Optimal treatment sequence in COPD: Can a consensus be found?

array:20 ["pii" => "X0873215916479478" "issn" => "08732159" "doi" => "10.1016/j.rppnen.2015.10.009" "estado" => "S300" "fechaPublicacion" => "2016-01-01" "documento" => "article" "licencia" => "http://www.elsevier.com/open-access/userlicense/1.0/" "subdocumento" => "fla" "cita" => "Rev Port Pneumol. 2016;22:39-49" "abierto" => array:3 [ "ES" => true "ES2" => true "LATM" => true ] "gratuito" => true "lecturas" => array:2 [ "total" => 749 "formatos" => array:2 [ "HTML" => 468 "PDF" => 281 ] ] "itemSiguiente" => array:16 [ "pii" => "X0873215916479486" "issn" => "08732159" "doi" => "10.1016/j.rppnen.2015.08.006" "estado" => "S300" "fechaPublicacion" => "2016-01-01" "documento" => "article" "licencia" => "http://www.elsevier.com/open-access/userlicense/1.0/" "subdocumento" => "fla" "cita" => "Rev Port Pneumol. 2016;22:50-2" "abierto" => array:3 [ "ES" => true "ES2" => true "LATM" => true ] "gratuito" => true "lecturas" => array:2 [ "total" => 395 "formatos" => array:2 [ "HTML" => 245 "PDF" => 150 ] ] "en" => array:9 [ "idiomaDefecto" => true "titulo" => "Social profile of the highest tuberculosis incidence areas in Portugal" "tienePdf" => "en" "tieneTextoCompleto" => "en" "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "50" "paginaFinal" => "52" ] ] "contieneTextoCompleto" => array:1 [ "en" => true ] "contienePdf" => array:1 [ "en" => true ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:8 [ "identificador" => "fig1" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "copyright" => "Elsevier España" "figura" => array:1 [ 0 => array:4 [ "imagen" => "320v22n01-90447948fig1.jpg" "Alto" => 2198 "Ancho" => 1785 "Tamanyo" => 861112 ] ] "descripcion" => array:1 [ "en" => "Variation of tuberculosis incidence rate, population density, proportion of people at working age and unemployment rate between 2002 and 2012, and proportion of immigrants between 2008 and 2012, in Greater Oporto, Greater Lisbon and Setúbal Peninsula." ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "I. Franco, P. Sousa, M. Gomes, A. Oliveira, A.R. Gaio, R. Duarte" "autores" => array:6 [ 0 => array:2 [ "Iniciales" => "I." "apellidos" => "Franco" ] 1 => array:2 [ "Iniciales" => "P." "apellidos" => "Sousa" ] 2 => array:2 [ "Iniciales" => "M." "apellidos" => "Gomes" ] 3 => array:2 [ "Iniciales" => "A." "apellidos" => "Oliveira" ] 4 => array:2 [ "Iniciales" => "A.R." "apellidos" => "Gaio" ] 5 => array:2 [ "Iniciales" => "R." "apellidos" => "Duarte" ] ] ] ] ] "idiomaDefecto" => "en" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/X0873215916479486?idApp=UINPBA00004E" "url" => "/08732159/0000002200000001/v0_201604141139/X0873215916479486/v0_201604141140/en/main.assets" ] "itemAnterior" => array:16 [ "pii" => "X087321591647946X" "issn" => "08732159" "doi" => "10.1016/j.rppnen.2015.09.001" "estado" => "S300" "fechaPublicacion" => "2016-01-01" "documento" => "article" "licencia" => "http://www.elsevier.com/open-access/userlicense/1.0/" "subdocumento" => "fla" "cita" => "Rev Port Pneumol. 2016;22:34-8" "abierto" => array:3 [ "ES" => true "ES2" => true "LATM" => true ] "gratuito" => true "lecturas" => array:2 [ "total" => 499 "formatos" => array:2 [ "HTML" => 318 "PDF" => 181 ] ] "en" => array:10 [ "idiomaDefecto" => true "titulo" => "Bronchial artery embolisation in management of hemoptysis – A retrospective analysis in a tertiary university hospital" "tienePdf" => "en" "tieneTextoCompleto" => "en" "tieneResumen" => "en" "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "34" "paginaFinal" => "38" ] ] "contieneResumen" => array:1 [ "en" => true ] "contieneTextoCompleto" => array:1 [ "en" => true ] "contienePdf" => array:1 [ "en" => true ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "H. Dabó, R. Gomes, A. Marinho, M. Madureira, J. Paquete, P. Morgado" "autores" => array:6 [ 0 => array:2 [ "Iniciales" => "H." "apellidos" => "Dabó" ] 1 => array:2 [ "Iniciales" => "R." "apellidos" => "Gomes" ] 2 => array:2 [ "Iniciales" => "A." "apellidos" => "Marinho" ] 3 => array:2 [ "Iniciales" => "M." "apellidos" => "Madureira" ] 4 => array:2 [ "Iniciales" => "J." "apellidos" => "Paquete" ] 5 => array:2 [ "Iniciales" => "P." "apellidos" => "Morgado" ] ] ] ] ] "idiomaDefecto" => "en" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/X087321591647946X?idApp=UINPBA00004E" "url" => "/08732159/0000002200000001/v0_201604141139/X087321591647946X/v0_201604141139/en/main.assets" ] "en" => array:14 [ "idiomaDefecto" => true "titulo" => "Optimal treatment sequence in COPD: Can a consensus be found?" "tieneTextoCompleto" => true "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "39" "paginaFinal" => "49" ] ] "autores" => array:1 [ 0 => array:4 [ "autoresLista" => "J. Ferreira, M. Drummond, N. Pires, G. Reis, C. Alves, C. Robalo-Cordeiro" "autores" => array:6 [ 0 => array:3 [ "Iniciales" => "J." "apellidos" => "Ferreira" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "affa" ] ] ] 1 => array:3 [ "Iniciales" => "M." "apellidos" => "Drummond" "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "b" "identificador" => "affb" ] 1 => array:2 [ "etiqueta" => "c" "identificador" => "affc" ] ] ] 2 => array:3 [ "Iniciales" => "N." "apellidos" => "Pires" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "d" "identificador" => "affd" ] ] ] 3 => array:3 [ "Iniciales" => "G." "apellidos" => "Reis" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "e" "identificador" => "affe" ] ] ] 4 => array:3 [ "Iniciales" => "C." "apellidos" => "Alves" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "f" "identificador" => "afff" ] ] ] 5 => array:4 [ "Iniciales" => "C." "apellidos" => "Robalo-Cordeiro" "email" => array:1 [ 0 => "carlos.crobalo@gmail.com" ] "referencia" => array:3 [ 0 => array:2 [ "etiqueta" => "g" "identificador" => "affg" ] 1 => array:2 [ "etiqueta" => "*" "identificador" => "cor1" ] 2 => array:2 [ "etiqueta" => "h" "identificador" => "affh" ] ] ] ] "afiliaciones" => array:8 [ 0 => array:3 [ "entidad" => "Pulmonology Department, Unidade Local de Saúde de Matosinhos, Portugal" "etiqueta" => "a" "identificador" => "affa" ] 1 => array:3 [ "entidad" => "Pulmonology Department, Centro Hospitalar de São João, Porto, Portugal" "etiqueta" => "b" "identificador" => "affb" ] 2 => array:3 [ "entidad" => "Porto Medical School, Porto University, Portugal" "etiqueta" => "c" "identificador" => "affc" ] 3 => array:3 [ "entidad" => "Pulmonology Department, Hospital Santa Maria Maior, Barcelos, Portugal" "etiqueta" => "d" "identificador" => "affd" ] 4 => array:3 [ "entidad" => "Pulmonology Department, Hospital Distrital de Santarém, Portugal" "etiqueta" => "e" "identificador" => "affe" ] 5 => array:3 [ "entidad" => "Pulmonology Department, Hospital de Nossa Senhora do Rosário, Barreiro, Portugal" "etiqueta" => "f" "identificador" => "afff" ] 6 => array:3 [ "entidad" => "Pulmonology Department, University Hospital, Coimbra, Portugal" "etiqueta" => "g" "identificador" => "affg" ] 7 => array:3 [ "entidad" => "Coimbra Medical School, Coimbra University, Portugal" "etiqueta" => "h" "identificador" => "affh" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor1" "etiqueta" => "*" "correspondencia" => "Corresponding author. carlos.crobalo@gmail.com" ] ] ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:8 [ "identificador" => "fig1" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "copyright" => "Elsevier España" "figura" => array:1 [ 0 => array:4 [ "imagen" => "320v22n01-90447947fig1.jpg" "Alto" => 1979 "Ancho" => 3091 "Tamanyo" => 539936 ] ] "descripcion" => array:1 [ "en" => "Proposed therapeutic scheme. From top to bottom: asthma component predominant to COPD component predominant." ] ] ] "textoCompleto" => "<a name="sec0005" class="elsevierStyleCrossRefs"></a>IntroductionOne of the main reasons that has precluded the establishment of a consensus treatment sequence in chronic obstructive pulmonary disease (COPD) is that patient stratification is not consensual across guidelines.<a href="#bib98" class="elsevierStyleCrossRefs">1</a>, <a href="#bib99" class="elsevierStyleCrossRefs">2</a>, <a href="#bib100" class="elsevierStyleCrossRefs">3</a>, <a href="#bib101" class="elsevierStyleCrossRefs">4</a> The first problem emerges with the classification by the Global Initiative for Chronic Obstructive Lung Disease (GOLD) only distinguishing two issues, symptoms and risk,<a href="#bib98" class="elsevierStyleCrossRefs">1</a> which are clearly not sufficient to define a patient with COPD, an extremely heterogeneous disease. The Spanish guidelines propose treatment based on four clinically relevant phenotypes,<a href="#bib99" class="elsevierStyleCrossRefs">2</a> but even this approach presents heterogeneity. Although it is fairly consensual that initial treatment should begin with an inhaled short-acting beta agonist (SABA), a short-acting muscarinic antagonist (SAMA), a long-acting beta-agonist (LABA) or a long-acting muscarinic antagonist (LAMA),<a href="#bib98" class="elsevierStyleCrossRefs">1</a>, <a href="#bib99" class="elsevierStyleCrossRefs">2</a>, <a href="#bib101" class="elsevierStyleCrossRefs">4</a>, <a href="#bib102" class="elsevierStyleCrossRefs">5</a> when and in which patients to use dual bronchodilation, inhaled corticosteroids (ICS) in combination with bronchodilation, or triple therapy, remains controversial,<a href="#bib103" class="elsevierStyleCrossRefs">6</a> except in patients with the Asthma-COPD overlap syndrome (ACOS), who should be initially treated with ICS.<a href="#bib104" class="elsevierStyleCrossRefs">7</a> ICS have been shown to have side effects, namely pneumonia,<a href="#bib103" class="elsevierStyleCrossRefs">6</a> and tuberculosis and the risk increases dose-dependently with ICS use.<a href="#bib105" class="elsevierStyleCrossRefs">8</a>Apart from the above mentioned molecules, other potentially useful non-inhaled therapies such as mucolytic agents, antibiotics, phosphodiesterase-4 inhibitors (PDE4i), methylxanthines and immunostimulating agents, are available, but again their use is not consensual.<a href="#bib98" class="elsevierStyleCrossRefs">1</a>, <a href="#bib99" class="elsevierStyleCrossRefs">2</a>, <a href="#bib100" class="elsevierStyleCrossRefs">3</a>, <a href="#bib101" class="elsevierStyleCrossRefs">4</a> Although increasingly relevant and important to the management of COPD, this paper does not include a section on non-pharmacological measures, which are duly addressed by Guimarães et al.<a href="#bib106" class="elsevierStyleCrossRefs">9</a>This paper reviews current guidelines and available evidence and proposes a therapeutic scheme for COPD patients.