Articles
Blood eosinophils and treatment response with triple and dual combination therapy in chronic obstructive pulmonary disease: analysis of the IMPACT trial

https://doi.org/10.1016/S2213-2600(19)30190-0Get rights and content

Summary

Background

Previous studies have highlighted a relationship between reduction in rate of exacerbations with therapies containing inhaled corticosteroids (ICS) and baseline blood eosinophil count in patients with chronic obstructive pulmonary disease (COPD). The IMPACT trial showed that once-daily single-inhaler triple therapy significantly reduced exacerbations versus dual therapies. Blood eosinophil counts and smoking status could be important modifiers of treatment response to ICS. We aimed to model these relationships and their interactions, including outcomes other than exacerbations.

Methods

IMPACT was a phase 3, randomised, double-blind, parallel-group, 52-week global study comparing once-daily single-inhaler triple therapy (fluticasone furoate–umeclidinium–vilanterol) with dual inhaled therapy (fluticasone furoate–vilanterol or umeclidinium–vilanterol). Eligible patients had moderate-to-very-severe COPD and at least one moderate or severe exacerbation in the previous year. We used fractional polynomials to model continuous blood eosinophil counts. We used negative binomial regression for numbers of moderate and severe exacerbations, severe exacerbations, and pneumonia. We modelled differences at week 52 in trough FEV1, St George's Respiratory Questionnaire (SGRQ) total score, and Transition Dyspnoea Index using repeated measurements mixed effect models. IMPACT was registered with ClinicalTrials.gov, number NCT02164513.

Findings

The magnitude of benefit of regimens containing ICS (fluticasone furoate–umeclidinium–vilanterol n=4151 and fluticasone furoate–vilanterol n=4134) in reducing rates of moderate and severe exacerbations increased in proportion with blood eosinophil count, compared with a non-ICS dual long-acting bronchodilator (umeclidinium–vilanterol n=2070). The moderate and severe exacerbation rate ratio for triple therapy versus umeclidinium–vilanterol was 0·88 (95% CI 0·74 to 1·04) at blood eosinophil count less than 90 cells per μL and 0·56 (0·47 to 0·66) at counts of 310 cells per μL or more; the corresponding rate ratio for fluticasone furoate–vilanterol versus umeclidinium–vilanterol was 1·09 (0·91 to 1·29) and 0·56 (0·47 to 0·66), respectively. Similar results were observed for FEV1, Transition Dyspnoea Index, and SGRQ total score; however, the relationship with FEV1 was less marked. At blood eosinophil counts less than 90 cells per μL and at counts of 310 cells per μL or more, the triple therapy versus umeclidinium–vilanterol treatment difference was 40 mL (95% CI 10 to 70) and 60 mL (20 to 100) for trough FEV1, −0·01 (–0·68 to 0·66) and 0·30 (–0·37 to 0·97) for Transition Dyspnoea Index score, and −0·01 (–1·81 to 1·78) and −2·78 (–4·64 to −0·92) for SGRQ total score, respectively. Smoking status modified the relationship between observed efficacy and blood eosinophil count for moderate or severe exacerbations, Transition Dyspnoea Index, and FEV1, with former smokers being more corticosteroid responsive at any eosinophil count than current smokers.

Interpretation

This analysis of the IMPACT trial shows that assessment of blood eosinophil count and smoking status has the potential to optimise ICS use in clinical practice in patients with COPD and a history of exacerbations.

Funding

GlaxoSmithKline.

Introduction

The 2019 Global initiative for chronic Obstructive Lung Disease (GOLD) strategy document recommends that pharmacological therapy for chronic obstructive pulmonary disease (COPD) should aim to reduce symptoms and the frequency and severity of exacerbations,1 which are key contributing factors to the high clinical and economic burden of the disease.2, 3, 4

Inhaled corticosteroids (ICS) reduce the rate of exacerbations (ie, the number of exacerbations per patient year) in patients with COPD and a history of exacerbations.5, 6, 7, 8 However, the heterogeneity of COPD leads to variability between individuals in the magnitude of ICS benefit, and the potential for drug-related adverse events such as pneumonia.9 Post-hoc and prespecified analyses of randomised controlled trials have shown that higher blood eosinophil counts are associated with greater ICS treatment effects.10, 11, 12, 13 A pooled analysis14 of clinical trials, which compared ICS and long-acting β2-agonist (LABA) combination therapy with LABA monotherapy, modelled this relationship with data from 4528 patients; beneficial effects of ICS on exacerbation reduction were apparent at blood eosinophil counts of more than 100 cells per μL, with greater effects observed at higher blood eosinophil counts.14 Dichotomising the eosinophil count into high and low on the basis of an arbitrary threshold10, 11 cannot fully describe the continuous nature of the relationship between blood eosinophils and ICS effect.14 The increasing effect of ICS at higher blood eosinophil counts has also been observed in other analyses of ICS/LABA versus LABA clinical trials involving multiple eosinophil subgroups.11, 12

Research in context

Evidence before this study

Therapies containing inhaled corticosteroids (ICS) reduce exacerbation rates (ie, number of exacerbations per patient per year) in patients with chronic obstructive pulmonary disease (COPD). Studies have shown that higher blood eosinophil counts are associated with a greater treatment benefit with ICS. We searched PubMed using the terms “inhaled corticosteroids”, “blood eosinophil count”, “exacerbation”, and “COPD” to identify studies published from Jan 1, 2008, onwards that investigated the association between blood eosinophil counts and response to ICS-containing therapies in COPD. The relationship between ICS and blood eosinophil count has been modelled in various post-hoc analyses, with the greatest effects of ICS on reduction of COPD exacerbations shown at higher eosinophil counts. The majority of these analyses focused on the response of patients to ICS and long-acting β2-agonist (LABA) therapy versus LABA monotherapy using dichotomised eosinophil counts. However, additional evidence is required to understand the relationship between blood eosinophil count as a continuous variable and the effect of ICS with both single-inhaler triple therapy and dual inhaled therapies in patients with COPD, and to determine whether this relationship is modified by other factors known to modulate the effects of ICS, such as cigarette smoking.

