Chronic obstructive pulmonary disease (COPD) is a highly prevalent disease among the Spanish population that places a heavy burden on both the patient and the health and social welfare system.1–3 In Spain, the EPISCAN study reported a prevalence of 10.2% among the adult population aged between 40 and 80 years,1,4,5 along with a high rate of underdiagnosis, particularly in individuals with mild disease and/or few symptoms.6

In recent years, new drugs and studies in patients with stable COPD have prompted several scientific societies and expert groups, both in Spain and in other countries, to draw up statements on the use of bronchodilators, which have been included in the consensus recently published by GOLD and other similar documents.7–14 Professionals responsible for the care of COPD patients with stable disease are currently expressing interest in the need to define and clarify the role of bronchodilators in monotherapy, in dual therapy and even as part of triple therapy in combination with inhaled corticosteroids.15

This document aims to define the degree of agreement among experts, to describe the available evidence regarding the management of patients with stable mild-to-moderate COPD, defined as FEV1≥50%, and to help clarify possible questions and areas of controversy in the use of single-agent bronchodilators. We present a series of statements that are intended to improve quality of care and assist in therapeutic decision-making, and should not be interpreted in any way as guidelines or as a COPD treatment protocol. In short, this document is presented as a tool that may optionally be adopted by clinicians involved in the management of these patients.

Nominal group techniques and Delphi methodology were used to prepare this document.16 In short, this is an expert consensus document generated by a group of professionals who undertook an extensive, systematic review of the literature in order to draw up statements about topical and/or controversial aspects that may be of value to their colleagues involved in the treatment of these patients. We insist that this not a treatment protocol or guideline, but rather a clinical tool. The degree of agreement was established using Delphi methodology, and the existing level of evidence for each of the recommendations is described.

The document was prepared by distributing tasks and relaying comments to the participants, with the help of a systematic review of the literature.

The steps followed are set out in detail below, in Fig. 1.

Fig. 1.

Phases in the development of the consensus document. SRL: systematic review of the literature.

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Phase 2. Systematic Review of the Literature

A research protocol was established and the questions generated in the previous phase (Table 1) were used to define the PICO: population (P), intervention (I), comparison (C) and outcomes (O). The PICO was used to design the search strategy and the inclusion and exclusion criteria of the review were defined in depth. Studies were selected that included adults with stable mild-to-moderate COPD (according to the different criteria developed by GOLD over time, but primarily patients with FEV1≥50% predicted value), receiving long-acting muscarinic antagonists (LAMA) (tiotropium, glycopyrronium, aclidinium, umeclidinium) and/or inhaled long-acting β2-agonists (LABA) (salmeterol, formoterol, vilanterol, indacaterol, olodaterol), irrespective of the dose, type, combinations with inhaled corticosteroids or other LABAs or LAMAs, versus a valid comparator group, placebo or other LABA or LAMA. These studies also had to include an analysis of clinical efficacy data, with at least one of the following parameters: dyspnea (functional class), exacerbation, quality of life, FEV1, lung volumes, inspiratory capacity, physical activity, exercise capacity, hospitalization, comorbidities, anxiety/depression, safety (cardiovascular, osteoporosis, mortality, etc.), or cost-effectiveness. Finally, studies with the following designs were included: meta-analyses, systematic reviews, clinical trials (>1 week duration). With regard to observational studies (including cross-sectional studies), only good quality examples were included (at least 50 patients, follow-up longer than 8 weeks, and well-defined methodology). Animal and basic science studies or other studies that did not meet any of the criteria described above were excluded.

An information specialist helped generate search strategies for the different databases, using MeSH and free-text terms. Searches were limited to studies in humans, published in English or Spanish. The following bibliographic databases were consulted: Medline, Embase and Cochrane Library, between their inception and March 2016. Given the large volume of citations retrieved, the gray literature from Spanish and international congresses in the past two years was excluded from the review. A secondary manual search of the list of references of the articles finally included was then performed. All citations retrieved from the searches were entered into the EndNote system for ease of management.

