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Review
. 2023 Dec 6;12(12):CD011600.
doi: 10.1002/14651858.CD011600.pub3.

Inhaled corticosteroids with combination inhaled long-acting beta2-agonists and long-acting muscarinic antagonists for chronic obstructive pulmonary disease

Wouter H van Geffen #  1 , Daniel J Tan #  2 , Julia Ae Walters  3 , E Haydn Walters  4
Affiliations
Review

Inhaled corticosteroids with combination inhaled long-acting beta2-agonists and long-acting muscarinic antagonists for chronic obstructive pulmonary disease

Wouter H van Geffen et al. Cochrane Database Syst Rev. .

Abstract

Background: Management of chronic obstructive pulmonary disease (COPD) commonly involves a combination of long-acting bronchodilators including beta2-agonists (LABA) and muscarinic antagonists (LAMA). LABA and LAMA bronchodilators are now available in single-combination inhalers. In individuals with persistent symptoms or frequent exacerbations, inhaled corticosteroids (ICS) are also used with combination LABA and LAMA inhalers. However, the benefits and risks of adding ICS to combination LABA/LAMA inhalers as a triple therapy remain unclear.

Objectives: To assess the effects of adding an ICS to combination LABA/LAMA inhalers for the treatment of stable COPD.

Search methods: We searched the Cochrane Airways Group Register of Trials, Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, and Embase up to 30 November 2022. We also searched ClinicalTrials.gov and the WHO ICTRP up to 30 November 2022.

Selection criteria: We included parallel-group randomised controlled trials of three weeks' duration or longer that compared the treatment of stable COPD with ICS in addition to combination LABA/LAMA inhalers against combination LABA/LAMA inhalers alone.

Data collection and analysis: We used standard Cochrane methodological procedures. The primary outcomes were acute exacerbations of COPD, respiratory health-related quality of life, pneumonia and other serious adverse events. The secondary outcomes were symptom scores, lung function, physical capacity, and mortality. We used GRADE to assess certainty of evidence for studies that contributed data to our prespecified outcomes.

Main results: Four studies with a total of 15,412 participants met the inclusion criteria. The mean age of study participants ranged from 64.4 to 65.3 years; the proportion of female participants ranged from 28% to 40%. Most participants had symptomatic COPD (COPD Assessment Test Score ≥ 10) with severe to very severe airflow limitation (forced expiratory volume in one second (FEV1) < 50% predicted) and one or more moderate-to-severe COPD exacerbations in the last 12 months. Trial medications differed amongst studies. The duration of follow-up was 52 weeks in three studies and 24 weeks in one study. We assessed the risk of selection, performance, and detection bias to be low in the included studies; one study was at high risk of attrition bias, and one study was at high risk of reporting bias. Triple therapy may reduce rates of moderate-to-severe COPD exacerbations compared to combination LABA/LAMA inhalers (rate ratio (RR) 0.74, 95% confidence interval (CI) 0.67 to 0.81; n = 15,397; low-certainty evidence). Subgroup analysis stratifying by blood eosinophil counts showed there may be a greater reduction in rate of moderate-to-severe COPD exacerbations with triple therapy in participants with high-eosinophils (RR 0.67, 95% CI 0.60 to 0.75) compared to low-eosinophils (RR 0.87, 95% CI 0.81 to 0.93) (test for subgroup differences: P < 0.01) (high/low cut-offs: 150 eosinophils/µL in three studies; 200 eosinophils/µL in one study). However, moderate-to-substantial heterogeneity was observed in both high- and low-eosinophil subgroups. These subgroup analyses are observational by nature and thus results should be interpreted with caution. Triple therapy may be associated with reduced rates of severe COPD exacerbations (RR 0.75, 95% CI 0.67 to 0.84; n = 14,131; low-certainty evidence). Triple therapy improved health-related quality of life assessed using the St George's Respiratory Questionnaire (SGRQ) by the minimal clinically important difference (MCID) threshold (4-point decrease) (35.3% versus 42.4%, odds ratio (OR) 1.35, 95% CI 1.26 to 1.45; n = 14,070; high-certainty evidence). Triple therapy may result in fewer symptoms measured using the Transition Dyspnoea Index (TDI) (OR 1.33, 95% CI 1.13 to 1.57; n = 3044; moderate-certainty evidence) and improved lung function as measured by change in trough FEV1 (mean difference 38.68 mL, 95% CI 22.58 to 54.77; n = 11,352; low-certainty evidence). However, these benefits fell below MCID thresholds for TDI (1-unit decrease) and trough FEV1 (100 mL), respectively. Triple therapy is probably associated with a higher risk of pneumonia as a serious adverse event compared to combination LABA/LAMA inhalers (3.3% versus 1.9%, OR 1.74, 95% CI 1.39 to 2.18; n = 15,412; moderate-certainty evidence). In contrast, all-cause serious adverse events may be similar between groups (19.7% versus 19.7%, OR 0.95, 95% CI 0.87 to 1.03; n = 15,412; low-certainty evidence). All-cause mortality may be lower with triple therapy (1.4% versus 2.0%, OR 0.70, 95% CI 0.54 to 0.90; n = 15,397; low-certainty evidence).