Added value of this study

The large size of the population in the IMPACT trial, which compared once-daily single-inhaler triple therapy (fluticasone furoate, umeclidinium, and vilanterol) with dual inhaled therapy (fluticasone furoate and vilanterol, and umeclidinium and vilanterol), allows modelling of the relationship between baseline blood eosinophil count as a continuous variable and the effect of ICS on COPD exacerbations and other outcomes. These analyses showed that greater ICS treatment effects were associated with increased blood eosinophil counts. This was seen in both former and current smokers, with larger benefit seen in former smokers.

Implications of all the available evidence

To our knowledge, this is the first analysis to use data modelling of single-inhaler triple therapy or ICS-LABA versus long-acting muscarinic antagonist–LABA to show that, in a population at high risk of exacerbations, the response to ICS-containing therapy can be predicted with blood eosinophil counts and smoking status. The continuous nature of the relationship between increasing blood eosinophil count and reduction in exacerbations with use of ICS is apparent. Assessment of blood eosinophils should, therefore, be used as part of a precision medicine approach to optimise the use of ICS within combination therapies in patients with COPD.

Recent clinical trials have shown the benefits of single-inhaler triple therapy versus the dual combination treatments ICS–LABA and long-acting muscarinic antagonists (LAMA)–LABA on exacerbation prevention.15, 16, 17, 18 Data modelling is needed to understand the effects of blood eosinophils on response to triple therapy versus LAMA–LABA, and ICS–LABA versus LAMA–LABA. Such data would support the use of blood eosinophil counts to aid decision-making regarding the use of these treatments in clinical practice. The InforMing the PAthway of COPD Treatment (IMPACT) trial18, 19 was designed to establish the relative benefits of the single-inhaler triple therapy containing fluticasone furoate–umeclidinium–vilanterol (ICS–LAMA–LABA) compared with both fluticasone furoate–vilanterol (ICS–LABA) and umeclidinium–vilanterol (LAMA–LABA) in patients with moderate-to-very-severe COPD and at risk of exacerbation. In IMPACT, 4877 (47%) of patients had at least two moderate exacerbations and 2671 (26%) had at least one severe exacerbation in the year before enrolment.18 The IMPACT results have been reported elsewhere,18 and show that single-inhaler triple therapy reduced moderate or severe COPD exacerbations, improved lung function, and improved quality of life compared with either dual combination therapy. There was also a reduction in the risk of on-treatment mortality with single-inhaler triple therapy versus umeclidinium–vilanterol.18 In a pre-specified analysis, a greater reduction in annual rate of moderate and severe exacerbations was reported with single-inhaler triple therapy versus umeclidinium–vilanterol in patients with at least 150 eosinophils per μL, compared with those with less than 150 eosinophils per μL.

Studies comparing single-inhaler triple therapy with LAMA–LABA, and ICS–LABA with LAMA–LABA, have used different bronchodilator molecules within the dual bronchodilator compared with the ICS-containing combination.17, 20 Furthermore, different inhaler devices and regimens (once vs twice a day) have been compared, which can introduce confounding. A strength of the IMPACT trial is the use of the same bronchodilator molecules, inhaler devices, doses, and regimen for all treatments, meaning that any differences observed cannot be attributed to these variables.18

We report an analysis of the IMPACT trial that modelled the relationship of blood eosinophil counts with ICS therapy across multiple clinical outcomes including exacerbations, lung function, and health status. It has previously been reported that current smoking modifies the relationship between blood eosinophil counts and ICS effect, with a greater ICS effect observed in former smokers.14, 21, 22 We therefore also investigated the effect of current or former smoking on this relationship in post-hoc analyses.

Section snippets

Study design

Details of the IMPACT trial design (GSK study number CTT116855; ClinicalTrials.gov number NCT02164513) have been published previously.18, 19 Briefly, IMPACT was a phase 3, randomised, double-blind, parallel-group, multicentre study. Patients continued taking their own medication during a 2-week run-in period and were then randomly assigned (2:2:1) to once-daily single-inhaler triple therapy containing ICS–LAMA–LABA (fluticasone furoate–umeclidinium–vilanterol 100/62·5/25 μg), once-daily dual

Results

Detailed characteristics of the IMPACT trial population have been published previously,18 and no clinically relevant differences among the three treatment groups were identified.18 Overall, 10 333 patients had available baseline blood eosinophil count data (4143 in the triple therapy group, 4125 in the fluticasone furoate–vilanterol group, and 2065 in the umeclidinium–vilanterol group). 6856 (66%) of patients were male, 6756 (65%) were former smokers, and had a mean age of 65·3 years (SD 8·3;

Discussion

To the best of our knowledge, the IMPACT trial is the largest completed clinical trial comparing the effects of single-inhaler triple therapy (fluticasone furoate–umeclidinium–vilanterol) with dual inhaled therapies (fluticasone furoate–vilanterol and umeclidinium–vilanterol) in symptomatic patients with COPD and a history of exacerbations.18 Statistical modelling showed that the effects of triple therapy compared with umeclidinium–vilanterol on exacerbation reduction were dependent on blood

Data sharing

Anonymised individual participant data and study documents can be requested for further research from www.clinicalstudydatarequest.com.

This online publication has been corrected. The corrected version first appeared at thelancet.com/respiratory on Nov 30, 2021

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