<a name="sec0010" class="elsevierStyleCrossRefs"></a>MethodsThe GI DPOC-Grupo de Interesse na Doença Pulmonar Obstrutiva Crónica convened on December 2014 to review and discuss previously distributed papers, scientific meeting presentations, current guidelines and practices related to the management of COPD. Papers had been identified through searching PubMed with the search terms “chronic obstructive pulmonary disease dual bronchodilation” and “chronic obstructive pulmonary disease triple therapy” with no date limits. Papers identified as described were searched manually. Distributed guidelines were GOLD 2014,<a href="#bib107" class="elsevierStyleCrossRefs">10</a> GesEPOC 2014,<a href="#bib99" class="elsevierStyleCrossRefs">2</a> NICE 2010<a href="#bib100" class="elsevierStyleCrossRefs">3</a> and The Canadian Thoracic Society recommendations for management of COPD 2007.<a href="#bib101" class="elsevierStyleCrossRefs">4</a> Additional new evidence was distributed after the meeting, including articles identified through searches of the authors’ own files. Subsequent discussions by email led to the preparation of the first draft of this paper. On February 2015 the GI-DPOC convened again, and discussed the first draft of the paper in light of GOLD 2015.<a href="#bib98" class="elsevierStyleCrossRefs">1</a> Additional new evidence was distributed after the meeting, including recent articles identified through searches of the authors’ own files. Subsequent discussions by email led to the preparation of the final text of this paper. The final reference list was generated on the basis of originality and relevance to the scope of this paper.<a name="sec0015" class="elsevierStyleCrossRefs"></a>Should therapy be initiated early?A clinical diagnosis of COPD should be considered in any patient who has dyspnea, chronic cough or sputum production, and a history of exposure to risk factors for the disease. Spirometry is required to establish a diagnosis of COPD.<a href="#bib98" class="elsevierStyleCrossRefs">1</a> The presence of a post-bronchodilator ratio of Forced Expiratory Volume in 1 second by Forced Vital Capacity (FEV1/FVC) < 0.70 confirms the presence of persistent airflow limitation and thus of COPD and a normal value for spirometry effectively excludes the diagnosis of clinically relevant COPD.<a href="#bib98" class="elsevierStyleCrossRefs">1</a> Spirometric screening of asymptomatic individuals is not supported by evidence. However, in individuals over 40 years old with a smoking history (>10 pack-years), spirometry may be performed with the aim of early diagnosis.<a href="#bib102" class="elsevierStyleCrossRefs">5</a>A correct diagnosis is mandatory to decide the best treatment approach.<a href="#bib108" class="elsevierStyleCrossRefs">11</a> Therapy should be initiated in early stages of the disease as even patients in GOLD stage 1 (as defined by GOLD prior to 2011) may respond to bronchodilators with physiological and symptomatic improvements.<a href="#bib109" class="elsevierStyleCrossRefs">12</a>, <a href="#bib110" class="elsevierStyleCrossRefs">13</a> Also, several studies have reported improvement with bronchodilators in GOLD stage 2 patients (as defined by GOLD prior to 2011).<a href="#bib111" class="elsevierStyleCrossRefs">14</a>, <a href="#bib112" class="elsevierStyleCrossRefs">15</a>, <a href="#bib113" class="elsevierStyleCrossRefs">16</a> A study assessing the ability of the GOLD 2011 stratification<a href="#bib114" class="elsevierStyleCrossRefs">17</a> to predict the clinical course of COPD showed that group B had significantly poorer survival than group C, concluding that this group warrants special attention, requiring additional assessment and treatment.<a href="#bib115" class="elsevierStyleCrossRefs">18</a>The Canadian Thoracic Society recommends therapy should be guided by the degree of disability, lung function and exacerbations<a href="#bib101" class="elsevierStyleCrossRefs">4</a> whereas the National Institute for Health and Care Excellence (NICE) guidelines propose therapy based on a variety of parameters such as lung function, improvement in symptoms, activities of daily living, exercise capacity, rapidity of symptom relief, exacerbations, patient preference, side effects and cost.<a href="#bib100" class="elsevierStyleCrossRefs">3</a> According to the GOLD guideliness, LAMA or LABA are alternative choices for group A patients and the recommended first choice for group B patients, with alternative choice of LAMA + LABA.<a href="#bib98" class="elsevierStyleCrossRefs">1</a> However, dual bronchodilation with a fixed-dose combination of indacaterol/glycopyrronium (IND/GLY) has been reported to have clinically meaningful and symptomatic improvement in moderate to severe non-exacerbating COPD patients, who by definition fall within the B category.<a href="#bib116" class="elsevierStyleCrossRefs">19</a>, <a href="#bib117" class="elsevierStyleCrossRefs">20</a> On the other hand, there are several potential advantages and beneficial effects of having a LABA + LAMA combination on the same device.<a href="#bib118" class="elsevierStyleCrossRefs">21</a>The Spanish guidelines propose that COPD treatment should be based on four clinical phenotypes (non-exacerbator, exacerbator with emphysema, exacerbator with chronic bronchitis, mixed COPD-asthma) and disease severity, and recommend LABA + LAMA as an option for all phenotypes with severity level > II (on a scale of I to IV).<a href="#bib99" class="elsevierStyleCrossRefs">2</a><a href="#t0005" class="elsevierStyleCrossRefs">Table 1</a> summarizes our proposals, suggestions and recommendations on diagnosis and early therapy.Table 1. Should therapy be initiated early?<a name="t0005" class="elsevierStyleCrossRefs"></a><table><tr align="left"><td>Diagnosis</td><td>• early diagnosis is of paramount importance to initiate treatment in the early stages of the disease</td></tr><tr align="left"><td>Therapy GOLD A patients</td><td>• monotherapy with a long-acting bronchodilator should be the first treatment choice</td></tr><tr align="left"><td>Therapy GOLD B patients</td><td>• in highly symptomatic GOLD B patients, dual bronchodilation should be initiated as soon as possible</td></tr><tr align="left"><td rowspan="3">Therapy in patients with bronchitic COPD</td><td>• the choice of single or dual bronchodilation will depend on the symptoms</td></tr><tr align="left"><td>• if the patient is a frequent exacerbator (≥2 exacerbations/year or 1 exacerbation requiring hospitalization), ICS should be added</td></tr><tr align="left"><td>• in these patients, mucolytic agents are also drugs to consider</td></tr></table><a name="sec0020" class="elsevierStyleCrossRefs"></a>ICS and triple therapyICS use has unequivocal benefits in asthma, but its position in COPD treatment is controversial.<a href="#bib108" class="elsevierStyleCrossRefs">11</a> Different guidelines recommend the use of ICS or triple therapy in different patient categories given that patient stratification is not consensual across guidelines.<a href="#bib98" class="elsevierStyleCrossRefs">1</a>, <a href="#bib99" class="elsevierStyleCrossRefs">2</a>, <a href="#bib100" class="elsevierStyleCrossRefs">3</a>, <a href="#bib101" class="elsevierStyleCrossRefs">4</a> The only apparent consensus is that ICS therapy alone is not recommended in COPD patients,<a href="#bib98" class="elsevierStyleCrossRefs">1</a>, <a href="#bib99" class="elsevierStyleCrossRefs">2</a>, <a href="#bib100" class="elsevierStyleCrossRefs">3</a>, <a href="#bib101" class="elsevierStyleCrossRefs">4</a>, <a href="#bib102" class="elsevierStyleCrossRefs">5</a>, <a href="#bib119" class="elsevierStyleCrossRefs">22</a> and even in the treatment of exacerbations, the recommendation is to add oral or intravenous corticosteroids and/or antibiotics, depending on symptom severity and the existence of infection.<a href="#bib98" class="elsevierStyleCrossRefs">1</a> Regardless of GOLD stage, severe exacerbations must be managed properly, since mortality increases as they become more frequent, particularly when these require hospital admission.<a href="#bib120" class="elsevierStyleCrossRefs">23</a>Several recent studies have investigated the benefits of ICS on COPD,<a href="#bib112" class="elsevierStyleCrossRefs">15</a>, <a href="#bib116" class="elsevierStyleCrossRefs">19</a>, <a href="#bib117" class="elsevierStyleCrossRefs">20</a>, <a href="#bib118" class="elsevierStyleCrossRefs">21</a>, <a href="#bib121" class="elsevierStyleCrossRefs">24</a>, <a href="#bib122" class="elsevierStyleCrossRefs">25</a>, <a href="#bib123" class="elsevierStyleCrossRefs">26</a>, <a href="#bib124" class="elsevierStyleCrossRefs">27</a>, <a href="#bib125" class="elsevierStyleCrossRefs">28</a> and the majority do not support the use of ICS in all patients. Two specific groups of patients may benefit from ICS: ACOS,<a href="#bib104" class="elsevierStyleCrossRefs">7</a> with a reported prevalence ranging from 15% to 55%, depending on age and gender,<a href="#bib126" class="elsevierStyleCrossRefs">29</a> whose patients cannot be treated with monotherapy LABA, and COPD with frequent exacerbations (≥2/year) regardless of treatment with bronchodilators.<a href="#bib108" class="elsevierStyleCrossRefs">11</a> A very recent review of available studies strongly recommends limiting use of ICS to a minority of COPD patients who might benefit from it, and suggests some indicators of likelihood of ICS patients’ response.<a href="#bib103" class="elsevierStyleCrossRefs">6</a>Several questions remain regarding the use of ICS in COPD patients: (a) do all ICSs increase the risk of pneumonia in COPD patients, or is it dependent on drug class?;<a href="#bib108" class="elsevierStyleCrossRefs">11</a>, <a href="#bib109" class="elsevierStyleCrossRefs">12</a>, <a href="#bib112" class="elsevierStyleCrossRefs">15</a>, <a href="#bib122" class="elsevierStyleCrossRefs">25</a>, <a href="#bib127" class="elsevierStyleCrossRefs">30</a> (b) treatment with ICS for 3 years has been reported to be safe,<a href="#bib112" class="elsevierStyleCrossRefs">15</a> but for more prolonged treatment the safety profile is still unknown;<a href="#bib109" class="elsevierStyleCrossRefs">12</a> (c) is the use of a specific ICS and its dose relevant to the efficacy/safety ratio?;<a href="#bib128" class="elsevierStyleCrossRefs">31</a> (d) Randomized Clinical Trials (RCTs) use very high doses of ICS – do they have the same safety and efficacy profile in lower doses?; and (e) should ICS be used only in patients for whom the benefits outweigh the risks?<a href="#bib108" class="elsevierStyleCrossRefs">11</a> Risks associated to ICS use should be clearly established and balanced against its clinical benefits such as exacerbation control.As for triple therapy, its recommendation in COPD patients at risk of exacerbations is generally accepted<a href="#bib128" class="elsevierStyleCrossRefs">31</a>, <a href="#bib129" class="elsevierStyleCrossRefs">32</a>, <a href="#bib130" class="elsevierStyleCrossRefs">33</a>, <a href="#bib131" class="elsevierStyleCrossRefs">34</a>, <a href="#bib132" class="elsevierStyleCrossRefs">35</a> (one or more exacerbations per year, on average, for 2 consecutive years).