Benefit/Risk Profile of Single-Inhaler Triple Therapy in COPD

Abstract

Chronic obstructive pulmonary disease (COPD) is associated with major healthcare and socioeconomic burdens. International consortia recommend a personalized approach to treatment and management that aims to reduce both symptom burden and the risk of exacerbations. Recent clinical trials have investigated single-inhaler triple therapy (SITT) with a long-acting muscarinic antagonist (LAMA), long-acting β2-agonist (LABA), and inhaled corticosteroid (ICS) for patients with symptomatic COPD. Here, we review evidence from randomized controlled trials showing the benefits of SITT and weigh these against the reported risk of pneumonia with ICS use. We highlight the challenges associated with cross-trial comparisons of benefit/risk, discuss blood eosinophils as a marker of ICS responsiveness, and summarize current treatment recommendations and the position of SITT in the management of COPD, including potential advantages in terms of improving patient adherence. Evidence from trials of SITT versus dual therapies in symptomatic patients with moderate to very severe airflow limitation and increased risk of exacerbations shows benefits in lung function and patient-reported outcomes. Moreover, the key benefits reported with SITT are significant reductions in exacerbations and hospitalizations, with data also suggesting reduced all-cause mortality. These benefits outweigh the ICS-class effect of higher incidence of study-reported pneumonia compared with LAMA/LABA. Important differences in trial design, baseline population characteristics, such as exacerbation history, and assessment of outcomes, have significant implications for interpreting data from cross-trial comparisons. Current understanding interprets the blood eosinophil count as a continuum that can help predict response to ICS and has utility alongside other clinical factors to aid treatment decision-making. We conclude that treatment decisions in COPD should be guided by an approach that considers benefit versus risk, with early optimization of treatment essential for maximizing long-term benefits and patient outcomes.

Keywords: ICS; LABA; LAMA; all-cause mortality; exacerbations; hospitalizations.

Conflict of interest statement

J. Bourbeau reports grants from CIHR and Canadian Respiratory Research Network (CRRN), Foundation of the McGill University Health Center, Aerocrine, AstraZeneca, Boehringer Ingelheim, Grifols, GSK, Novartis, and Trudell; personal conference and advisory board fees from Canadian Thoracic Society, CHEST, Astra Zeneca, Boehringer Ingelheim, Grifols, GSK, Novartis, and Trudell. M. Bafadhel reports grants from AstraZeneca; advisory board attendance for AstraZeneca, Chiesi, Boehringer Ingelheim, and GSK; attendance at educational meetings facilitated by AstraZeneca, Chiesi, and Boehringer Ingelheim; and scientific advisor for ProAxsis and AlbusHealth. C. Compton, P.W. Jones, N.C. Barnes, D.A. Lipson, V. Di Boscio, and G. Weiss are employees of GSK and hold stocks and shares in GSK. N. Martin was an employee of GSK at the time the study was conducted. D.M.G. Halpin has received personal fees from AstraZeneca, Boehringer Ingelheim, Chiesi, GSK, Novartis, Pfizer, and Sanofi and non-financial support from Boehringer Ingelheim and Novartis. The authors report no other conflicts of interest in this work.

© 2021 Bourbeau et al.

Figures

Figure 1

Disease severity and exacerbation history are strongly correlated with pneumonia risk whereas ICS only adds a small additional risk.

Figure 2

All-cause mortality benefits with SITT are similar to, or better than, smoking cessation and cardioprotective treatments. aPooled analysis of AEs leading to a fatal outcome (safety population); bon- and off-treatment deaths in post hoc analysis with additional vital status follow-up (vital status available for 99.6% of patients at nominal Week 52); canalysis included all observed data regardless of whether patients continued to receive their assigned treatment.