Authors' conclusions: The available evidence suggests that triple therapy may reduce rates of COPD exacerbations (low-certainty evidence) and results in an improvement in health-related quality of life (high-certainty evidence) compared to combination LABA/LAMA inhalers, but probably confers an increased pneumonia risk as a serious adverse event (moderate-certainty evidence). Triple therapy probably improves respiratory symptoms and may improve lung function (moderate- and low-certainty evidence, respectively); however, these benefits do not appear to be clinically significant. Triple therapy may reduce the risk of all-cause mortality compared to combination LABA/LAMA inhalers (low-certainty evidence). The certainty of the evidence was downgraded most frequently for inconsistency or indirectness. Across the four included studies, there were important differences in inclusion criteria, trial medications, and duration of follow-up. Investigation of heterogeneity was limited due to the small number of included studies. We found limited data on the effects of triple therapy compared to combination LABA/LAMA inhalers in patients with mild-moderate COPD and those without a recent exacerbation history.

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Conflict of interest statement

Wouter H van Geffen: Fiduciary Officer, Long Range Planning Committee ERS Assembly 11 – Thoracic Oncology, European Respiratory Society (ERS); Board Member, Dutch Society of Respiratory Physicians (NVALT); Consultant Respiratory Physician, Medical Centre Leeuwarden; affiliated to ERS and NVALT; member, Editorial Board of Cochrane Airways (closed in March 2023) but was not involved in the editorial decision‐making of this Cochrane Review update.

Daniel J Tan: no relevant interests; General Medicine Registrar at the Royal Melbourne Hospital, Melbourne, Victoria, Australia.

Julia AE Walters: none known.

E Haydn Walters: no relevant interests; Acute Physician, Alfred Hospital Melbourne.

