Comparative effectiveness of LABA-ICS versus LAMA as initial treatment in COPD targeted by blood eosinophils: a population-based cohort study

doi:10.1016/S2213-2600(18)30368-0

The Lancet Respiratory Medicine

Volume 6, Issue 11, November 2018, Pages 855-862

https://doi.org/10.1016/S2213-2600(18)30368-0 Get rights and content

Summary

Background

Long-acting β₂ agonists (LABAs) and long-acting muscarinic antagonists (LAMAs) are the recommended initial maintenance treatment for chronic obstructive pulmonary disease (COPD), with almost all LABAs dispensed in fixed combination with inhaled corticosteroids (LABA-ICS). We compared the effectiveness and safety of LABA-ICS versus LAMA treatment initiation as a function of blood eosinophilia, a potential biomarker of ICS effectiveness, in a real-world setting.

Methods

In this population-based cohort study, we identified a cohort of patients with COPD initiating treatment with a LAMA or LABA-ICS during 2002–15, age 55 years or older, from the UK's Clinical Practice Research Datalink. We excluded patients who initiated treatment with both bronchodilators on the same date. All patients required at least 1 year of medical history and a measure of blood eosinophil concentration before cohort entry, defined by the date of the first cohort-defining bronchodilator prescription. Patients initiating a LAMA were matched on high-dimensional propensity scores with patients initiating a LABA-ICS. They were followed up for 1 year for the occurrence of a moderate or severe COPD exacerbation and for severe pneumonia. Sensitivity analyses included, among others, repeating the analysis among patients with two blood eosinophil concentration measures and stratification by concurrent asthma and previous exacerbations.

Findings

The base cohort included 539 643 patients with a prescription for LABAs or LAMAs from Jan 1, 2002, to Dec 31, 2015, of whom 18 500 were initiated on LABA-ICS and 13 870 on LAMAs. Propensity score analysis resulted in 12 366 initiators of LAMAs (mainly tiotropium) matched to 12 366 initiators of LABA-ICS. The hazard ratio (HR) of COPD exacerbation associated with LABA-ICS initiation, relative to LAMA initiation, was 0·95 (95% CI 0·90–1·01). In patients with blood eosinophil concentrations of less than 2% of white blood cell count, the HR was 1·03 (95% CI 0·93–1·13) and for those with eosinophil concentrations of 2–4%, the HR was 1·00 (0·91–1·10). For patients with eosinophil concentrations of more than 4%, the HR was 0·79 (0·70–0·88). The incidence of pneumonia increased with LABA-ICS initiation (HR 1·37 [95% CI 1·17–1·60]) and was similar across all eosinophil concentrations. Sensitivity analyses were consistent with these findings, but the incidence of exacerbation with LABA-ICS among the 2766 (11%) of all 24 732 patients with two or more COPD exacerbations during the baseline year was marginally lower (HR 0·87 [95% CI 0·79–0·97]).

Interpretation

In this real-world, clinical practice, observational study, initial COPD treatment with LABA-ICS inhalers was only more effective than with LAMAs in patients with high blood eosinophil concentrations (>4%) or counts (>300 cells per μL) and possibly in frequent exacerbators. Because of the increased risk of pneumonia associated with the ICS component, initiation with a LAMA should be preferred in patients with blood eosinophil concentrations of less than 4%.

Funding

Canadian Institutes of Health Research, Canadian Foundation for Innovation.

Introduction

Long-acting bronchodilators, including long-acting β₂ agonists (LABAs) and long-acting muscarinic antagonists (LAMAs), are recommended as first-line maintenance therapy in the management of chronic obstructive pulmonary disease (COPD).1, 2 Treatment guidelines recommend that inhaled glucocorticoids (ICS) be reserved for patients with severe symptoms and frequent exacerbations, despite maximised long-acting bronchodilator treatment. Yet, most LABAs used in clinical practice are dispensed as a fixed combination with an ICS (LABA-ICS), including those prescribed as initial treatment.3, 4

The comparative net benefit of these two long-acting bronchodilator choices is uncertain because of the modest effectiveness of adding ICS in COPD and concerns about their increased pneumonia risk.5, 6, 7 No randomised trials have compared LAMAs with LABA inhalers as an initial treatment of COPD, because trials included patients already using these treatments before randomisation.8, 9 Furthermore, evidence is growing that the modest effectiveness of ICS might be due to them being only effective in a subset of patients with COPD.² In particular, peripheral blood eosinophilia has been identified as a promising biomarker of ICS effectiveness,¹⁰ with post-hoc analyses of randomised trial data reporting that ICS were particularly effective at reducing the incidence of COPD exacerbations in patients with a higher blood eosinophil concentration.11, 12, 13 However, whether the threshold of eosinophil concentration (as a proportion of total white blood cell count) should be above 2% for effective ICS treatment or the higher 4% value is debatable, particularly if the risk of pneumonia with ICS outweighs the benefit in the range between 2% and 4%.14, 15, 16 Moreover, the role of concurrent asthma in the so-called asthma–COPD overlap, in parallel with eosinophilia, is another important element to consider to better target ICS-containing treatment in COPD.17, 18

