The role of triple therapy in the management of COPD

ABSTRACT

Introduction

Triple therapy in COPD is becoming increasingly important with the cumulative documentation of its ability to reduce the risk of AECOPD. However, it must be established which patients benefit most from it compared to other treatments.

Areas covered

We critically review the literature to determine, if possible, the real role of triple therapy in the treatment of COPD. We have identified studies from several databases and selected the information thought to be more significant.

Expert opinion

It is still unclear whether and when addition of an ICS to the LAMA/LABA combination provides real additional clinical value, regardless of a preventive effect on exacerbations. There are many doubts about the value of the blood eosinophil count as a valid biomarker to predict AECOPD risk and the clinical response to ICS, also because no association was found in observational studies. In any case, before starting a therapy involving ICS, the risk factors for the development of pneumonia must always be evaluated. Adding a LAMA to an ICS/LABA combination seems to be less problematic. However, each LABA/LAMA combination has a specific efficacy/safety profile that needs to be considered for personalized therapy in COPD even in the context of triple therapy.

KEYWORDS:

• Chronic obstructive pulmonary disease
• fixed-dose combinations
• inhaled corticosteroids
• long-acting β₂-agonists
• long-acting muscarinic receptor antagonists
• triple therapy

Article highlights

• A solid pharmacological rationale supports the combination of an ICS with a LABA in COPD. When tested all together, ICSs, LABAs and LAMAs elicit strong synergy in relaxing human ASM because of mechanisms prevalently related with the activity of intracellular GRs and partially associated with the activation of G_sα subunit G-protein of β₂-ARs.

• The growing clinical evidence suggesting that triple therapy with ICSs, LABAs and LAMAs is efficacious made it an attractive combination in COPD, but COPD guidelines and strategies are not very thorough when recommending the use of triple therapy.

• All available information leads to the conclusion that triple therapy, regardless of whether fixed-dose or open combination, is effective in reducing the risk of AECOPD and improving pulmonary function. However, triple therapy is associated with a significantly higher risk of pneumonia, at least when compared to LABA/LAMA therapy.

• Mounting evidence suggests that triple combination therapy offers only a further modest clinical benefit in the general COPD population, but it is clinically relevant when a patient is on LABA/LAMA therapy and still suffers from AECOPD and has blood eosinophil counts ≥300 cells·μl⁻¹; however, adding a LAMA to an ICS/LABA combination induces a relevant clinical benefit in the general COPD population without increasing the risk of cardiovascular severe adverse events.

• Triple therapy should be considered as first choice for patients discharged from the hospital after an AECOPD, and in which COPD has been formulated for the first time because of the severe AECOPD, and also for COPD patients who present with a significant lung function decline.

• There are many doubts about the value of the blood eosinophil count as a valid biomarker to predict AECOPD risk and the clinical response to ICS also because no association was found in observational studies.

Declaration of interest

L.C. has participated as advisor in scientific meetings under the sponsorship of Novartis, received non-financial support by AstraZeneca, received a research grant partially funded by Chiesi Farmaceutici and Novartis. His department was funded by Novartis and Chiesi Farmaceutici. M.G.M. has participated as a speaker and advisor in scientific meetings and courses under the sponsorship of AstraZeneca, Chiesi Farmaceutici, GlaxoSmithKline, and Novartis and has been a consultant to Chiesi Farmaceutici. Her department was funded by GlaxoSmithKline, and Novartis. P.R. participated as a speaker and advisor in scientific meetings and courses under the sponsorship of AstraZeneca, Chiesi Farmaceutici, GlaxoSmithKline, Menarini Group, and Novartis. Her department was funded by Novartis, and Chiesi Farmaceutici. M.C. has participated as a speaker and advisor in scientific meetings and courses under the sponsorship of AstraZeneca, Chiesi Farmaceutici, Cipla, GlaxoSmithKline, Menarini Group and Novartis, and has been a consultant to Chiesi Farmaceutici. His department was funded by Novartis.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.