<a href="#bib132" class="elsevierStyleCrossRefs">35</a> Triple therapy seems to improve lung function, Quality of Life (QoL),<a href="#bib125" class="elsevierStyleCrossRefs">28</a>, <a href="#bib130" class="elsevierStyleCrossRefs">33</a> and hospitalization rates,<a href="#bib125" class="elsevierStyleCrossRefs">28</a> to provide greater reduction in airway wall thickness<a href="#bib130" class="elsevierStyleCrossRefs">33</a> and seems to confer benefits on cardiovascular mortality.<a href="#bib133" class="elsevierStyleCrossRefs">36</a> On the other hand, a National Health Service (NHS) review concluded that, although triple therapy decreased the hospitalization rate due to severe/acute COPD exacerbations compared with LAMA monotherapy, there was insufficient evidence to determine whether triple therapy was superior to dual bronchodilation.<a href="#bib134" class="elsevierStyleCrossRefs">37</a> Several authors pointed out that evidence in favor of triple therapy use is scarce, study results heterogeneous,<a href="#bib119" class="elsevierStyleCrossRefs">22</a>, <a href="#bib127" class="elsevierStyleCrossRefs">30</a>, <a href="#bib131" class="elsevierStyleCrossRefs">34</a> and the studies were too short to lead to any strong recommendations.<a href="#bib131" class="elsevierStyleCrossRefs">34</a> However, it should be noted that future triple therapy, with all drugs in the same device, may have added advantages compared to triple therapy in different devices, given the possible synergism between molecules, as already shown for LABA + LAMA<a href="#bib123" class="elsevierStyleCrossRefs">26</a> and ICS + LABA.<a href="#bib135" class="elsevierStyleCrossRefs">38</a>Also, it has to be taken into account that triple therapy is expensive and has its own inherent risks.<a href="#bib129" class="elsevierStyleCrossRefs">32</a> A recent review from UK general practice showed that, from 2004 to 2009, the use of triple therapy in all COPD degrees increased: from 25% to 59% in patients with very severe COPD, and as much as 14% and 19% in patients with mild and moderate COPD, respectively. Up to a third of patients with mild or moderate COPD were on triple therapy, and the authors raise the question of whether these patients are indeed frequent exacerbators, and thus are being treated according to current guidelines.<a href="#bib136" class="elsevierStyleCrossRefs">39</a> These numbers are somewhat worrying given the available evidence, and may indicate that ICSs are being over-prescribed and, consequently, patients are being overtreated. Some authors propose that ICS should be withdrawn from patients who do not benefit from it. Gradual ICS withdrawal in moderate COPD patients does not increase moderate to severe exacerbations, although a greater decrease in lung function during the final step of withdrawal was shown.<a href="#bib121" class="elsevierStyleCrossRefs">24</a>Some authors defend the position that, given the risks associated with ICS therapy, and the overall safety and effectiveness of long-acting bronchodilators, bronchodilators without ICS should be favored at all levels of COPD severity, except if there is an asthma component associated with COPD.<a href="#bib103" class="elsevierStyleCrossRefs">6</a> Dual bronchodilation with IND/GLY may be preferable, since it has demonstrated superiority versus treatment with its monocomponents, indacaterol and glycopyrronium,<a href="#bib123" class="elsevierStyleCrossRefs">26</a> suggesting the existence of synergistic activity. The potential advantages and beneficial effects of having a combination of LABA + LAMA on the same device are: (1) prevention of disease progression, (2) increased efficacy compared to single agents given their different mechanisms of action, (3) health status improvement by reducing symptoms and increasing physical activity, and (4) increased compliance – once daily, same device.<a href="#bib118" class="elsevierStyleCrossRefs">21</a>GOLD recommends dual bronchodilation for symptom optimization as the second treatment choice in B, C and D patients.<a href="#bib98" class="elsevierStyleCrossRefs">1</a><a href="#t0010" class="elsevierStyleCrossRefs">Table 2</a> and <a href="#f0005" class="elsevierStyleCrossRefs">Figure 1</a> summarize our proposals, suggestions and recommendations on COPD treatment sequence.Table 2. ICS and triple therapy.<a name="t0010" class="elsevierStyleCrossRefs"></a><table><tr align="left"><td>ICS and triple therapy</td><td>• proposal of therapeutic scheme depicted in Fig. 1 </td></tr><tr align="left"><td>Recommendation</td><td>• strong recommendation for a personalized, patient-oriented approach, taking into account each patient's clinical and personal characteristics and preferences</td></tr></table><a name="f0005" class="elsevierStyleCrossRefs"></a><img src="320v22n01-90447947fig1.jpg" alt="Proposed therapeutic scheme. From top to bottom: asthma component predominant to COPD component predominant."></img>Figure 1. Proposed therapeutic scheme. From top to bottom: asthma component predominant to COPD component predominant.<a name="sec0025" class="elsevierStyleCrossRefs"></a>Compliance and new moleculesDifficulties in early interventions (GOLD stage 1 and 2) are mainly due to low compliance, with increased mortality rate regardless of the type of therapy.<a href="#bib109" class="elsevierStyleCrossRefs">12</a> A patient with dyspnea and fatigue will be more likely to comply with treatment whereas a less symptomatic patient will tend to be non-compliant. Focus should be given to informing patients<a href="#bib109" class="elsevierStyleCrossRefs">12</a>, <a href="#bib116" class="elsevierStyleCrossRefs">19</a>, <a href="#bib117" class="elsevierStyleCrossRefs">20</a> about therapy benefits. As previously mentioned, one of the potential advantages and beneficial effects of having a combination LABA + LAMA therapy on the same device is an increased compliance – once daily.<a href="#bib116" class="elsevierStyleCrossRefs">19</a>, <a href="#bib117" class="elsevierStyleCrossRefs">20</a>, <a href="#bib118" class="elsevierStyleCrossRefs">21</a> However, the choice of an inhaler should consider a range of different factors, including price and availability, similarity to other inhalers the patient uses, ability for the health care provider to correctly train the patient, ability of the patient to handle the inhaler, and patient preference.<a href="#bib137" class="elsevierStyleCrossRefs">40</a> In this regard, studies have shown some advantages of the Breezhaler in comparison to the Handihaler in COPD patients with different disease severities: (1) Breezhaler has mechanisms that assure the drug is completely inhaled by the patient;<a href="#bib138" class="elsevierStyleCrossRefs">41</a> (2) it delivers a higher fine particle fraction and generates a greater and more consistent intrathoracic deposition<a href="#bib139" class="elsevierStyleCrossRefs">42</a> and (3) patients seem to prefer the Breezhaler because it is easier and more comfortable to use.<a href="#bib138" class="elsevierStyleCrossRefs">41</a>As for the development of new drugs, the combination of a muscarinic antagonist with a beta2 agonist (MABA) is an interesting new approach, since it has the potential to demonstrate additive or synergistic bronchodilation over either component alone.<a href="#bib140" class="elsevierStyleCrossRefs">43</a> A phase I trial to determine the pharmacokinetics of a MABA has already been completed, but the results are not yet available.<a href="#bib141" class="elsevierStyleCrossRefs">44</a><a href="#t0015" class="elsevierStyleCrossRefs">Table 3</a> summarizes our proposals, suggestions and recommendations on compliance and new molecules.Table 3. Compliance and new molecules.<a name="t0015" class="elsevierStyleCrossRefs"></a><table><tr align="left"><td rowspan="2">Compliance</td><td>• proposal of focusing on patient information and education to increase compliance</td></tr><tr align="left"><td>• having a combination of drugs on the same device increases compliance, and the choice of an inhaler should be based on several factors</td></tr><tr align="left"><td>New Molecules (MABA)</td><td>• results not available</td></tr></table><a name="sec0030" class="elsevierStyleCrossRefs"></a>Additional useful non-inhaled therapiesThere are a few useful non-inhaled therapies that can be used in the management of COPD, namely mucolytic agents, macrolides, PDE4i, xanthine derivatives and immunostimulating agents. Some guidelines have already incorporated these additional therapies,<a href="#bib98" class="elsevierStyleCrossRefs">1</a>, <a href="#bib99" class="elsevierStyleCrossRefs">2</a>, <a href="#bib100" class="elsevierStyleCrossRefs">3</a>, <a href="#bib142" class="elsevierStyleCrossRefs">45</a> but which therapy to use in which group of patients remains controversial.<a name="sec0035" class="elsevierStyleCrossRefs"></a>Mucolytic agentsCarbocysteine, N-acetylcysteine (NAC) and erdosteine are the most common mucolytic agents used in COPD. They all exhibit antioxidant activity,<a href="#bib98" class="elsevierStyleCrossRefs">1</a> with carbocysteine and NAC being also anti-inflammatory.<a href="#bib143" class="elsevierStyleCrossRefs">46</a>, <a href="#bib144" class="elsevierStyleCrossRefs">47</a> Carbocysteine seems to decrease exacerbations in frequent exacerbators not receiving ICS.<a href="#bib143" class="elsevierStyleCrossRefs">46</a>, <a href="#bib145" class="elsevierStyleCrossRefs">48</a> High-dose NAC seems to decrease exacerbation frequency regardless of ICS therapy,<a href="#bib144" class="elsevierStyleCrossRefs">47</a>, <a href="#bib146" class="elsevierStyleCrossRefs">49</a> but only in patients at high risk of exacerbations.<a href="#bib147" class="elsevierStyleCrossRefs">50</a> This effect appears to be particularly evident in patients with moderate COPD,<a href="#bib148" class="elsevierStyleCrossRefs">51</a> but limitations due to study population may preclude generalization of these conclusions.<a href="#bib149" class="elsevierStyleCrossRefs">52</a>, <a href="#bib150" class="elsevierStyleCrossRefs">53</a> Low-dose NAC has no effect on exacerbation frequency<a href="#bib146" class="elsevierStyleCrossRefs">49</a>, <a href="#bib151" class="elsevierStyleCrossRefs">54</a>, <a href="#bib152" class="elsevierStyleCrossRefs">55</a> or clinical outcomes.<a href="#bib151" class="elsevierStyleCrossRefs">54</a>, <a href="#bib152" class="elsevierStyleCrossRefs">55</a> Data from a meta-analysis supports the use of erdosteine in COPD, given the significant symptom improvement,<a href="#bib153" class="elsevierStyleCrossRefs">56</a> but the reliability of this conclusion is disputed.<a href="#bib154" class="elsevierStyleCrossRefs">57</a> The Spanish guidelines consider the addition of carbocysteine in the exacerbator patient with chronic bronchitis phenotype and severity level > II.