Research in context

Evidence before this study

We searched PubMed for articles published before Aug 7, 2018, using the search terms “COPD treatment effectiveness eosinophils”. Of the 56 search results, seven presented data from post-hoc analyses of data from randomised trials investigating the effectiveness of inhaled corticosteroid (ICS)-containing treatment as a function of blood eosinophil concentration, two were small clinical studies, and one the protocol of a future trial. We found no real-world observational study data on the head-to-head comparison of the effectiveness and safety of the two long-acting bronchodilators commonly used in clinical practice as initial treatment of chronic obstructive pulmonary disease (COPD), namely a long-acting muscarinic antagonist (LAMA) versus a long-acting β₂ agonist (LABA) combined with an inhaled corticosteroid, as a function of blood eosinophil concentration.

Added value of this study

Our study, to our knowledge, is the first real-world study in a clinical practice setting to specifically compare the effects of the two most common single inhaler therapies used as initial treatment in COPD on the rate of exacerbations and the risk of pneumonia, as a function of the baseline blood eosinophil concentration.

Implications of all the available evidence

Blood eosinophil concentrations can be important precision medicine guides in the selection of the optimal initial inhaler for the maintenance treatment of COPD. For patients with high blood eosinophil concentrations or counts (>4% or >300 cells per μL), a LABA-ICS inhaler is more effective than a LAMA inhaler and should be preferred for such eosinophilic patients. For most other patients with lower blood eosinophil concentrations, LABA-ICS and LAMA inhalers are equally effective at preventing exacerbations but a LAMA inhaler should be preferred because of the increased risk of pneumonia associated with the ICS component of the LABA-ICS inhaler. A possible exception could be for frequent exacerbators, but more data are needed for this phenotype.

We assessed the comparative effectiveness of long-acting bronchodilator treatment initiation of COPD, comparing LABA-ICS with LAMAs on the incidence of COPD exacerbations and the risk of pneumonia using a large population-based cohort from real-world, clinical practice data. In particular, we analysed the effect of blood eosinophil concentration on the effectiveness of the ICS-containing long-acting bronchodilator.

Section snippets

Data source

For this study we used the Clinical Practice Research Datalink (CPRD), a primary care database from the UK that contains primary care medical records for over 10 million people enrolled from over 600 practices. Trained participating general practitioners record medical information, including demographic data, lifestyle factors, and medical diagnoses, using the Read classification. Prescriptions are automatically transcribed with the UK Prescription Pricing Authority Dictionary. For over half of

Results

The base cohort included 539 643 patients with a prescription for LABAs or LAMAs from Jan 1, 2002, to Dec 31, 2015, of whom 18 500 were initiated on LABA-ICS and 13 870 on LAMAs (figure 1). After matching, the study cohort included 12 366 initiators of LABA-ICS (LABA-ICS cohort) and 12 366 of LAMAs (LAMA cohort). The LABA-ICS cohort was composed of patients who received, for their ICS, fluticasone propionate (8142 [65·8%]), budesonide (3434 [27·8%]), or beclomethasone (703 [5·7%]), along with

Discussion

In this real-world study of initial long-acting bronchodilator treatment in COPD, we found that initiation of treatment with a LABA-ICS inhaler was equally effective at reducing the incidence of COPD exacerbation as initiation with a LAMA inhaler, mainly tiotropium in our study, exclusively among patients with a blood eosinophil concentration less than 4% of the total white blood count. However, LABA-ICS were more effective at reducing the incidence of COPD exacerbation than LAMAs among

