Role of Tiotropium in Reducing Exacerbations of Chronic Obstructive Pulmonary Disease When Combined With Long‐Acting β₂‐Agonists and Inhaled Corticosteroids: The OUTPUL Study

Abstract

Combined inhaled therapy in chronic obstructive pulmonary disease (COPD) is commonly used, but its benefits remain controversial. We assessed the effect of tiotropium in reducing COPD exacerbations when combined with long‐acting β2 agonists (LABA) and/or inhaled corticosteroids (ICS). This new‐user cohort study is based on administrative data from 3 Italian regions. We identified adults hospitalized for COPD from 2006 to 2009 who were newly prescribed a fixed LABA/ICS combination (double therapy). We classified patients according to whether tiotropium was also prescribed (triple therapy), using both intention‐to‐treat and as‐treated approaches, and followed them for 1 year. COPD exacerbations were measured as outcomes. Multivariate and propensity score‐adjusted hazard ratios (HRs, 95%CI) were calculated with Cox regression models. We identified 5717 new users of LABA/ICS of which 31.9% initiated triple therapy. In the intention‐to‐treat analysis, the multivariate adjusted HR for moderate, severe, and any exacerbations were 1.02 (95%CI 0.89‐1.16), 0.92 (95%CI 0.76‐1.12), and 1.08 (95%CI 0.91‐1.28), respectively. The propensity score adjustment produced similar results. In the subcohort of patients with previous exacerbations, triple therapy was significantly associated with reduced risk of moderate exacerbations, compared to double therapy (HR 0.68, 95%CI 0.48‐0.98 in intention‐to‐treat approach). In conclusion, the addition of tiotropium to LABA/ICS did not reduce COPD exacerbations compared to LABA/ICS alone. A protective role for moderate exacerbations was found in patients at risk of frequent exacerbations. Given the impact of exacerbations on health status and prognosis, it is crucial to target COPD patients for optimal treatment.

Triple versus dual inhaler therapy in moderate‐to‐severe COPD: A systematic review and meta‐analysis of randomized controlled trials

“…In our meta‐analysis, there was no direct comparison between both dual therapies, though our subgroup analysis demonstrated a greater reduction of COPD exacerbations in patients using triple therapy vs LABA/LAMA (29%) than in triple therapy vs ICS/LABA (18%); however, the difference was not statistically significant between both groups ( P = 0.38) (Figure ). Conversely, Ferroni et al conducted the OUTPUL study, which suggested no significant difference in moderate‐to‐severe COPD exacerbations between triple and ICS/LABA in a large cohort study; however, the difference was more significant when sub‐cohort analysis was performed in patients who had moderate‐to‐severe COPD exacerbations in the past year . The OUTPUL study was neither randomized nor controlled, which increased the risk of bias and confounding variables that may have affected the results.…”

“…Conversely, Ferroni et al conducted the OUTPUL study, which suggested no significant difference in moderate-tosevere COPD exacerbations between triple and ICS/LABA in a large cohort study; however, the difference was more significant when sub-cohort analysis was performed in patients who had moderate-to-severe COPD exacerbations in the past year. 24 The OUTPUL study was neither randomized nor controlled, which increased the risk of bias and confounding variables that may have affected the results. COPD) trial showed reduction of moderate-to-severe COPD exacerbations with triple therapy consisting of budesonide, glycopyrrolate and formoterol fumarate in comparison to LABA/LAMA (glycopyrrolate and formoterol fumarate), but not dual therapy ICS/LABA (budesonide and formoterol).…”

Lung and kidney: a dangerous liaison? A population-based cohort study in COPD patients in Italy

“… 5 Frequent acute exacerbations also play an important role in decreased lung function and thereby increase disease severity and mortality. 6 , 7 …”

Inhaled therapies for chronic obstructive pulmonary disease: a systematic review and meta-analysis

“…There is evidence that patient characteristics may play an important role in therapeutic efficacy, including exacerbation history and eosinophils; two key characteristics that we could not include here, and the heterogeneity in the literature has likely contributed to the differences in advice from GOLD and NICE. Additionally, the OUTPUL 38 observational study found no difference in risk for exacerbation comparing triple therapy to LABA+ICS; however, when narrowed to a pool of frequent exacerbators, they saw a significantly reduced risk for moderate exacerbations in triple therapy patients.…”