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Abstract

We thank Wang et al for their letter on our real-world study of the comparative effects of triple vs dual bronchodilator therapy COPD as it relates to the risk of pneumonia.1Suissa S, Dell’Aniello S, Ernst P. Comparative effects of LAMA-LABA-ICS vs LAMA-LABA for COPD: cohort study in real-world clinical practice. Chest. 2020;157(4):846-855.Google Scholar Indeed, our study found that the inhaled corticosteroid (ICS)-containing triple therapy is associated with an increased incidence of serious pneumonia requiring hospitalization, compared with long-acting muscarinic antagonist, long-acting beta2-agonist. Wang et al remind us that the different ICS have been associated with varying risks of pneumonia. We agree; this is an important point. Our previous large cohort study of more than 160,000 patients with COPD found that the highest risk of serious pneumonia was with fluticasone (rate ratio [RR], 2.01; 95% CI, 1.93-2.10) and much lower with budesonide (RR, 1.17; 95% CI, 1.09-1.26), compared with nonusers (Fig 1).2Suissa S. Patenaude V. Lapi F. Ernst P. Inhaled corticosteroids in COPD and the risk of serious pneumonia.Thorax. 2013; 68: 1029-1036Crossref PubMed Scopus (334) Google Scholar This difference is consistent with a Swedish study that reported a 74% higher risk of serious pneumonia with fluticasone compared with budesonide.3Janson C. Larsson K. Lisspers K.H. et al.Pneumonia and pneumonia related mortality in patients with COPD treated with fixed combinations of inhaled corticosteroid and long acting β2 agonist: observational matched cohort study (PATHOS).BMJ. 2013; 346: f3306Crossref PubMed Scopus (151) Google Scholar Although our current study does not provide this information, another study using the same data source identified that 66% of ICS-based prescriptions were for fluticasone, 28% for budesonide, and 6% for beclomethasone.4Suissa S. Dell'Aniello S. Ernst P. Comparative effectiveness of LABA-ICS versus LAMA as initial treatment in COPD targeted by blood eosinophils: a population-based cohort study.Lancet Respir Med. 2018; 6: 855-862Abstract Full Text Full Text PDF PubMed Scopus (62) Google Scholar Hence, our estimated hazard ratio of 1.46 for the risk of pneumonia with the ICS-containing triple therapy is most likely an average of a higher risk with fluticasone and a lower one with budesonide. Wang et al suggest from the meta-analysis of randomized trials that triple therapy involving beclomethasone does not increase the risk of pneumonia (RR, 1.04; 95% CI, 0.62-1.75).5Lai C.-C. Chen C.-H. Lin C.Y.H. Wang C.-Y. Wang Y.-H. The effects of single inhaler triple therapy vs single inhaler dual therapy or separate triple therapy for the management of chronic obstructive pulmonary disease: a systematic review and meta-analysis of randomized controlled trials.Int J Chron Obstruct Pulmon Dis. 2019; 14: 1539-1548Crossref Scopus (27) Google Scholar This finding must be interpreted with caution. Indeed, these trials used reported pneumonia that did not require radiographic confirmation, which could have contributed to dilute the effect, and the CI is wide, consistent with an elevated risk. Our previous large cohort study found an elevated risk of serious pneumonia requiring hospitalization with a group of ICSs that included mainly beclomethasone (RR, 1.41; 95% CI, 1.33-1.51), though lower than that with fluticasone propionate (Fig 1).2Suissa S. Patenaude V. Lapi F. Ernst P. Inhaled corticosteroids in COPD and the risk of serious pneumonia.Thorax. 2013; 68: 1029-1036Crossref PubMed Scopus (334) Google Scholar In all, we agree with Wang et al that when addressing the safety of ICS, fluticasone-containing inhalers should be emphasized for their particularly higher risk of pneumonia. On the other hand, there remains some discrepancy in the reports on the risk of pneumonia with beclomethasone-containing inhalers, though the trials suggesting an absence of risk may have been underpowered and used an unverified definition of pneumonia which could have diluted the effect. This is in contrast with the much larger observational studies that reported an elevated risk. Comparative Effects of LAMA-LABA-ICS vs LAMA-LABA for COPD: Cohort Study in Real-World Clinical PracticeCHESTVol. 157Issue 4PreviewTriple therapy combinations of a long-acting muscarinic antagonist (LAMA), a long-acting beta2-agonist (LABA), and an inhaled corticosteroid (ICS) for COPD were studied in randomized trials and observational studies, with variable results. We compared the effectiveness and safety of triple therapy with a LAMA-LABA combination in a real-world clinical practice setting. Full-Text PDF Different ICSs and the Risk of PneumoniaCHESTVol. 157Issue 5PreviewWe read with great interest the recent article by Suissa et al1 in a recent issue of CHEST (April 2020), in which they found that the incidence of severe pneumonia requiring hospitalization was increased in patients with COPD initiating long-acting muscarinic antagonist, long-acting beta2-agonist, and inhaled corticosteroid (LAMA-LABA-ICS) treatment compared with those initiating LAMA-LABA treatment (hazard ratio, 1.46; 95% CI, 1.03-2.06). We agree with the authors about the safety issue of LAMA-LABA-ICS-associated pneumonia, and our recent study2 on single inhaler triple therapy with LAMA-LABA-ICS showed similar findings, with a higher risk of pneumonia compared with LABA/LAMA (risk ratio [RR], 1.38; 95% CI, 1.14-1.67; I2 = 0) dual therapy. Full-Text PDF