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2023 Canadian Thoracic Society Guideline on Pharmacotherapy in Patients With Stable COPD
2023, Chest
Chronic obstructive pulmonary disease patient care must include confirming a diagnosis with postbronchodilator spirometry. Because of the clinical heterogeneity and the reality that airflow obstruction assessed by spirometry only partially reflects disease severity, a thorough clinical evaluation of the patient should include assessment of symptom burden and risk of exacerbations that permits the implementation of evidence-informed pharmacologic and nonpharmacologic interventions. This guideline provides recommendations from a comprehensive systematic review with a meta-analysis and expert-informed clinical remarks to optimize maintenance pharmacologic therapy for individuals with stable COPD, and a revised and practical treatment pathway based on new evidence since the 2019 update of the Canadian Thoracic Society (CTS) Guideline. The key clinical questions were developed using the Patients/Population (P), Intervention(s) (I), Comparison/Comparator (C), and Outcome (O) model for three questions that focuses on the outcomes of symptoms (dyspnea)/health status, acute exacerbations, and mortality. The evidence from this systematic review and meta-analysis leads to the recommendation that all symptomatic patients with spirometry-confirmed COPD should receive long-acting bronchodilator maintenance therapy. Those with moderate to severe dyspnea (modified Medical Research Council ≥ 2) and/or impaired health status (COPD Assessment Test ≥ 10) and a low risk of exacerbations should receive combination therapy with a long-acting muscarinic antagonist/long-acting ẞ2-agonist (LAMA/LABA). For those with a moderate/severe dyspnea and/or impaired health status and a high risk of exacerbations should be prescribed triple combination therapy (LAMA/LABA/inhaled corticosteroids) azithromycin, roflumilast or N-acetylcysteine is recommended for specific populations; a recommendation against the use of theophylline, maintenance systemic oral corticosteroids such as prednisone and inhaled corticosteroid monotherapy is made for all COPD patients.
Fractional Exhaled Nitric Oxide Guided-Therapy in Chronic Obstructive Pulmonary Disease: A Stratified, Randomized, Controlled Trial
2022, Archivos de Bronconeumologia
Chronic obstructive pulmonary disease (COPD) with eosinophilic airway inflammation represents a distinct phenotype that might respond to treatment with inhaled corticosteroids. Fractional exhaled nitric oxide (FENO) might predict eosinophilic inflammation and guide treatment option. We hypothesized that COPD patients with different baseline levels of FENO might have differentiated response to treatment with salmeterol/fluticasone (SFC) or tiotropium (TIO).
This open-label, randomized-controlled trial enrolled treatment-naïve COPD patients who were stratified into high- (≥23.5 ppb) and low-FENO group, followed by 12-week treatment with SFC or TIO. A linear mixed model with repeated measures was applied to analyze the changes in FENO (primary outcome), COPD assessment test (CAT) score, FEV₁, and parameters in induced sputum and blood after treatment.
134 patients were divided into 4 subgroups: low-FENO/SFC (n = 30), low-FENO/TIO (n = 29), high-FENO/SFC (n = 37), and high-FENO/TIO (n = 38). At baseline, FENO 23.5 ppb clearly differentiated between eosinophilic and non-eosinophilic inflammation groups based on the eosinophils in induced sputum and blood. FENO significantly correlated with sputum and blood eosinophils at baseline. High-FENO/SFC (vs. high-FENO/TIO) subgroup had significant reduction in FENO and sputum inflammation profiles (including eosinophils, macrophages, matrix metalloproteinase-9, and interlukin-8) after treatment. These differences were not replicated between low-FENO/SFC and low-FENO/TIO subgroups. The improvement in CAT and FEV₁ after treatment was indiscriminate between SFC and TIO in the low- and high-FENO groups.
High baseline FENO can serve as an indicator of eosinophilic airway inflammation in COPD patients who may respond favorably to treatment with inhaled corticosteroids/long-acting β₂-agonists.
ClinicalTrials.gov Identifier: NCT02546349.
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Citation Excerpt :
Pharmacological treatments for the prevention of exacerbations have largely targeted patients with at least two exacerbations in the past year (or at least one resulting in admission to hospital). Therapies of value beyond inhaled bronchodilators and ICS include azithromycin and roflumilast (figure 3).118,177,178 Azithromycin is associated with reduction of exacerbations and improved quality of life;198 subgroup analyses have shown higher efficacy among former smokers.199