Three reviewers (EL, TO, MJ) independently analyzed the articles retrieved from the search strategy. Any instances of discrepancy were resolved by a fourth person (LC). The search result was first cleaned according to the title and summary in sessions lasting up to 60 minutes. The selected articles were subsequently analyzed in detail (the article was read in full). The results of the selection of articles are shown in Fig. 2. The 3 reviewers collected the data from the studies included using specific templates designed in advance for this review. The Jadad scale was used to evaluate the methodological quality of the randomized clinical trials included, and the Oxford scale was used for the others.17

Fig. 2.

Flow diagram of the selection of articles for the systematic review.

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A series of provisional statements was generated from the results of the systematic review.

Twelve of the 17 statements generated from the Delphi survey were accepted (see results of the Delphi survey in Table 2).

Following the recent incorporation of new drugs in the therapeutic arsenal for the treatment of COPD and the publication of various research studies, the diagnostic and therapeutic management of patients with stable COPD has become the subject of numerous national and international guidelines and recommendations.7,14,42 However, treatment indications are less well defined and more controversial for certain individuals among the mild-to-moderate COPD subgroup.

If clinical practice is to improve, explicit statements addressing important aspects such as the evaluation of these patients and the appropriate use of inhaled bronchodilators must be available. Although the evidence is scant in some areas and there may be some limitations to implementing the recommendations in clinical practice, this document presents a series of statements that in our opinion are relevant and useful for clinicians.

COPD is a heterogeneous disease that is currently generating some controversy in terms of patient classification. Conventionally, spirometric classification of lung function was used as a criterion for severity, although it is not clear whether the prognostic implications of spirometry are as important as the symptomatic impact of dyspnea, loss of quality of life, and exacerbations. The scientific evidence on the implications of early treatment of COPD is currently being widely discussed, and there is no doubt of the pivotal importance of bronchodilation in the pharmacological treatment of these patients. The progress of the mild-to-moderate COPD patient will depend on appropriate diagnostic management and the administration of treatment that will modify the natural history of the disease, or in other words, the prognosis of these patients.

Despite innovative strategies involving dual or triple bronchodilator therapy, there is now sufficient quality of evidence to underline the importance of the use of single-agent inhaled bronchodilation in the initial treatment of stable COPD patients classified as mild or moderate with different characteristics: dyspnea mMRC ≥1 (level of evidence 1b), presence of bronchial symptoms (cough and/or expectoration and/or wheezing) (level of evidence 1b), limitation in physical activity (level of evidence 1b).35,42

This document shows that Spanish experts agree on a considerable number of statements regarding the use of inhaled bronchodilators in monotherapy for stable COPD.

Interestingly, however, no agreement was reached on the indication of this treatment in exacerbators or in patients with a risk of exacerbation, suggesting that this remains a controversial topic, from both a diagnostic and a therapeutic point of view, despite recent studies that will clearly mark a turning point in recommendations and guidelines. Another area of uncertainty generated by the current lack of valid evidence is highlighted by the lack of agreement on the choice of a particular bronchodilator. In daily practice, however, there is a slight trend toward using LAMA as an initial therapy in a patient with a risk of exacerbation.

Incidentally, other aspects such as bronchodilation were discussed and evaluated while preparing the document, although not in as much depth as monotherapy (bronchodilation was evaluated in the systematic review). The expert group considered, for example, that treatment could be initiated with dual bronchodilation (LABA+LAMA) in patients with stable mild-to-moderate COPD and dyspnea mMRC≥2.

Studies have been published in which dual bronchodilation (LAMA+LAMA), in the short term at least (less than 6 months), was seen to be superior to monotherapy in improving functional parameters such as FEV1, but no clear difference was observed between dual and single-agent therapy in terms of lung volumes, inspiratory capacity, dyspnea, and/or exacerbations in these patients.35,42–47 No differences were found in the safety profile. Patients previously treated with LAMA have a worse response to dual bronchodilation than those who received it de novo.44

Dual therapy in patients with ≥1 severe and/or ≥2 moderate exacerbations in the previous year was also assessed. The recent publication of the FLAME study supports this approach in a certain patient population (severe or very severe COPD).14

Patients with ACO, on the other hand, can start treatment with LABA+inhaled corticosteroids, since these patients present a higher degree of bronchial eosinophilic inflammation that would explain their greater clinical and spirometric response to inhaled corticosteroids.12,13,37

It was also suggested that withdrawal of inhaled corticosteroids can be considered in patients with stable mild-to-moderate COPD without ACO. These drugs are overused, and the recommendation for their withdrawal is justified by their well-documented high rate of adverse effects. Some recent publications also suggest that patients with stable mild-to-moderate COPD and no exacerbation in the previous year and appropriate bronchodilation, may also be good candidates for the discontinuation of inhaled corticosteroids.48

Finally, we did not believe it appropriate to assess triple therapy as initial treatment in patients with stable mild-to-moderate COPD.

