Single-Inhaler Triple versus Dual Bronchodilator Therapy in COPD: Real-World Comparative Effectiveness and Safety

Abstract

Purpose

Randomized trials report that single-inhaler triple therapy is more effective than dual bronchodilators at reducing exacerbations in patients with chronic obstructive pulmonary disease (COPD). However, this effect may have been influenced by the forced withdrawal of inhaled corticosteroids (ICS) at randomization. We used an adaptive selection new-user design to compare single-inhaler triple therapy with dual bronchodilators in real-world clinical practice.

Patients and Methods

We identified a cohort of COPD patients, 40 years or older, treated during 2017–2020, from the United Kingdom’s Clinical Practice Research Datalink, a real-world practice setting. ICS-naïve patients initiating single-inhaler triple therapy or dual bronchodilators were compared on the incidence of COPD exacerbation and pneumonia over one year, after adjustment by propensity score weighting.

Results

The cohort included 4106 new users of single-inhaler triple therapy and 29,702 of dual bronchodilators. Single-inhaler triple therapy was the first maintenance treatment in 44% of the users and 43% had no COPD exacerbations in the prior year. The adjusted hazard ratio (HR) of a first moderate or severe exacerbation with triple therapy relative to dual bronchodilators was 1.08 (95% confidence interval (CI): 1.00–1.16). Among patients with two or more prior exacerbations the HR was 0.83 (95% CI: 0.74–0.92), while for those with prior asthma diagnosis it was 0.86 (95% CI: 0.70–1.06) and with blood eosinophil count >300 cells/µL it was 0.89 (95% CI: 0.76–1.05). The incidence of severe pneumonia was increased with triple therapy (HR 1.50; 95% CI: 1.29–1.75).

Conclusion

In a real-world setting of COPD treatment among ICS-naïve patients, thus unaffected by ICS withdrawal, single-inhaler triple therapy was not more effective than dual bronchodilators at reducing the incidence of exacerbation, except among patients with multiple exacerbations. Single-inhaler triple therapy should be initiated mainly in patients with multiple exacerbations while, for most others, dual bronchodilators are just as effective whilst avoiding the excess risk of severe pneumonias.

Keywords:

• cohort studies
• COPD exacerbation
• pneumonia
• propensity scores
• real-world evidence

Abbreviation

AECOPD, acute exacerbation of COPD; CI, confidence interval; COPD, chronic obstructive pulmonary disease; CPRD, Clinical Practice Research Datalink; ETHOS, Efficacy and Safety of Triple Therapy in Obstructive Lung Disease; HES, Hospital Episodes Statistics; HR, hazard ratio; ICS, inhaled corticosteroids; LAMA, long-acting muscarinic antagonists; LABA, long-acting beta₂-agonists; LRTI, lower respiratory tract infection; IMPACT, Informing the Pathway of COPD Treatment; UK, United Kingdom; sd, standard deviation.

Data Sharing Statement

This study is based in part on data from the Clinical Practice Research Datalink obtained under license from the UK Medicines and Healthcare products Regulatory Agency. The data are provided by patients and collected by the UK National Health Service as part of their care and support. The interpretation and conclusions contained in this study are those of the author/s alone. Because electronic health records are classified as “sensitive data” by the UK Data Protection Act, information governance restrictions (to protect patient confidentiality) prevent data sharing via public deposition. Data are available with approval through the individual constituent entities controlling access to the data. Specifically, the primary care data can be requested via application to the Clinical Practice Research Datalink (https://www.cprd.com).

Author Contributions

All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.

Disclosure

SS attended scientific advisory committee meetings or consulted for AstraZeneca, Atara, Bristol-Myers-Squibb, Merck, Novartis, Panalgo, Pfizer and Seqirus, and received speaking fees from AstraZeneca, Boehringer-Ingelheim and Novartis. Dr. Ernst and Ms Dell’Aniello have no conflicts of interest.

Additional information

Funding

This study is not funded. Pr. Suissa is the recipient of the Distinguished James McGill Professorship award.