Chronic obstructive pulmonary disease (COPD) is a major cause of morbidity, mortality, and health-care use worldwide. COPD is caused by exposure to inhaled noxious particles, notably tobacco smoke and pollutants. However, the broad range of factors that increase the risk of development and progression of COPD throughout the life course are increasingly being recognised. Innovations in omics and imaging techniques have provided greater insight into disease pathobiology, which might result in advances in COPD prevention, diagnosis, and treatment. Although few novel treatments have been approved for COPD in the past 5 years, advances have been made in targeting existing therapies to specific subpopulations using new biomarker-based strategies. Additionally, COVID-19 has undeniably affected individuals with COPD, who are not only at higher risk for severe disease manifestations than healthy individuals but also negatively affected by interruptions in health-care delivery and social isolation. This Seminar reviews COPD with an emphasis on recent advances in epidemiology, pathophysiology, imaging, diagnosis, and treatment.
Evaluating a Cox marginal structural model to assess the comparative effectiveness of inhaled corticosteroids versus no inhaled corticosteroid treatment in chronic obstructive pulmonary disease
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To evaluate the potential of a Cox marginal structural model (MSM) to estimate the time-varying causal inference of a known clinical trial association where the effectiveness of inhaled corticosteroid- (ICS-) versus non–ICS-containing treatments has been compared in patients with chronic obstructive pulmonary disease (COPD).
This retrospective study from 2006–2016 used linked data from Clinical Practice Research Datalink-GOLD, Hospital Episode Statistics, and Office for National Statistics mortality. A Cox MSM, incorporating a new-user design, was deemed capable of replicating a clinical trial-like pathway. Repeated outcomes for exacerbation events and stabilized weights were used to include time-varying and fixed covariate exposures.
Of 45,958 patients, 55% were male; 52% had moderate COPD. ICS-treated patients had a higher incidence of comorbid asthma than non–ICS-treated patients. Adjusted hazard risk ratios for any exacerbation event: ICS and/or long-acting β₂-agonist (LABA) versus long-acting muscarinic antagonist (LAMA), 1.07 (95% confidence interval 1.04–1.10); ICS/LABA versus LABA and/or LAMA, 1.05 (1.00–1.10); ICS and/or LABA and/or LAMA versus LAMA, 1.04 (1.01–1.06); ICS and/or LABA and/or LAMA versus LABA and/or LAMA 1.02 (0.97–1.07).
The Cox MSM was not able to fully demonstrate results consistent with the previously established benefits of ICS-containing treatments seen in clinical trials. Future studies should continue to investigate causal inference methods and their capability to estimate the long-term outcomes of treatment in COPD.
Spanish COPD Guidelines (GesEPOC) 2021: Updated Pharmacological treatment of stable COPD
2022, Archivos de Bronconeumologia
La Guía Española de la Enfermedad Pulmonar Obstructiva Crónica (GesEPOC) se publicó por primera vez en 2012 y desde entonces ha experimentado una serie de actualizaciones que incorporan las nuevas evidencias sobre el diagnóstico y tratamiento de la EPOC. GesEPOC es una guía de práctica clínica elaborada con la colaboración de las sociedades científicas implicadas en el tratamiento de la EPOC y del Foro Español de Pacientes. Sus recomendaciones se basan en una evaluación de la evidencia mediante la metodología GRADE y en una descripción narrativa de la evidencia en aquellas cuestiones en que la aplicación de GRADE no es posible. En este artículo se resumen las recomendaciones sobre el tratamiento farmacológico de la EPOC estable basadas en la elaboración de nueve preguntas PICO. El proceso de tratamiento de la EPOC comprende cuatro etapas: 1) diagnóstico, 2) determinación del nivel de riesgo, 3) tratamiento inhalado inicial y de continuación e 4) identificación y abordaje de los rasgos tratables. Para la elección del tratamiento inhalado los pacientes de alto riesgo se dividirán en tres fenotipos: no agudizador, agudizador eosinofílico y agudizador no eosinofílico. Los rasgos tratables comprenden unos de tipo general, que deben investigarse en todos los pacientes, como el tabaquismo o la técnica inhalatoria y otros más específicos, que afectan sobre todo a los pacientes graves, como la hipoxemia crónica o la infección bronquial crónica. La base del tratamiento de la EPOC la constituyen los broncodilatadores de larga duración en monoterapia o en combinación según el nivel de riesgo del paciente. Los pacientes agudizadores eosinofílicos deben recibir corticosteroides inhalados y los no eosinofílicos requieren una evaluación más detallada para elegir la mejor opción terapéutica. La nueva GesEPOC también incluye recomendaciones sobre la retirada de corticosteroides inhalados y sobre la indicación de tratamiento con alfa-1 antitripsina. GesEPOC supone una aproximación al tratamiento de la EPOC más individualizada según las características clínicas de los pacientes y su nivel de riesgo o de complejidad.