<a href="#bib99" class="elsevierStyleCrossRefs">2</a> GOLD considers carbocysteine as an option for GOLD D patients,<a href="#bib98" class="elsevierStyleCrossRefs">1</a> and the NICE guidelines consider mucolytic therapy for patients with a chronic cough productive of sputum, but do not recommend routine use of mucolytic drugs to prevent exacerbations in patients with stable COPD.<a href="#bib100" class="elsevierStyleCrossRefs">3</a><a name="sec0040" class="elsevierStyleCrossRefs"></a>MacrolidesMacrolides are the most widely studied antibiotics for continuous long-term or intermittent use in COPD.<a href="#bib155" class="elsevierStyleCrossRefs">58</a> Available evidence supports the continuous use of macrolides to prevent exacerbations<a href="#bib156" class="elsevierStyleCrossRefs">59</a>, <a href="#bib157" class="elsevierStyleCrossRefs">60</a>, <a href="#bib158" class="elsevierStyleCrossRefs">61</a>, <a href="#bib159" class="elsevierStyleCrossRefs">62</a> and hospitalizations,<a href="#bib159" class="elsevierStyleCrossRefs">62</a> but which patient population would benefit the most, as well as optimal dose and duration of treatment, remain unknown.<a href="#bib155" class="elsevierStyleCrossRefs">58</a>, <a href="#bib159" class="elsevierStyleCrossRefs">62</a>, <a href="#bib160" class="elsevierStyleCrossRefs">63</a> A small study in patients with 3 or more exacerbations in the previous year showed that 500 mg azithromycin 3 times per week for 12 months significantly decreased exacerbation rate and suggested that this regimen should be considered for use in patients with the frequent exacerbator phenotype who are refractory to standard care.<a href="#bib157" class="elsevierStyleCrossRefs">60</a> However, a large study where 250 mg azithromycin was given to patients daily for 12 months concluded that azithromycin was most effective in preventing exacerbations requiring both antibiotic and steroid treatment, and reported a greater efficacy in older patients and in those with less severe COPD.<a href="#bib158" class="elsevierStyleCrossRefs">61</a> A systematic review including only trials with patients who were frequent exacerbators and who needed treatment with antibiotics or systemic steroids for those events, or who were on supplemental oxygen, concluded that the impact of intermittent use of macrolides (either 5 days every two months or 3 consecutive days per month) on exacerbation frequency and quality of life remains uncertain.<a href="#bib156" class="elsevierStyleCrossRefs">59</a> A recent literature review concluded that, in Belgium, beyond the positive impact on exacerbations and related hospitalizations, the prevention of COPD exacerbations with azithromycin would not only be cost saving<a href="#bib159" class="elsevierStyleCrossRefs">62</a> but also cost-effective.<a href="#bib161" class="elsevierStyleCrossRefs">64</a>, <a href="#bib162" class="elsevierStyleCrossRefs">65</a>Two additional concerns regarding prophylactic long-term antibiotic treatment are the possibility of developing antibiotic resistance<a href="#bib155" class="elsevierStyleCrossRefs">58</a>, <a href="#bib156" class="elsevierStyleCrossRefs">59</a>, <a href="#bib159" class="elsevierStyleCrossRefs">62</a>, <a href="#bib160" class="elsevierStyleCrossRefs">63</a>, <a href="#bib163" class="elsevierStyleCrossRefs">66</a> and the unknown potential adverse effects.<a href="#bib155" class="elsevierStyleCrossRefs">58</a>, <a href="#bib156" class="elsevierStyleCrossRefs">59</a>, <a href="#bib160" class="elsevierStyleCrossRefs">63</a>, <a href="#bib163" class="elsevierStyleCrossRefs">66</a>All current guidelines recommend the use of antibiotics only for the treatment of infectious or severe exacerbations, and do not support the use of prophylactic antibiotic therapy.<a href="#bib98" class="elsevierStyleCrossRefs">1</a>, <a href="#bib99" class="elsevierStyleCrossRefs">2</a>, <a href="#bib100" class="elsevierStyleCrossRefs">3</a>, <a href="#bib101" class="elsevierStyleCrossRefs">4</a>, <a href="#bib102" class="elsevierStyleCrossRefs">5</a> The Spanish guidelines also consider the addition of antibiotics in the exacerbator with chronic bronchitis phenotype with severity level IV.<a href="#bib99" class="elsevierStyleCrossRefs">2</a> Macrolides are one of the first choice class of antibiotics to be used when necessary,<a href="#bib98" class="elsevierStyleCrossRefs">1</a>, <a href="#bib100" class="elsevierStyleCrossRefs">3</a>, <a href="#bib101" class="elsevierStyleCrossRefs">4</a>, <a href="#bib102" class="elsevierStyleCrossRefs">5</a> but teophylline dose should be reduced during macrolide treatment<a href="#bib100" class="elsevierStyleCrossRefs">3</a>, <a href="#bib102" class="elsevierStyleCrossRefs">5</a> since macrolides increase the serum concentration of theophylline.<a href="#bib98" class="elsevierStyleCrossRefs">1</a><a name="sec0045" class="elsevierStyleCrossRefs"></a>Phosphodiesterase-4 inhibitorsAlthough PDE4i are currently not available in Portugal, its use in COPD is already considered in the Spanish<a href="#bib99" class="elsevierStyleCrossRefs">2</a> and GOLD<a href="#bib98" class="elsevierStyleCrossRefs">1</a> guidelines. PDE4i are thought to reduce airway inflammation and bronchoconstriction. A very large systematic review concluded that PDE4i improve short-term lung function and reduce exacerbations, but have minimal or no impact on daily symptoms, QoL or life expectancy. Moreover, they are associated with gastrointestinal adverse effects and headaches, with roflumilast in particular being associated with significant weight loss and some psychiatric symptoms. These authors suggest that use of PDE4i should be limited to add-on therapy in a subgroup of patients with persistent symptoms or exacerbations despite optimal COPD management, and recognize that the role of PDE4i and its positioning in COPD management remains to be defined.<a href="#bib164" class="elsevierStyleCrossRefs">67</a> Another very large systematic review of roflumilast reached the same overall conclusions, and further reported that roflumilast significantly reduced moderate to severe exacerbations, but not severe exacerbations alone.<a href="#bib165" class="elsevierStyleCrossRefs">68</a> Both reviews agree that longer-term trials are needed to determine the actual benefits of PDE4i and their long-term safety. A more recent study confirmed these results by reporting a borderline statistical significance in the reduction of severe COPD exacerbations with roflumilast versus placebo in patients with severe to very severe COPD.<a href="#bib166" class="elsevierStyleCrossRefs">69</a> However, all roflumilast results derived from industry-sponsored trials have been disputed, with some authors defending that these trials were appropriate<a href="#bib167" class="elsevierStyleCrossRefs">70</a> and others criticizing them.<a href="#bib168" class="elsevierStyleCrossRefs">71</a> A very recent study concluded that, in patients with severe chronic obstructive pulmonary disease at risk for exacerbations, already receiving ICS + LABA, with or without tiotropium, roflumilast reduces exacerbations and hospital admissions,<a href="#bib169" class="elsevierStyleCrossRefs">72</a> and these results were corroborated in a small “real-life” population of severe COPD patients with frequent exacerbations already receiving triple therapy.<a href="#bib170" class="elsevierStyleCrossRefs">73</a> Roflumilast showed particular benefit in patients with 4 or more exacerbations prior to initiating therapy.<a href="#bib170" class="elsevierStyleCrossRefs">73</a>The Spanish guidelines consider the addition of PDE4i in the ACOS phenotype with severity level IV if associated with exacerbations and sputum, and in the exacerbator with chronic bronchitis phenotype with severity level > I PDE4i are one of the recommended choices.<a href="#bib99" class="elsevierStyleCrossRefs">2</a> GOLD guidelines recommend PDE4i as alternative choice treatments for GOLD C and D patients, and state that they may be useful to reduce exacerbations in patients with FEV1 < 50% predicted, chronic bronchitis, and frequent exacerbations. Despite this, PDE4i should always be used in combination with at least one long-acting bronchodilator.<a href="#bib98" class="elsevierStyleCrossRefs">1</a><a name="sec0050" class="elsevierStyleCrossRefs"></a>MethylxanthinesMethylxanthines are nonspecific inhibitors of all phosphodiesterase enzyme subsets, and have a wide range of adverse effects<a href="#bib98" class="elsevierStyleCrossRefs">1</a> related to plasma concentrations, including nausea, vomiting, and headaches and, at higher concentrations, cardiac arrhythmias and seizures.<a href="#bib171" class="elsevierStyleCrossRefs">74</a> Theophylline, the most widely used methylxanthine, has shown clinically relevant results in patients with stable COPD, namely FEV1 and FVC improvement,<a href="#bib172" class="elsevierStyleCrossRefs">75</a>, <a href="#bib173" class="elsevierStyleCrossRefs">76</a> as well as improvements in maximal O2 uptake (VO2max), O2 partial pressure (PaO2) and CO2 partial pressure (PaCO2).<a href="#bib173" class="elsevierStyleCrossRefs">76</a> Theophylline has a role in the management of stable COPD, and is currently used as add-on therapy in severe COPD patients not controlled by bronchodilator therapy.<a href="#bib171" class="elsevierStyleCrossRefs">74</a> However, its wider use is hampered by the fact that blood levels need to be closely monitored due to serious, even potentially life-threatening side-effects.<a href="#bib172" class="elsevierStyleCrossRefs">75</a>, <a href="#bib173" class="elsevierStyleCrossRefs">76</a> As for the use of methylxanthines in the management of COPD exacerbations, current evidence does not support it, given that the possible beneficial effects in lung function and clinical endpoints are modest and inconsistent, whereas adverse effects are significant.<a href="#bib174" class="elsevierStyleCrossRefs">77</a> All current guidelines stand by this point of view.The Spanish guidelines consider the addition of theophylline in all phenotypes, but only with severity level IV.<a href="#bib99" class="elsevierStyleCrossRefs">2</a> GOLD recommends theophylline as an alternative choice treatment for all GOLD classes, but only if other long-term treatment bronchodilators are unavailable or unaffordable.<a href="#bib98" class="elsevierStyleCrossRefs">1</a> The NICE guidelines propose that theophylline should only be used after a trial of short-acting bronchodilators and long-acting bronchodilators, or in patients who are unable to use inhaled therapy.<a href="#bib100" class="elsevierStyleCrossRefs">3</a> The Canadian guidelines only recommend trying theophylline in patients with severe symptoms and frequent exacerbations despite use of both tiotropium and a LABA/ICS.