The objective of these statements is to help dispel the doubts or uncertainties that professionals involved in the treatment of mild-to-moderate COPD may encounter in their routine clinical practice. They are, however, merely expert opinions and lack in the scientific study-based evidence needed to support the more controversial issues. As such, they are subject to the bias or limitations inherent in this type of document.

Another of the limitations of these statements is rooted in the lack of studies and insufficient scientific evidence supporting the use of monotherapy in certain situations that could be termed special: should we approach men and women differently? Should active smokers or former smokers be managed differently? How should stage 0 (at risk) COPD be managed? Should smokers or former smokers with mild asymptomatic COPD be treated? Some recent studies have suggested that future lines of research should head in this direction.

Finally, as in any chronic disease, patients may perceive their symptoms differently, irrespective of their degree of severity, and this may influence their response and adherence to treatment. Health education will be the key to selecting the best treatment, although further studies are needed to standardize the method used to evaluate response to prescribed inhaled treatment.

This document has generated a series of statements agreed upon by Spanish experts on the use of inhaled bronchodilator therapy in monotherapy in patients with stable mild-to-moderate COPD. Consensus was reached regarding the indication of monotherapy as an initial treatment in patients with dyspnea mMRC≥1, cough-expectoration-wheezing, CAT≥10, limitation in physical activity. The use of dual bronchodilation is recommended as an initial treatment in patients with mild-to-moderate COPD with dyspnea mMRC≥2 or in patients refractory to monotherapy. The lack of agreement on the treatment of patients with a history of exacerbations and the choice of a specific type of bronchodilator highlights the uncertainty surrounding these issues and the pressing need for future studies in these areas.

The project was funded by Gebro Pharma, which did not intervene in the design of the project or in the development of the recommendations.

Juan Antonio Riesco Miranda states that he has received fees for lectures and/or scientific consultancy from AstraZeneca, Boehringer-Ingelheim, Chiesi, Gebro Pharma, Group Ferrer, GSK, Laboratories Esteve, Menarini, Novartis and Pfizer.

Inmaculada Alfageme Michavila states that in the last three years she has received fees for lectures and/or scientific consultancy from AstraZeneca, Gebro Pharma, Roche, GSK, Laboratorios Esteve, Novartis, Teva and Chiesi.

Bernadino Alcázar Navarrete states that he has received fees for lectures and/or scientific consultancy from AstraZeneca, Boehringer-Ingelheim, Chiesi, Gebro Pharma, Grupo Ferrer, GSK, Laboratorios Esteve, Laboratorios Menarini, Novartis, and Rovi.

Ciro Casanova Macario states that in the last three years he has received fees for lectures and/or scientific consultancy from AstraZeneca, Boehringer-Ingelheim, Gebro Pharma, GSK, Laboratories Esteve, Menarini, Novartis, and Rovi.

Bartolome Celli states that he received expenses from AstraZeneca for the division where he works to conduct COPD studies. He has received fees for consultancy from Glaxo Smith Kline, Boehringer-Ingelheim, AstraZeneca, Medimmune, and Novartis. Neither he nor his family have economic interests in any company, including any related to tobacco.

Juan P. de-Torres states that he received fees for lectures and/or scientific consultancy from AstraZeneca, Chiesi, Gebro Pharma, GSK, Menarini, Novartis, and Teva.

Carlos A. Jiménez-Ruiz states that he has received fees for speaking engagements and/or scientific consultancy from AstraZeneca, Boehringer-Ingelheim, Gebro Pharma, Laboratorios Esteve, Menarini, Novartis and Pfizer.