Figures

1
1
PRISMA study flow diagram.
2
2
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
3
3
Risk of bias summary figure presenting all judgements in a cross‐tabulation of study by entry.
1.1
1.1. Analysis
Comparison 1: Triple therapy versus LABA/LAMA combination, Outcome 1: Moderate‐to‐severe exacerbations (Rate)
1.2
1.2. Analysis
Comparison 1: Triple therapy versus LABA/LAMA combination, Outcome 2: Moderate‐to‐severe exacerbations (Time‐to‐first)
1.3
1.3. Analysis
Comparison 1: Triple therapy versus LABA/LAMA combination, Outcome 3: Moderate‐to‐severe exacerbations (≥ 1 exacerbation)
1.4
1.4. Analysis
Comparison 1: Triple therapy versus LABA/LAMA combination, Outcome 4: Moderate‐to‐severe exacerbations (Rate, stratified by eosinophil count)
1.5
1.5. Analysis
Comparison 1: Triple therapy versus LABA/LAMA combination, Outcome 5: Moderate‐to‐severe exacerbations (Rate, stratified by baseline ICS use)
1.6
1.6. Analysis
Comparison 1: Triple therapy versus LABA/LAMA combination, Outcome 6: Severe exacerbations (Rate)
1.7
1.7. Analysis
Comparison 1: Triple therapy versus LABA/LAMA combination, Outcome 7: Severe exacerbations (Time‐to‐first)
1.8
1.8. Analysis
Comparison 1: Triple therapy versus LABA/LAMA combination, Outcome 8: All exacerbations (Rate)
1.9
1.9. Analysis
Comparison 1: Triple therapy versus LABA/LAMA combination, Outcome 9: Change in SGRQ
1.10
1.10. Analysis
Comparison 1: Triple therapy versus LABA/LAMA combination, Outcome 10: SGRQ, ≥ 4 decrease from baseline
1.11
1.11. Analysis
Comparison 1: Triple therapy versus LABA/LAMA combination, Outcome 11: SGRQ, end of study
1.12
1.12. Analysis
Comparison 1: Triple therapy versus LABA/LAMA combination, Outcome 12: Pneumonia
1.13
1.13. Analysis
Comparison 1: Triple therapy versus LABA/LAMA combination, Outcome 13: Pneumonia (Time‐to‐first)
1.14
1.14. Analysis
Comparison 1: Triple therapy versus LABA/LAMA combination, Outcome 14: Serious adverse events, pneumonia
1.15
1.15. Analysis
Comparison 1: Triple therapy versus LABA/LAMA combination, Outcome 15: Serious adverse event, all‐cause
1.16
1.16. Analysis
Comparison 1: Triple therapy versus LABA/LAMA combination, Outcome 16: Change in E‐RS
1.17
1.17. Analysis
Comparison 1: Triple therapy versus LABA/LAMA combination, Outcome 17: TDI, ≥ 1‐unit increase
1.18
1.18. Analysis
Comparison 1: Triple therapy versus LABA/LAMA combination, Outcome 18: TDI (Focal score), over 24 weeks
1.19
1.19. Analysis
Comparison 1: Triple therapy versus LABA/LAMA combination, Outcome 19: Change in trough FEV1 (mL)
1.20
1.20. Analysis
Comparison 1: Triple therapy versus LABA/LAMA combination, Outcome 20: Trough FEV1, end of study (mL)
1.21
1.21. Analysis
Comparison 1: Triple therapy versus LABA/LAMA combination, Outcome 21: FEV1 AUC 0 to 4 (mL), end of study
1.22
1.22. Analysis
Comparison 1: Triple therapy versus LABA/LAMA combination, Outcome 22: Change in trough FVC (mL)
1.23
1.23. Analysis
Comparison 1: Triple therapy versus LABA/LAMA combination, Outcome 23: Death, all causes
1.24
1.24. Analysis
Comparison 1: Triple therapy versus LABA/LAMA combination, Outcome 24: Death, all causes (Time‐to‐event)
1.25
1.25. Analysis
Comparison 1: Triple therapy versus LABA/LAMA combination, Outcome 25: Death, cardiovascular causes
1.26
1.26. Analysis
Comparison 1: Triple therapy versus LABA/LAMA combination, Outcome 26: Death, respiratory causes
1.27
1.27. Analysis
Comparison 1: Triple therapy versus LABA/LAMA combination, Outcome 27: Death, COPD‐related
2.1
2.1. Analysis
Comparison 2: Triple therapy versus LABA/LAMA combination – Exclude Papi 2018, Outcome 1: Moderate‐to‐severe exacerbations (Rate)
2.2
2.2. Analysis
Comparison 2: Triple therapy versus LABA/LAMA combination – Exclude Papi 2018, Outcome 2: Moderate‐to‐severe exacerbations (Time‐to‐first)