<a href="#bib101" class="elsevierStyleCrossRefs">4</a> In the management of exacerbations, intravenous methylxanthines (theophylline or aminophylline) are considered second-line therapy, only to be used in selected cases when there is insufficient response to short-acting bronchodilators.<a href="#bib98" class="elsevierStyleCrossRefs">1</a>, <a href="#bib100" class="elsevierStyleCrossRefs">3</a>, <a href="#bib102" class="elsevierStyleCrossRefs">5</a> When using theophylline, it is necessary to monitor blood levels, side effects and potential drug interactions.<a href="#bib101" class="elsevierStyleCrossRefs">4</a><a name="sec0055" class="elsevierStyleCrossRefs"></a>Immunostimulating agentsA few small studies have reported a potential benefit of the immunostimulating agent OM-85 in the prevention of severe respiratory events, risk of hospitalization and duration of hospital stay in severe and very severe COPD patients,<a href="#bib175" class="elsevierStyleCrossRefs">78</a> and in the decrease of acute exacerbations, symptoms, and need for antibiotics and symptomatic relief medications, in patients with chronic bronchitis and COPD.<a href="#bib176" class="elsevierStyleCrossRefs">79</a> OM-85 was well tolerated.<a href="#bib176" class="elsevierStyleCrossRefs">79</a> In patients with chronic bronchitis or mild COPD, a decrease in exacerbation frequency was observed after 6 months of intermittent OM-85 administration (30 days followed by three 10-day courses for months 3, 4 and 5), and OM-85 was also well tolerated.<a href="#bib177" class="elsevierStyleCrossRefs">80</a> However, these studies were small and the longest follow-up period lasted for only 1 year.GOLD does not recommend regular use of immunostimulating agents due to the lack of studies on their long-term effects.<a href="#bib98" class="elsevierStyleCrossRefs">1</a><a href="#t0020" class="elsevierStyleCrossRefs">Table 4</a> summarizes our proposals, suggestions and recommendations on additional non-inhaled therapies.Table 4. Additional useful non-inhaled therapies.<a name="t0020" class="elsevierStyleCrossRefs"></a><table><tr align="left"><td rowspan="2">Mucolytic agents</td><td>• seem to prevent exacerbations in certain subtypes of COPD patients</td></tr><tr align="left"><td>• suggestion to use in a patient-oriented manner</td></tr><tr align="left"><td rowspan="3">Macrolides</td><td>• current uncertainties of long-term macrolide use</td></tr><tr align="left"><td>• proposal of, when considering this approach, continuous use is preferable to intermittent use and severe frequent exacerbators are the phenotype of choice</td></tr><tr align="left"><td>• decision should be patient-oriented, considering the risk/benefit ratio for each individual</td></tr><tr align="left"><td rowspan="3">Phosphodiesterase-4 inhibitors (PDE4i)</td><td>• identification of the group of patients that could benefit the most from PDE4i remains elusive</td></tr><tr align="left"><td>• proposal that this alternative should be offered to more severe patients, frequent exacerbators or with chronic bronchitis, without low BMI</td></tr><tr align="left"><td>• weight loss and gastrointestinal adverse effects should be monitored closely</td></tr><tr align="left"><td rowspan="4">Methylxanthines in COPD exacerbations</td><td>• current evidence does not support their use in the management of COPD exacerbations</td></tr><tr align="left"><td>• possible beneficial effects in lung function and clinical endpoints are modest and inconsistent, whereas adverse effects are significant</td></tr><tr align="left"><td>• intravenous methylxanthines (theophylline or aminophylline) are considered second-line therapy, only to be used in selected cases when there is insufficient response to short-acting bronchodilators</td></tr><tr align="left"><td>• when using theophylline, it is necessary to monitor blood levels, side effects and potential drug interactions</td></tr><tr align="left"><td rowspan="4">Theophylline for Stable COPD</td><td>• to be considered in all phenotypes, but only with severity level IV</td></tr><tr align="left"><td>• recommended as an alternative choice treatment for all GOLD classes, but only if other long-term treatment bronchodilators are unavailable or unaffordable</td></tr><tr align="left"><td>• should only be used after a trial of short-acting bronchodilators and long-acting bronchodilators, or in patients who are unable to use inhaled therapy</td></tr><tr align="left"><td>• only recommended to try in patients with severe symptoms and frequent exacerbations despite use of both tiotropium and a LABA/ICS</td></tr><tr align="left"><td>Immunostimulating agents</td><td>• not recommended due to lack of studies on their long-term effects</td></tr></table><a name="sec0060" class="elsevierStyleCrossRefs"></a>Treatment of co-morbiditiesThere are no conclusive data establishing that treatment of COPD co-morbidities will reduce morbidity and mortality rates in patients. The fact that patients with clinically relevant co-morbidities are usually excluded from clinical trials of COPD, and that patients with COPD are also usually excluded from clinical trials on other pathologies, has prevented evidence-based clinical treatment guidelines in these patients. However, co-morbidities should be adequately controlled due to their potential negative impact on COPD prognosis.<a href="#bib98" class="elsevierStyleCrossRefs">1</a><a name="sec0065" class="elsevierStyleCrossRefs"></a>Cardiovascular co-morbidities<a name="sec0070" class="elsevierStyleCrossRefs"></a>Cardiovascular medicationsA large retrospective study reported that statins, angiotensin-converting-enzyme inhibitors (ACEi), and angiotensin-receptor blockers (ARBs) could have cardioprotective properties in patients with COPD, substantially altering their prognosis. Also, COPD hospitalization and total mortality rates were reduced, as well as the myocardial infarction rate in COPD patients with high cardiovascular risk, independently of the concomitant use of steroids. The largest benefits were observed with the combination of statins and either ACEi or ARBs.<a href="#bib178" class="elsevierStyleCrossRefs">81</a> Several further studies were conducted to assess the potential effect of statins and ACEi on COPD, and reviews of those studies concluded that they were beneficial.<a href="#bib179" class="elsevierStyleCrossRefs">82</a>, <a href="#bib180" class="elsevierStyleCrossRefs">83</a>, <a href="#bib181" class="elsevierStyleCrossRefs">84</a>, <a href="#bib182" class="elsevierStyleCrossRefs">85</a>, <a href="#bib183" class="elsevierStyleCrossRefs">86</a> However, all these studies were observational, and a very recent large RCT on the effects of simvastatin on exacerbations and FEV1 in COPD patients was terminated due to futility.<a href="#bib184" class="elsevierStyleCrossRefs">87</a> Other RCTs also failed to prove the benefits of ACEi<a href="#bib185" class="elsevierStyleCrossRefs">88</a> or ARBs<a href="#bib186" class="elsevierStyleCrossRefs">89</a> in different COPD outcomes. GOLD guidelines do not mention the use of these medications and state that cardiovascular co-morbidities should be treated according to their specific guidelines.<a href="#bib98" class="elsevierStyleCrossRefs">1</a><a name="sec0075" class="elsevierStyleCrossRefs"></a>β-BlockersThere has been concern that prescription of β-blockers for patients with COPD might cause bronchoconstriction and worsen respiratory symptoms.<a href="#bib109" class="elsevierStyleCrossRefs">12</a> However, cardioselective β-blockers have been shown to be associated with reduced mortality in patients with COPD undergoing vascular surgery,<a href="#bib187" class="elsevierStyleCrossRefs">90</a> and a meta-analysis did not find significant differences in FEV1 or respiratory symptoms between patients treated with a cardioselective β-blocker and those treated with placebo, even in patients with severe COPD.<a href="#bib188" class="elsevierStyleCrossRefs">91</a> Another very recent meta-analysis concluded that the use of β-blockers in patients with COPD with or without co-morbid cardiovascular diseases, may not only decrease the risk of overall mortality but also reduce the risk of exacerbations, concluding that, given the benefits of β-blockers in conditions such as hypertension, heart failure and coronary artery disease, these drugs should not be withheld because of COPD.<a href="#bib189" class="elsevierStyleCrossRefs">92</a> In a fairly large population (n = 825) of inpatients admitted for acute exacerbations of COPD, the use of β-blockers was well tolerated and associated with reduced mortality.<a href="#bib190" class="elsevierStyleCrossRefs">93</a> Current guidelines recommend the use of β-blockers to treat specific associated co-morbidities,<a href="#bib98" class="elsevierStyleCrossRefs">1</a>, <a href="#bib99" class="elsevierStyleCrossRefs">2</a> preferably cardioselective β-blockers,<a href="#bib98" class="elsevierStyleCrossRefs">1</a> with the added advantage of reducing exacerbations and mortality associated with some cardiovascular co-morbidities.<a href="#bib99" class="elsevierStyleCrossRefs">2</a><a name="sec0080" class="elsevierStyleCrossRefs"></a>Gastroesophageal reflux disease (GERD)GERD is one of the most common causes of chronic cough and is a frequent co-morbidity in COPD patients, also being associated with exacerbations.<a href="#bib191" class="elsevierStyleCrossRefs">94</a>, <a href="#bib192" class="elsevierStyleCrossRefs">95</a>, <a href="#bib193" class="elsevierStyleCrossRefs">96</a> Older age and female gender<a href="#bib192" class="elsevierStyleCrossRefs">95</a> are associated with GERD in COPD patients, and the association between GERD and obesity is well known. A very recent large study reported that COPD patients with GERD were at increased risk of medically treated COPD exacerbations, defined as a short course treatment with oral corticosteroids alone or in combination with antibiotics, only if they did not use acid inhibitory treatment regularly.<a href="#bib193" class="elsevierStyleCrossRefs">96</a> These results are in accordance with a small study that reported that proton pump inhibitor use was associated with a significant decrease in COPD exacerbations in older patients.<a href="#bib194" class="elsevierStyleCrossRefs">97</a> Also, it has been reported that most of COPD medications except LAMA are associated with GERD.<a href="#bib192" class="elsevierStyleCrossRefs">95</a> GOLD guidelines state that proton pump inhibitors are often used for treatment of GERD, but the most effective treatment for this condition in patients with COPD has yet to be established.<a href="#bib98" class="elsevierStyleCrossRefs">1</a><a href="#t0025" class="elsevierStyleCrossRefs">Table 5</a> summarizes our proposals, suggestions and recommendations on the treatment of cardiovascular co-morbidities and GERD.Table 5. Treatment of co-morbidities.