PMID- 38054551
OWN - NLM
STAT- MEDLINE
DCOM- 20231207
LR  - 20240411
IS  - 1469-493X (Electronic)
IS  - 1361-6137 (Linking)
VI  - 12
IP  - 12
DP  - 2023 Dec 6
TI  - Inhaled corticosteroids with combination inhaled long-acting beta2-agonists and 
      long-acting muscarinic antagonists for chronic obstructive pulmonary disease.
PG  - CD011600
LID - 10.1002/14651858.CD011600.pub3 [doi]
LID - CD011600
AB  - 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/microL 
      in three studies; 200 eosinophils/microL 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.
CI  - Copyright (c) 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
FAU - van Geffen, Wouter H
AU  - van Geffen WH
AD  - Department of Pulmonary Diseases, Medical Center Leeuwarden, Leeuwarden, 
      Netherlands.
FAU - Tan, Daniel J
AU  - Tan DJ
AD  - Allergy and Lung Health Unit, Melbourne School of Population and Global Health, 
      University of Melbourne, Melbourne, Australia.
FAU - Walters, Julia Ae
AU  - Walters JA
AD  - School of Medicine, University of Tasmania, Hobart, Australia.
FAU - Walters, E Haydn
AU  - Walters EH
AD  - NHMRC Centre of Research Excellence for Chronic Respiratory Disease, School of 
      Medicine, University of Tasmania, Hobart, Australia.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Review
PT  - Systematic Review
DEP - 20231206
PL  - England
TA  - Cochrane Database Syst Rev
JT  - The Cochrane database of systematic reviews
JID - 100909747
RN  - 0 (Muscarinic Antagonists)
RN  - 0 (Bronchodilator Agents)
RN  - 0 (Adrenergic beta-2 Receptor Agonists)
RN  - 0 (Adrenal Cortex Hormones)
SB  - IM
UOF - Cochrane Database Syst Rev. 2016 Nov 10;11:CD011600. PMID: 27830584
MH  - Humans
MH  - Female
MH  - Middle Aged
MH  - Aged
MH  - Muscarinic Antagonists
MH  - Bronchodilator Agents/therapeutic use
MH  - Adrenergic beta-2 Receptor Agonists/therapeutic use
MH  - Quality of Life
MH  - *Pulmonary Disease, Chronic Obstructive/drug therapy
MH  - Adrenal Cortex Hormones/therapeutic use
MH  - Dyspnea/drug therapy
MH  - *Pneumonia/drug therapy
MH  - Disease Progression
PMC - PMC10698842
COIS- 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.
EDAT- 2023/12/06 12:43
MHDA- 2023/12/07 12:42
PMCR- 2024/12/06
CRDT- 2023/12/06 08:16
PHST- 2024/12/06 00:00 [pmc-release]
PHST- 2023/12/07 12:42 [medline]
PHST- 2023/12/06 12:43 [pubmed]
PHST- 2023/12/06 08:16 [entrez]
AID - CD011600.pub3 [pii]
AID - 10.1002/14651858.CD011600.pub3 [doi]
PST - epublish
SO  - Cochrane Database Syst Rev. 2023 Dec 6;12(12):CD011600. doi: 
      10.1002/14651858.CD011600.pub3.