The Spanish COPD Guidelines (GesEPOC) were first published in 2012, and since then have undergone a series of updates incorporating new evidence on the diagnosis and treatment of COPD. GesEPOC was drawn up in partnership with scientific societies involved in the treatment of COPD and the Spanish Patients’ Forum. Their recommendations are based on an evaluation of the evidence using GRADE methodology, and a narrative description of the evidence in areas in which GRADE cannot be applied. In this article, we summarize the recommendations on the pharmacological treatment of stable COPD based on 9 PICO questions. COPD treatment is a 4-step process: 1) diagnosis, 2) determination of the risk level, 3) initial and subsequent inhaled therapy, and 4) identification and management of treatable traits. For the selection of inhaled therapy, high-risk patients are divided into 3 phenotypes: non-exacerbator, eosinophilic exacerbator, and non-eosinophilic exacerbator. Some treatable traits are general and should be investigated in all patients, such as smoking or inhalation technique, while others affect severe patients in particular, such as chronic hypoxemia and chronic bronchial infection. COPD treatment is based on long-acting bronchodilators with single agents or in combination, depending on the patient's risk level. Eosinophilic exacerbators must receive inhaled corticosteroids, while non-eosinophilic exacerbators require a more detailed evaluation to choose the best therapeutic option. The new GesEPOC also includes recommendations on the withdrawal of inhaled corticosteroids and on indications for alpha-1 antitrypsin treatment. GesEPOC offers a more individualized approach to COPD treatment tailored according to the clinical characteristics of patients and their level of complexity.
Comparing initial LABA-ICS inhalers in COPD: Real-world effectiveness and safety
2021, Respiratory Medicine
Citation Excerpt :
In particular, the information on medications and diagnoses has been validated and shown to be of high quality [15,16,18]. These databases have been used extensively for studies of COPD [19–24]. The study cohort was formed of all subjects with a medical diagnosis of COPD during 1995–2018 who subsequently were new users of a LABA-ICS single inhaler combination from January 2002 until November 2018.
Guidelines for the treatment of chronic obstructive pulmonary disease (COPD) patients with multiple exacerbations and eosinophilia recommend a long-acting beta₂-agonist (LABA) and inhaled corticosteroid (ICS) combined inhaler, with no distinction between different agents. We compared the effectiveness and safety of budesonide-formoterol versus fluticasone-salmeterol on the incidence of exacerbations and pneumonia in a real-world clinical practice setting of COPD, particularly considering eosinophilia, an important marker for ICS effectiveness.
We identified a cohort of patients with COPD, new users of a LABA-ICS during 2002–2018, age 50 or older, from the UK's CPRD database, and followed for one year. The hazard ratio (HR) of exacerbation and of pneumonia was estimated using the Cox regression model, weighted by fine stratification of the propensity score of treatment initiation.
The cohort included 24,973 of budesonide-formoterol and 61,251 initiators of fluticasone-salmeterol. The adjusted HR of a first moderate or severe exacerbation with budesonide-formoterol relative to fluticasone-salmeterol was 0.98 (95% CI: 0.95–1.01), while for severe exacerbation it was 0.92 (95% CI: 0.85–0.99). The HR of severe pneumonia with budesonide-formoterol was 0.76 (95% CI: 0.70–0.83), and was particularly decreased with higher blood eosinophil count, dropping to 0.62 (95% CI: 0.51–0.77) at >300 cells/μL.
In a real-world clinical setting of COPD treatment, a budesonide-formoterol inhaler was generally as effective at reducing the incidence of moderate-severe exacerbations as fluticasone-salmeterol. However, budesonide-formoterol was more effective than fluticasone-salmeterol at reducing the incidence of severe exacerbation and the risk of severe pneumonia, particularly in patients with higher blood eosinophil counts.

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ArticlesComparative effectiveness of LABA-ICS versus LAMA as initial treatment in COPD targeted by blood eosinophils: a population-based cohort study

Summary

Background

Methods

Findings

Interpretation

Funding

Introduction

Section snippets

Data source

Results

Discussion

Chest

Chest

Lancet Respir Med

Lancet Respir Med

Lancet Respir Med

Lancet Respir Med

Lancet Respir Med

Lancet Respir Med

Chest

Chest

J Clin Epidemiol

Chest

Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: GOLD executive summary

Am J Respir Crit Care Med

Misdiagnosis of patients receiving inhaled therapies in primary care

Int J Chron Obstruct Pulmon Dis

Inhaled corticosteroids in COPD: a case in favour

Eur Respir J

Inhaled corticosteroids in COPD: the case against

Eur Respir J

Inhaled corticosteroids in COPD: the clinical evidence

Eur Respir J

Tiotropium versus salmeterol for the prevention of exacerbations of COPD

N Engl J Med

Articles
Comparative effectiveness of LABA-ICS versus LAMA as initial treatment in COPD targeted by blood eosinophils: a population-based cohort study