<a name="t0025" class="elsevierStyleCrossRefs"></a><table><tr align="left"><td rowspan="2">Cardiovascular</td><td>• cardiovascular co-morbidities should be treated according to their specific guidelines</td></tr><tr align="left"><td>• in the presence of some cardiovascular co-morbidities, cardioselective beta-blockers are not only safe but also beneficial in the control of COPD</td></tr><tr align="left"><td rowspan="2">Gastroesophageal reflux disease (GERD)</td><td>• special attention should be given to older patients, women, and obese patients</td></tr><tr align="left"><td>• a proton pump inhibitor is advisable</td></tr></table><a name="sec0085" class="elsevierStyleCrossRefs"></a>ConclusionsAlthough this paper proposes a therapeutic scheme for COPD patients, a full consensus on optimal treatment sequence in COPD cannot be found at present. There are still too many unknown variables, no reliable biomarkers to guide treatment, and a poor definition of clinically relevant COPD phenotypes. It is imperative that active research continues in order not only to identify specific groups of patients that can benefit from specific treatments, but also to develop new molecules or combinations of molecules, that are more effective in symptom control. The ultimate goal would be to stop disease progression, but this goal may not be attainable. At present, COPD should be treated in a personalized, tailor-made, patient-oriented manner.<a name="sec0090" class="elsevierStyleCrossRefs"></a>Ethical responsibilities<a name="sec0095" class="elsevierStyleCrossRefs"></a>Protection of human and animal subjectsThe authors declare that no experiments were performed on humans or animals for this study.<a name="sec0100" class="elsevierStyleCrossRefs"></a>Confidentiality of dataThe authors declare that no patient data appear in this article.<a name="sec0105" class="elsevierStyleCrossRefs"></a>Right to privacy and informed consentThe authors declare that no patient data appear in this article.<a name="sec0110" class="elsevierStyleCrossRefs"></a>Conflict of interestThe authors declare collaborating and receiving fees from pharmaceutical companies other than Novartis either through participation in advisory board or consultancy meetings, congress symposia, clinical trial conduct or investigator-initiated trials.<a name="sec0115" class="elsevierStyleCrossRefs"></a>Role of funding sourceFunding for this paper was provided by Novartis Portugal. Funding was used to access all necessary scientific bibliography and cover meeting expenses. Novartis Portugal had no role in the collection, analysis and interpretation of data, in the writing of the paper and in the decision to submit the paper for publication.AcknowledgementsThe authors wish to thank Novartis Portugal for the funding for this paper, which was used to access all necessary scientific bibliography and cover meeting expenses.Received 8 August 2015 Accepted 20 October 2015 Corresponding author. carlos.crobalo@gmail.com" "pdfFichero" => "320v22n01a90447947pdf001.pdf" "tienePdf" => true "PalabrasClave" => array:1 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec640961" "palabras" => array:9 [ 0 => "COPD" 1 => "Treatment sequence" 2 => "SABA" 3 => "SAMA" 4 => "LABA" 5 => "LAMA" 6 => "ICS" 7 => "Triple therapy" 8 => "Non-inhaled therapies" ] ] ] ] "tieneResumen" => true "resumen" => array:1 [ "en" => array:1 [ "resumen" => " Abstract There is currently no consensus on the treatment sequence in chronic obstructive pulmonary disease (COPD), although it is recognized that early diagnosis is of paramount importance to start treatment in the early stages of the disease. Although it is fairly consensual that initial treatment should be with an inhaled short-acting beta agonist, a short-acting muscarinic antagonist, a long-acting beta-agonist or a long-acting muscarinic antagonist. As the disease progresses, several therapeutic options are available, and which to choose at each disease stage remains controversial. When and in which patients to use dual bronchodilation? When to use inhaled corticosteroids? And triple therapy? Are the existing non-inhaled therapies, such as mucolytic agents, antibiotics, phosphodiesterase-4 inhibitors, methylxanthines and immunostimulating agents, useful? If so, which patients would benefit? Should co-morbitities be taken into account when choosing COPD therapy for a patient? This paper reviews current guidelines and available evidence and proposes a therapeutic scheme for COPD patients. We also propose a treatment algorithm in the hope that it will help physicians to decide the best approach for their patients. The authors conclude that, at present, a full consensus on optimal treatment sequence in COPD cannot be found, mainly due to disease heterogeneity and lack of biomarkers to guide treatment. For the time being, and although some therapeutic approaches are consensual, treatment of COPD should be patient-oriented." ] ] "multimedia" => array:2 [ 0 => array:8 [ "identificador" => "fig1" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "copyright" => "Elsevier España" "figura" => array:1 [ 0 => array:4 [ "imagen" => "320v22n01-90447947fig1.jpg" "Alto" => 1979 "Ancho" => 3091 "Tamanyo" => 539936 ] ] "descripcion" => array:1 [ "en" => "Proposed therapeutic scheme. From top to bottom: asthma component predominant to COPD component predominant." ] ] 1 => array:6 [ "identificador" => "fig2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "copyright" => "Elsevier España" "descripcion" => array:1 [ "en" => "Proposed therapeutic scheme. From top to bottom: asthma component predominant to COPD component predominant." ] ] ] "bibliografia" => array:2 [ "titulo" => "Bibliography" "seccion" => array:1 [ 0 => array:1 [ "bibliografiaReferencia" => array:97 [ 0 => array:3 [ "identificador" => "bib98" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Global Strategy for the Diagnosis, Management and Prevention of Chronic Obstructive Pulmonary Disease (Updated). 2015. " "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "Global Strategy for the Diagnosis, Management and Prevention of Chronic Obstructive Pulmonary Disease (Updated)." "idioma" => "en" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ 0 => "Global Initiative for Chronic Obstructive Lung Disease." ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:1 [ "tituloSerie" => "2015. " ] ] ] ] ] ] 1 => array:3 [ "identificador" => "bib99" "etiqueta" => "2" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Spanish guideline for COPD (GesEPOC). Update 2014. Arch Bronconeumol. 2014; 50(Suppl. 1):1-16. " "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "Spanish guideline for COPD (GesEPOC). Update 2014." "idioma" => "en" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:7 [ 0 => "Miravitlles M" 1 => "Soler-Cataluna JJ" 2 => "Calle M" 3 => "Molina J" 4 => "Almagro P" 5 => "Quintano JA" 6 => "et-al." ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:3 [ "tituloSerie" => "Arch Bronconeumol. " "fecha" => "2014" "volumen" => "50" ] ] ] ] ] ] 2 => array:3 [ "identificador" => "bib100" "etiqueta" => "3" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Chronic obstructive pulmonary disease: management of chronic obstructive pulmonary disease in adults in primary and secondary care (partial update). 2010. <inter-ref>http://www.nice.org.uk/guidance/CG101</inter-ref>. " "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "Chronic obstructive pulmonary disease: management of chronic obstructive pulmonary disease in adults in primary and secondary care (partial update). 2010. http://www.nice. " "idioma" => "en" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ 0 => "National Institute for Health and Care Excellence." ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:2 [ "tituloSerie" => "org. " "fecha" => "uk/guidance/CG101</inter-ref>" ] ] ] ] ] ] 3 => array:3 [ "identificador" => "bib101" "etiqueta" => "4" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Canadian Thoracic Society recommendations for management of chronic obstructive pulmonary disease – 2007 update. Can Respir J. 2007; 14(Suppl. B):5B-32B. " "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "Canadian Thoracic Society recommendations for management of chronic obstructive pulmonary disease – 2007 update." "idioma" => "en" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:7 [ 0 => "O’Donnell DE" 1 => "Aaron S" 2 => "Bourbeau J" 3 => "Hernandez P" 4 => "Marciniuk DD" 5 => "Balter M" 6 => "et-al." ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:3 [ "tituloSerie" => "Can Respir J. " "fecha" => "2007" "volumen" => "14" ] ] ] ] ] ] 4 => array:3 [ "identificador" => "bib102" "etiqueta" => "5" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Norma nr 028/2011 – Diagnóstico e Tratamento da Doença Pulmonar Obstrutiva Crónica. Portugal. 2013. " "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "Norma nr 028/2011 – Diagnóstico e Tratamento da Doença Pulmonar Obstrutiva Crónica. Portugal." "idioma" => "pt" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ 0 => "Direcção Geral de Saúde." ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:1 [ "tituloSerie" => "2013. " ] ] ] ] ] ] 5 => array:3 [ "identificador" => "bib103" "etiqueta" => "6" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Inhaled corticosteroids in COPD: the clinical evidence. Eur Respir J. 2015; 45:525-37. " "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "Inhaled corticosteroids in COPD: the clinical evidence." "idioma" => "en" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => "Ernst P" 1 => "Saad N" 2 => "Suissa S." ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:3 [ "tituloSerie" => "Eur Respir J. " "fecha" => "2015" "volumen" => "45:525-37." ] ] ] ] ] ] 6 => array:3 [ "identificador" => "bib104" "etiqueta" => "7" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "The asthma-chronic obstructive pulmonary disease overlap syndrome (ACOS): opportunities and challenges. Curr Opin Pulm Med. 2015; 21:74-9. " "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "The asthma-chronic obstructive pulmonary disease overlap syndrome (ACOS): opportunities and challenges." "idioma" => "en" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => "Barrecheguren M" 1 => "Esquinas C" 2 => "Miravitlles M." ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:3 [ "tituloSerie" => "Curr Opin Pulm Med. " "fecha" => "2015" "volumen" => "21:74-9." ] ] ] ] ] ] 7 => array:3 [ "identificador" => "bib105" "etiqueta" => "8" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Use of inhaled corticosteroids and the risk of tuberculosis. Thorax. 2013; 68:1105-13. " "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "Use of inhaled corticosteroids and the risk of tuberculosis." "idioma" => "en" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ 0 => "Lee CH" 1 => "Kim K" 2 => "Hyun MK" 3 => "Jang EJ" 4 => "Lee NR" 5 => "Yim JJ." ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:3 [ "tituloSerie" => "Thorax. " "fecha" => "2013" "volumen" => "68:1105-13." ] ] ] ] ] ] 8 => array:3 [ "identificador" => "bib106" "etiqueta" => "9" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Guimarães M, Bugalho A, Oliveira AS, Moita J, Marques M. COPD symptoms control: can a consensus be found? submitted for publication. " "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Guimarães M, Bugalho A, Oliveira AS, Moita J, Marques M." "idioma" => "pt" ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:1 [ "tituloSerie" => "COPD symptoms control: can a consensus be found? submitted for publication. " ] ] ] ] ] ] 9 => array:3 [ "identificador" => "bib107" "etiqueta" => "10" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Global Strategy for the Diagnosis, Management and Prevention of Chronic Obstructive Pulmonary Disease (Updated). 2014. " "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "Global Strategy for the Diagnosis, Management and Prevention of Chronic Obstructive Pulmonary Disease (Updated)." "idioma" => "en" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ 0 => "Global Initiative for Chronic Obstructive Lung Disease." ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:1 [ "tituloSerie" => "2014. " ] ] ] ] ] ] 10 => array:3 [ "identificador" => "bib108" "etiqueta" => "11" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Risk-to-benefit ratio of inhaled corticosteroids in patients with COPD. Prim Care Respir J. 2013; 22:92-100. " "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "Risk-to-benefit ratio of inhaled corticosteroids in patients with COPD." "idioma" => "en" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ 0 => "Price D" 1 => "Yawn B" 2 => "Brusselle G" 3 => "Rossi A." ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:3 [ "tituloSerie" => "Prim Care Respir J. " "fecha" => "2013" "volumen" => "22:92-100." ] ] ] ] ] ] 11 => array:3 [ "identificador" => "bib109" "etiqueta" => "12" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Controversies in treatment of chronic obstructive pulmonary disease. Lancet. 2011; 378:1038-47. " "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "Controversies in treatment of chronic obstructive pulmonary disease." "idioma" => "en" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "Rabe KF" 1 => "Wedzicha JA." ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:3 [ "tituloSerie" => "Lancet. " "fecha" => "2011" "volumen" => "378:1038-47." ] ] ] ] ] ] 12 => array:3 [ "identificador" => "bib110" "etiqueta" => "13" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Tiotropium versus salmeterol for the prevention of exacerbations of COPD. N Engl J Med. 2011; 364:1093-103. " "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "Tiotropium versus salmeterol for the prevention of exacerbations of COPD." "idioma" => "en" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:7 [ 0 => "Vogelmeier C" 1 => "Hederer B" 2 => "Glaab T" 3 => "Schmidt H" 4 => "Rutten-van Molken MP" 5 => "Beeh KM" 6 => "et-al." ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:3 [ "tituloSerie" => "N Engl J Med. " "fecha" => "2011" "volumen" => "364:1093-103." ] ] ] ] ] ] 13 => array:3 [ "identificador" => "bib111" "etiqueta" => "14" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Susceptibility to exacerbation in chronic obstructive pulmonary disease. N Engl J Med. 2010; 363:1128-38. " "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "Susceptibility to exacerbation in chronic obstructive pulmonary disease." "idioma" => "en" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:7 [ 0 => "Hurst JR" 1 => "Vestbo J" 2 => "Anzueto A" 3 => "Locantore N" 4 => "Mullerova H" 5 => "Tal-Singer R" 6 => "et-al." ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:3 [ "tituloSerie" => "N Engl J Med. " "fecha" => "2010" "volumen" => "363:1128-38." ] ] ] ] ] ] 14 => array:3 [ "identificador" => "bib112" "etiqueta" => "15" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Salmeterol and fluticasone propionate and survival in chronic obstructive pulmonary disease. N Engl J Med. 2007; 356:775-89. " "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "Salmeterol and fluticasone propionate and survival in chronic obstructive pulmonary disease." "idioma" => "en" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:7 [ 0 => "Calverley PM" 1 => "Anderson JA" 2 => "Celli B" 3 => "Ferguson GT" 4 => "Jenkins C" 5 => "Jones PW" 6 => "et-al." ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:3 [ "tituloSerie" => "N Engl J Med. " "fecha" => "2007" "volumen" => "356:775-89." ] ] ] ] ] ] 15 => array:3 [ "identificador" => "bib113" "etiqueta" => "16" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Effect of tiotropium on outcomes in patients with moderate chronic obstructive pulmonary disease (UPLIFT): a prespecified subgroup analysis of a randomised controlled trial. Lancet. 2009; 374:1171-8. " "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "Effect of tiotropium on outcomes in patients with moderate chronic obstructive pulmonary disease (UPLIFT): a prespecified subgroup analysis of a randomised controlled trial." "idioma" => "en" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ 0 => "Decramer M" 1 => "Celli B" 2 => "Kesten S" 3 => "Lystig T" 4 => "Mehra S" 5 => "Tashkin DP." ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:3 [ "tituloSerie" => "Lancet. " "fecha" => "2009" "volumen" => "374:1171-8." ] ] ] ] ] ] 16 => array:3 [ "identificador" => "bib114" "etiqueta" => "17" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Global Strategy for the Diagnosis, Management and Prevention of Chronic Obstructive Pulmonary Disease (Revised). 2011. " "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "Global Strategy for the Diagnosis, Management and Prevention of Chronic Obstructive Pulmonary Disease (Revised)." "idioma" => "en" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ 0 => "Global Initiative for Chronic Obstructive Lung Disease." ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:1 [ "tituloSerie" => "2011. " ] ] ] ] ] ] 17 => array:3 [ "identificador" => "bib115" "etiqueta" => "18" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Prediction of the clinical course of chronic obstructive pulmonary disease, using the new GOLD classification: a study of the general population. Am J Respir Crit Care Med. 2012; 186:975-81. " "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "Prediction of the clinical course of chronic obstructive pulmonary disease, using the new GOLD classification: a study of the general population." "idioma" => "en" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:7 [ 0 => "Lange P" 1 => "Marott JL" 2 => "Vestbo J" 3 => "Olsen KR" 4 => "Ingebrigtsen TS" 5 => "Dahl M" 6 => "et-al." ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:3 [ "tituloSerie" => "Am J Respir Crit Care Med. " "fecha" => "2012" "volumen" => "186:975-81." ] ] ] ] ] ] 18 => array:3 [ "identificador" => "bib116" "etiqueta" => "19" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Efficacy and safety of once-daily QVA149 compared with twice-daily salmeterol-fluticasone in patients with chronic obstructive pulmonary disease (ILLUMINATE): a randomised, double-blind, parallel group study. Lancet Respir Med. 2013; 1:51-60. " "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "Efficacy and safety of once-daily QVA149 compared with twice-daily salmeterol-fluticasone in patients with chronic obstructive pulmonary disease (ILLUMINATE): a randomised, double-blind, parallel group study." "idioma" => "en" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:7 [ 0 => "Vogelmeier CF" 1 => "Bateman ED" 2 => "Pallante J" 3 => "Alagappan VK" 4 => "D’Andrea P" 5 => "Chen H" 6 => "et-al." ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:3 [ "tituloSerie" => "Lancet Respir Med. " "fecha" => "2013" "volumen" => "1:51-60." ] ] ] ] ] ] 19 => array:3 [ "identificador" => "bib117" "etiqueta" => "20" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Efficacy and safety of once-daily QVA149 compared with twice-daily salmeterol/fluticasone combination (SFC) in patients with COPD: the LANTERN study. Poster Presented at the European Respiratory Society Annual Congress. 6-10 September 2014, Munich, Germany. 2014. A2331. " "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "Efficacy and safety of once-daily QVA149 compared with twice-daily salmeterol/fluticasone combination (SFC) in patients with COPD: the LANTERN study. Poster Presented at the European Respiratory Society Annual Congress. 6-10 September 2014, Munich, Germany. 2014." "idioma" => "en" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:7 [ 0 => "Zhong N" 1 => "Wang C" 2 => "Zhou X" 3 => "Zhang N" 4 => "Patalano F" 5 => "Humphries M" 6 => "et-al." ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:1 [ "tituloSerie" => "A2331. " ] ] ] ] ] ] 20 => array:3 [ "identificador" => "bib118" "etiqueta" => "21" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Analysis of chronic obstructive pulmonary disease exacerbations with the dual bronchodilator QVA149 compared with glycopyrronium and tiotropium (SPARK): a randomised, double-blind, parallel-group study. Lancet Respir Med. 2013; 1:199-209. " "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "Analysis of chronic obstructive pulmonary disease exacerbations with the dual bronchodilator QVA149 compared with glycopyrronium and tiotropium (SPARK): a randomised, double-blind, parallel-group study." "idioma" => "en" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:7 [ 0 => "Wedzicha JA" 1 => "Decramer M" 2 => "Ficker JH" 3 => "Niewoehner DE" 4 => "Sandstrom T" 5 => "Taylor AF" 6 => "et-al." ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:3 [ "tituloSerie" => "Lancet Respir Med. " "fecha" => "2013" "volumen" => "1:199-209." ] ] ] ] ] ] 21 => array:3 [ "identificador" => "bib119" "etiqueta" => "22" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Tailoring of corticosteroids in COPD management. Curr Respir Care Rep. 2014; 3:121-32. " "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "Tailoring of corticosteroids in COPD management." "idioma" => "en" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "De Coster DA" 1 => "Jones M." ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:3 [ "tituloSerie" => "Curr Respir Care Rep. " "fecha" => "2014" "volumen" => "3:121-32." ] ] ] ] ] ] 22 => array:3 [ "identificador" => "bib120" "etiqueta" => "23" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Severe acute exacerbations and mortality in patients with chronic obstructive pulmonary disease. Thorax. 