Association of Inhaled Corticosteroids With All-Cause Mortality Risk in Patients With COPD

Background Inhaled corticosteroids (ICSs) have been used widely in the maintenance therapy of COPD. However, whether inhaled therapy containing ICSs can reduce the all-cause mortality risk and the possible benefited patient subgroups is unclear. Research Question Does inhaled therapy containing ICSs reduce the all-cause mortality risk in patients with COPD compared with other inhaled therapies not containing ICSs? Study Design and Methods We searched PubMed, Cochrane Library, Embase, and ClinicalTrials.gov for relevant randomized clinical trials (RCTs). Pooled results were calculated using Peto ORs with corresponding 95% CIs. Results Sixty RCTs enrolling 103,034 patients were analyzed. Inhaled therapy containing ICSs (Peto OR, 0.90; 95% CI, 0.84-0.97), especially triple therapy (Peto OR, 0.73; 95% CI, 0.60-0.90), was associated with a reduction in the all-cause mortality risk among patients with COPD when compared with inhaled therapy without ICSs. Subgroup analyses revealed that treatment duration of > 6 months (Peto OR, 0.90; 95% CI, 0.83-0.97), medium-dose ICSs (Peto OR, 0.71; 95% CI, 0.56-0.91), low-dose ICSs (Peto OR, 0.88; 95% CI, 0.79-0.97), and budesonide (Peto OR, 0.75; 95% CI, 0.59-0.94) were involved in this association. The predictors of this association included eosinophil counts of ≥ 200/μL or percentage of ≥ 2%, documented history of ≥ 2 moderate and severe exacerbations in the previous year, Global Initiative for Chronic Obstructive Lung Disease stages III or IV, age younger than 65 years, and BMI of ≥ 25 kg/m2, among which eosinophil counts of ≥ 200/μL (Peto OR, 0.58; 95% CI, 0.36-0.95) were the strongest predictor. Interpretation Inhaled therapy containing ICSs, especially triple therapy, of longer than 6 months was associated with a reduction in the all-cause mortality risk in patients with COPD. The predictors of this association included medication factors and patient characteristics, among which eosinophil counts of ≥ 200/μL were the strongest predictor. Trial Registry PROSPERO; No.: CRD42022304725; URL: https://www.crd.york.ac.uk/prospero/ Inhaled corticosteroids (ICSs) have been used widely in the maintenance therapy of COPD. However, whether inhaled therapy containing ICSs can reduce the all-cause mortality risk and the possible benefited patient subgroups is unclear. Does inhaled therapy containing ICSs reduce the all-cause mortality risk in patients with COPD compared with other inhaled therapies not containing ICSs? We searched PubMed, Cochrane Library, Embase, and ClinicalTrials.gov for relevant randomized clinical trials (RCTs). Pooled results were calculated using Peto ORs with corresponding 95% CIs. Sixty RCTs enrolling 103,034 patients were analyzed. Inhaled therapy containing ICSs (Peto OR, 0.90; 95% CI, 0.84-0.97), especially triple therapy (Peto OR, 0.73; 95% CI, 0.60-0.90), was associated with a reduction in the all-cause mortality risk among patients with COPD when compared with inhaled therapy without ICSs. Subgroup analyses revealed that treatment duration of > 6 months (Peto OR, 0.90; 95% CI, 0.83-0.97), medium-dose ICSs (Peto OR, 0.71; 95% CI, 0.56-0.91), low-dose ICSs (Peto OR, 0.88; 95% CI, 0.79-0.97), and budesonide (Peto OR, 0.75; 95% CI, 0.59-0.94) were involved in this association. The predictors of this association included eosinophil counts of ≥ 200/μL or percentage of ≥ 2%, documented history of ≥ 2 moderate and severe exacerbations in the previous year, Global Initiative for Chronic Obstructive Lung Disease stages III or IV, age younger than 65 years, and BMI of ≥ 25 kg/m2, among which eosinophil counts of ≥ 200/μL (Peto OR, 0.58; 95% CI, 0.36-0.95) were the strongest predictor. Inhaled therapy containing ICSs, especially triple therapy, of longer than 6 months was associated with a reduction in the all-cause mortality risk in patients with COPD. The predictors of this association included medication factors and patient characteristics, among which eosinophil counts of ≥ 200/μL were the strongest predictor. PROSPERO; No.: CRD42022304725; URL: https://www.crd.york.ac.uk/prospero/ Corrigendum to: CHEST 2023;163(1):100-114CHESTVol. 