.50–0.87).	In a real-world clinical practice setting of COPD treatment, combined LABA-LAMA inhalers appear to be as effective as combined LABA-ICS inhalers in preventing COPD exacerbations. However, a LABA-LAMA combination may be preferred because it is associated with fewer severe pneumonias.

AFFIRM COPD, Aclidinium and Formoterol Findings in Respiratory Medicine COPD; AUC, area under the curve; BID, twice a day; CAT, COPD Assessment Test; CI, confidence interval; COPD, chronic obstructive pulmonary disease; DPI, dry powder inhaler; FDC, fixed-dose combination; FEV1, forced expiratory volume in 1 s; FF, fluticasone furoate; FP, fluticasone propionate; FVC, forced vital capacity; GLY, glycopyrronium; GOLD, Global Initiative for Chronic Obstructive Lung Disease; HR, hazard ratio; ICS, inhaled corticosteroids; IMPACT, InforMing the PAthway of COPD Treatment; IND, indacaterol; LABA, long-acting β2-agonist; LAMA, long-acting muscarinic antagonist; mMRC, modified Medical Research Council; OD, once a day; PFT, pulmonary function test; POWER, Prospective cohort study for the real-life effectiveness evaluation of glycOpyrronium With indacatERol combination in the management of COPD in Canada; QoL, quality of life; SAL, salmeterol; SFC, salmeterol/fluticasone; SGRQ-C, St. George’s Respiratory Questionnaire for COPD; TDI, transition dyspnea index; UMEC, umeclidinium; VI, vilanterol; wm, weighted mean.

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