Risk of Pneumonia with Inhaled Corticosteroid versus Long-Acting Bronchodilator Regimens in Chronic Obstructive Pulmonary Disease: A New-User Cohort Study

et al. (2014) Risk of Pneumonia with Inhaled Corticosteroid versus Long-Acting Bronchodilator Regimens in Chronic Obstructive Pulmonary Disease: A New-User Cohort Study. PLoS ONE 9(5): e97149. doi:10.1371/journal.pone.0097149 Risk of Pneumonia with Inhaled Corticosteroid versus Long-Acting Bronchodilator Regimens in Chronic Obstructive Pulmonary Disease: A New-User Cohort Study Rachael L. DiSantostefano 0 Tim Sampson 0 Hoa Van Le 0 David Hinds 0 Kourtney J. Davis 0 Nawar Diar Bakerly 0 Gernot G.U. Rohde, Maastricht University Medical Center (MUMC), Netherlands 0 1 Worldwide Epidemiology , GlaxoSmithKline, Research Triangle Park , North Carolina, United States of America, 2 Salford Royal NHS Foundation Trust and Manchester University , Manchester , United Kingdom Introduction: Observational studies using case-control designs have showed an increased risk of pneumonia associated with inhaled corticosteroid (ICS)-containing medications in patients with chronic obstructive pulmonary disease (COPD). New-user observational cohort designs may minimize biases associated with previous case-control designs. Objective: To estimate the association between ICS and pneumonia among new users of ICS relative to inhaled long-acting bronchodilator (LABD) monotherapy. Methods: Pneumonia events in COPD patients $45 years old were compared among new users of ICS medications (n = 11,555; ICS, ICS/long-acting b2-agonist [LABA] combination) and inhaled LABD monotherapies (n = 6,492; LABA, longacting muscarinic antagonists) using Cox proportional hazards models, with propensity scores to adjust for confounding. Setting: United Kingdom electronic medical records with linked hospitalization and mortality data (2002-2010). New users were censored at earliest of: pneumonia event, death, changing/discontinuing treatment, or end of follow-up. Outcomes: severe pneumonia (primary) and any pneumonia (secondary). Results: Following adjustment, new use of ICS-containing medications was associated with an increased risk of pneumonia hospitalization (n = 322 events; HR = 1.55, 95% CI: 1.14, 2.10) and any pneumonia (n = 702 events; HR = 1.49, 95% CI: 1.22, 1.83). Crude incidence rates of any pneumonia were 48.7 and 30.9 per 1000 person years among the ICS-containing and LABD cohorts, respectively. Excess risk of pneumonia with ICS was reduced when requiring $1 month or $ 6 months of new use. There was an apparent dose-related effect, with greater risk at higher daily doses of ICS. There was evidence of channeling bias, with more severe patients prescribed ICS, for which the analysis may not have completely adjusted. Conclusions: The results of this new-user cohort study are consistent with published findings; ICS were associated with a 20-50% increased risk of pneumonia in COPD, which reduced with exposure time. This risk must be weighed against the benefits when prescribing ICS to patients with COPD. - Competing Interests: RLD, TS, HVL and KJD are employees of and hold stock in GlaxoSmithKline. DH is a full-time contractor at GlaxoSmithKline. NDB had received unrestricted educational grants from GSK, Novartis and Boehringer Ingelheim, as well as advising GSK and Novartis on various study designs. GSK manufactures inhaled corticosteroid-containing medications including fluticasone propionate, fluticasone propionate/salmeterol in combination, and fluticasone furoate/vilanterol in combination. This study was conducted to evaluate the safety of the ICS-containing medication class in an observational setting in patients with COPD and includes fluticasone propionate-containing medications in the analysis period. This does not alter the authors adherence to PLOS ONE policies on sharing data and materials. Pneumonia can result in significant morbidity and mortality, particularly among the elderly and patients with chronic obstructive pulmonary disease (COPD) [14]. Risk factors for the development of pneumonia, including pneumonia requiring hospitalization, have been well characterized in clinical and observational studies and include older age, current smoking status, low body mass index (BMI), chronic comorbid conditions (e.g., dementia, diabetes, cardiovascular disease), higher levels of dyspnea, and markers of COPD disease severity [58]. In patients with COPD, randomized controlled trials (RCT) [6,9], meta-analyses [1013] and observational studies [1416] have generally observed an increased risk of pneumonia associated with the use of inhaled corticosteroid (ICS)-containing medications relative to non-steroid medications, including some evidence of a dose-related effect [10,14,16]. The mechanism by which ICS increase risk of pneumonia is unclear but may relate to reduced inflammatory response [17]. Comparisons across these individual studies have limitations, including disparate study populations and time periods, differing doses, molecules and devices, and variable definitions of pneumonia, which are discussed elsewhere [11]. Some previous (...truncated)