163Issue 5PreviewThe January 2023 original research article titled "Association of Inhaled Corticosteroids With All-Cause Mortality Risk in Patients With COPD: A Meta-analysis of 60 Randomized Controlled Trials" by Chen et al (CHEST. 2023;163[1]:100-114) contained the following errors: Full-Text PDF ResponseCHESTVol. 163Issue 5PreviewWe thank Dr Oba for his interest in our study about the association of inhaled corticosteroids (ICSs) with all-cause mortality risk in patients with COPD.1 The data of our meta-analysis were completely extracted from the 60 included randomized controlled trials, as detailed in the online supplement of the article. We agree with some of the comments from Dr Oba on data issues. These comments are of great value, help to improve our article, and have important guiding significance for our research. Full-Text PDF Data Collection Issues With Mortality Risk of Inhaled Corticosteroids in COPDCHESTVol. 163Issue 5PreviewThere appear to be major issues with the data collection and conduct of the meta-analysis by Chen et al1 in CHEST (January 2023). For instance, in Figure 3B, the authors included data of triple combinations for the inhaled corticosteroid/long-acting β2-agonist (ICS/LABA) arm in studies by Ferguson et al2(2018), Lipson et al3 (2018), and Rabe et al4 (2020). There are no qualifying data for this comparison in Chapman et al5 (2018) because there was no ICS/LABA arm. Ichinose et al6 (2019) and Kerwin et al7 (2019) are extension studies of Ferguson et al2 (2018) (KRONOS), which could introduce bias because of withdrawals due to death before the extension portion of the studies. Full-Text PDF ResponseCHESTVol. 162Issue 6PreviewIn response to Dr Samy Suissa's comments on the article "Association of Inhaled Corticosteroids With All-cause Death Risk in COPD Patients: A Meta-analysis of Sixty Randomized Controlled Trials,"1 our responses are as follows: Full-Text PDF Inhaled Corticosteroids and Mortality in COPD: Biases in Randomized TrialsCHESTVol. 162Issue 6PreviewThe meta-analysis of 60 randomized trials by Chen et al1 in CHEST reports that inhaled corticosteroids (ICS) to treat COPD reduce all-cause mortality by 10% (OR, 0.90; 95% CI, 0.84-0.97) and up to 40% in some subgroups.1 We note from Figure 2 of Chen et al that the pooled results are largely driven by three large trials, SUMMIT, IMPACT, and ETHOS, the latter two contributing 41% and 32% reductions in mortality with ICS use, respectively. However, the design of these triple-therapy trials included patients already treated with maintenance therapy that had to be abruptly discontinued before randomization, which could affect the results. Full-Text PDF Inhaled Corticosteroids and COPD: 25 Years Later and We Are Still Not ThereCHESTVol. 163Issue 1PreviewAlready in 2007, the Towards a Revolution in COPD Health (TORCH) trial1 provided the strong tendency toward significance (P = .052) that an inhaled corticosteroid/long-acting β2-adrenoceptor agonist (inhaled corticosteroids [ICS]/long-acting beta-agonists [LABA]) fixed-dose combination (FDC) may reduce the risk of death in patients with COPD vs placebo (hazard ratio [HR] 0.825, 95% CI, 0.681-1.002). Although the TORCH study did not meet the predetermined level of statistical significance for the primary outcome of death from any cause, this trial was recognized as an example of trials whose findings are worthy of more constructive interpretation than that of negative trials. Full-Text PDF