2.3
2.3. Analysis
Comparison 2: Triple therapy versus LABA/LAMA combination – Exclude Papi 2018, Outcome 3: Moderate‐to‐severe exacerbations (≥ 1 exacerbation)
2.4
2.4. Analysis
Comparison 2: Triple therapy versus LABA/LAMA combination – Exclude Papi 2018, Outcome 4: Moderate‐to‐severe exacerbations (Rate, stratified by eosinophil count)
2.5
2.5. Analysis
Comparison 2: Triple therapy versus LABA/LAMA combination – Exclude Papi 2018, Outcome 5: Moderate‐to‐severe exacerbations (Rate, stratified by baseline ICS use)
2.6
2.6. Analysis
Comparison 2: Triple therapy versus LABA/LAMA combination – Exclude Papi 2018, Outcome 6: Severe exacerbations (Rate)
2.7
2.7. Analysis
Comparison 2: Triple therapy versus LABA/LAMA combination – Exclude Papi 2018, Outcome 7: Severe exacerbations (Time‐to‐first)
2.8
2.8. Analysis
Comparison 2: Triple therapy versus LABA/LAMA combination – Exclude Papi 2018, Outcome 8: All exacerbations (Rate)
2.9
2.9. Analysis
Comparison 2: Triple therapy versus LABA/LAMA combination – Exclude Papi 2018, Outcome 9: Change in SGRQ
2.10
2.10. Analysis
Comparison 2: Triple therapy versus LABA/LAMA combination – Exclude Papi 2018, Outcome 10: SGRQ, ≥ 4 decrease from baseline
2.11
2.11. Analysis
Comparison 2: Triple therapy versus LABA/LAMA combination – Exclude Papi 2018, Outcome 11: SGRQ, end of study
2.12
2.12. Analysis
Comparison 2: Triple therapy versus LABA/LAMA combination – Exclude Papi 2018, Outcome 12: Pneumonia
2.13
2.13. Analysis
Comparison 2: Triple therapy versus LABA/LAMA combination – Exclude Papi 2018, Outcome 13: Pneumonia (Time‐to‐first)
2.14
2.14. Analysis
Comparison 2: Triple therapy versus LABA/LAMA combination – Exclude Papi 2018, Outcome 14: Serious adverse events, pneumonia
2.15
2.15. Analysis
Comparison 2: Triple therapy versus LABA/LAMA combination – Exclude Papi 2018, Outcome 15: Serious adverse event, all‐cause
2.16
2.16. Analysis
Comparison 2: Triple therapy versus LABA/LAMA combination – Exclude Papi 2018, Outcome 16: Change in E‐RS
2.17
2.17. Analysis
Comparison 2: Triple therapy versus LABA/LAMA combination – Exclude Papi 2018, Outcome 17: TDI, ≥ 1‐unit increase
2.18
2.18. Analysis
Comparison 2: Triple therapy versus LABA/LAMA combination – Exclude Papi 2018, Outcome 18: TDI (Focal score), over 24 weeks
2.19
2.19. Analysis
Comparison 2: Triple therapy versus LABA/LAMA combination – Exclude Papi 2018, Outcome 19: Change in trough FEV1 (mL)
2.20
2.20. Analysis
Comparison 2: Triple therapy versus LABA/LAMA combination – Exclude Papi 2018, Outcome 20: Trough FEV1, end of study (mL)
2.21
2.21. Analysis
Comparison 2: Triple therapy versus LABA/LAMA combination – Exclude Papi 2018, Outcome 21: FEV1 AUC 0 to 4 (mL), end of study
2.22
2.22. Analysis
Comparison 2: Triple therapy versus LABA/LAMA combination – Exclude Papi 2018, Outcome 22: Change in trough FVC (mL)
2.23
2.23. Analysis
Comparison 2: Triple therapy versus LABA/LAMA combination – Exclude Papi 2018, Outcome 23: Death, all causes
2.24
2.24. Analysis
Comparison 2: Triple therapy versus LABA/LAMA combination – Exclude Papi 2018, Outcome 24: Death, all causes (Time‐to‐event)
2.25
2.25. Analysis
Comparison 2: Triple therapy versus LABA/LAMA combination – Exclude Papi 2018, Outcome 25: Death, cardiovascular causes
2.26
2.26. Analysis
Comparison 2: Triple therapy versus LABA/LAMA combination – Exclude Papi 2018, Outcome 26: Death, respiratory causes
2.27
2.27. Analysis
Comparison 2: Triple therapy versus LABA/LAMA combination – Exclude Papi 2018, Outcome 27: Death, COPD‐related
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References

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References to other published versions of this review

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