2005; 60:925-31. " "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "Severe acute exacerbations and mortality in patients with chronic obstructive pulmonary disease." "idioma" => "en" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ 0 => "Soler-Cataluna JJ" 1 => "Martinez-Garcia MA" 2 => "Roman Sanchez P" 3 => "Salcedo E" 4 => "Navarro M" 5 => "Ochando R." ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:3 [ "tituloSerie" => "Thorax. " "fecha" => "2005" "volumen" => "60:925-31." ] ] ] ] ] ] 23 => array:3 [ "identificador" => "bib121" "etiqueta" => "24" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Withdrawal of inhaled glucocorticoids and exacerbations of COPD. N Engl J Med. 2014; 371:1285-94. " "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "Withdrawal of inhaled glucocorticoids and exacerbations of COPD." "idioma" => "en" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:7 [ 0 => "Magnussen H" 1 => "Disse B" 2 => "Rodriguez-Roisin R" 3 => "Kirsten A" 4 => "Watz H" 5 => "Tetzlaff K" 6 => "et-al." ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:3 [ "tituloSerie" => "N Engl J Med. " "fecha" => "2014" "volumen" => "371:1285-94." ] ] ] ] ] ] 24 => array:3 [ "identificador" => "bib122" "etiqueta" => "25" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "The prevention of chronic obstructive pulmonary disease exacerbations by salmeterol/fluticasone propionate or tiotropium bromide. Am J Respir Crit Care Med. 2008; 177:19-26. " "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "The prevention of chronic obstructive pulmonary disease exacerbations by salmeterol/fluticasone propionate or tiotropium bromide." "idioma" => "en" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ 0 => "Wedzicha JA" 1 => "Calverley PM" 2 => "Seemungal TA" 3 => "Hagan G" 4 => "Ansari Z" 5 => "Stockley RA." ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:3 [ "tituloSerie" => "Am J Respir Crit Care Med. " "fecha" => "2008" "volumen" => "177:19-26." ] ] ] ] ] ] 25 => array:3 [ "identificador" => "bib123" "etiqueta" => "26" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Dual bronchodilation with QVA149 versus single bronchodilator therapy: the SHINE study. Eur Respir J. 2013; 42:1484-94. " "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "Dual bronchodilation with QVA149 versus single bronchodilator therapy: the SHINE study." "idioma" => "en" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:7 [ 0 => "Bateman ED" 1 => "Ferguson GT" 2 => "Barnes N" 3 => "Gallagher N" 4 => "Green Y" 5 => "Henley M" 6 => "et-al." ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:3 [ "tituloSerie" => "Eur Respir J. " "fecha" => "2013" "volumen" => "42:1484-94." ] ] ] ] ] ] 26 => array:3 [ "identificador" => "bib124" "etiqueta" => "27" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Dual bronchodilation with QVA149 reduces patient-reported dyspnoea in COPD: the BLAZE study. Eur Respir J. 2014; 43:1599-609. " "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "Dual bronchodilation with QVA149 reduces patient-reported dyspnoea in COPD: the BLAZE study." "idioma" => "en" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:7 [ 0 => "Mahler DA" 1 => "Decramer M" 2 => "D’Urzo A" 3 => "Worth H" 4 => "White T" 5 => "Alagappan VK" 6 => "et-al." ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:3 [ "tituloSerie" => "Eur Respir J. " "fecha" => "2014" "volumen" => "43:1599-609." ] ] ] ] ] ] 27 => array:3 [ "identificador" => "bib125" "etiqueta" => "28" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Tiotropium in combination with placebo, salmeterol, or fluticasone-salmeterol for treatment of chronic obstructive pulmonary disease: a randomized trial. Ann Intern Med. 2007; 146:545-55. " "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "Tiotropium in combination with placebo, salmeterol, or fluticasone-salmeterol for treatment of chronic obstructive pulmonary disease: a randomized trial." "idioma" => "en" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:7 [ 0 => "Aaron SD" 1 => "Vandemheen KL" 2 => "Fergusson D" 3 => "Maltais F" 4 => "Bourbeau J" 5 => "Goldstein R" 6 => "et-al." ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:3 [ "tituloSerie" => "Ann Intern Med. " "fecha" => "2007" "volumen" => "146:545-55." ] ] ] ] ] ] 28 => array:3 [ "identificador" => "bib126" "etiqueta" => "29" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "GINA Global Strategy for Asthma Management and Prevention. 2014. " "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "GINA Global Strategy for Asthma Management and Prevention." "idioma" => "en" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ 0 => "Global Initiative for Asthma (GINA)." ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:1 [ "tituloSerie" => "2014. " ] ] ] ] ] ] 29 => array:3 [ "identificador" => "bib127" "etiqueta" => "30" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Management and prevention of exacerbations of COPD. BMJ. 2014; 349:g5237. " "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "Management and prevention of exacerbations of COPD." "idioma" => "en" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ 0 => "Aaron SD." ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:3 [ "tituloSerie" => "BMJ. " "fecha" => "2014" "volumen" => "349:g5237." ] ] ] ] ] ] 30 => array:3 [ "identificador" => "bib128" "etiqueta" => "31" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Inhaled steroids in COPD: when should they be used. Lancet Respir Med. 2014; 2:869-71. " "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "Inhaled steroids in COPD: when should they be used." "idioma" => "en" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "Agusti A" 1 => "Fabbri LM." ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:3 [ "tituloSerie" => "Lancet Respir Med. " "fecha" => "2014" "volumen" => "2:869-71." ] ] ] ] ] ] 31 => array:3 [ "identificador" => "bib129" "etiqueta" => "32" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Appropriateness of triple therapy after COPD exacerbation. Can J Hosp Pharm. 2013; 66:41-2. " "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "Appropriateness of triple therapy after COPD exacerbation." "idioma" => "en" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ 0 => "Manderville JR." ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:3 [ "tituloSerie" => "Can J Hosp Pharm. " "fecha" => "2013" "volumen" => "66:41-2." ] ] ] ] ] ] 32 => array:3 [ "identificador" => "bib130" "etiqueta" => "33" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Effects of tiotropium and salmeterol/fluticasone propionate on airway wall thickness in chronic obstructive pulmonary disease. Respiration. 2013; 86:280-7. " "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "Effects of tiotropium and salmeterol/fluticasone propionate on airway wall thickness in chronic obstructive pulmonary disease." "idioma" => "en" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "Hoshino M" 1 => "Ohtawa J." ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:3 [ "tituloSerie" => "Respiration. " "fecha" => "2013" "volumen" => "86:280-7." ] ] ] ] ] ] 33 => array:3 [ "identificador" => "bib131" "etiqueta" => "34" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Triple combinations in chronic obstructive pulmonary disease – is three better than two. Expert Opin Pharmacother. 2014; 15:2475-8. " "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "Triple combinations in chronic obstructive pulmonary disease – is three better than two." "idioma" => "en" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "Cazzola M" 1 => "Matera MG." ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:3 [ "tituloSerie" => "Expert Opin Pharmacother. " "fecha" => "2014" "volumen" => "15:2475-8." ] ] ] ] ] ] 34 => array:3 [ "identificador" => "bib132" "etiqueta" => "35" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Management of chronic obstructive pulmonary disease in patients admitted to a tertiary care centre for exacerbation of their disease. Can J Hosp Pharm. 2012; 65:373-9. " "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "Management of chronic obstructive pulmonary disease in patients admitted to a tertiary care centre for exacerbation of their disease." "idioma" => "en" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:7 [ 0 => "Dault R" 1 => "Dube AI" 2 => "Blais L" 3 => "Boileau R" 4 => "Larrivee P" 5 => "Dumas ME" 6 => "et-al." ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:3 [ "tituloSerie" => "Can J Hosp Pharm. " "fecha" => "2012" "volumen" => "65:373-9." ] ] ] ] ] ] 35 => array:3 [ "identificador" => "bib133" "etiqueta" => "36" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Impact of long-acting bronchodilators and exposure to inhaled corticosteroids on mortality in COPD: a real-life retrospective cohort study. Lung. 2014; 192:649-52. " "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "Impact of long-acting bronchodilators and exposure to inhaled corticosteroids on mortality in COPD: a real-life retrospective cohort study." "idioma" => "en" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ 0 => "Manoharan A" 1 => "Short PM" 2 => "Anderson WJ" 3 => "Lipworth BJ." ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:3 [ "tituloSerie" => "Lung. " "fecha" => "2014" "volumen" => "192:649-52." ] ] ] ] ] ] 36 => array:3 [ "identificador" => "bib134" "etiqueta" => "37" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Triple therapy for the management of COPD: a review. COPD. 2011; 8:206-43. " "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "Triple therapy for the management of COPD: a review." "idioma" => "en" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:7 [ 0 => "Gaebel K" 1 => "McIvor RA" 2 => "Xie F" 3 => "Blackhouse G" 4 => "Robertson D" 5 => "Assasi N" 6 => "et-al." ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:3 [ "tituloSerie" => "COPD. " "fecha" => "2011" "volumen" => "8:206-43." ] ] ] ] ] ] 37 => array:3 [ "identificador" => "bib135" "etiqueta" => "38" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Advances in asthma and COPD treatment: combination therapy with inhaled corticosteroids and long-acting beta 2-agonists. Curr Pharm Des. 2006; 12:3261-79. " "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "Advances in asthma and COPD treatment: combination therapy with inhaled corticosteroids and long-acting beta 2-agonists." "idioma" => "en" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "Miller-Larsson A" 1 => "Selroos O." ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:3 [ "tituloSerie" => "Curr Pharm Des. " "fecha" => "2006" "volumen" => "12:3261-79." ] ] ] ] ] ] 38 => array:3 [ "identificador" => "bib136" "etiqueta" => "39" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Trends in management and outcomes of COPD patients in primary care, 2000–2009: a retrospective cohort study. NPJ Prim Care Respir Med. 2014; 24:14015. " "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "Trends in management and outcomes of COPD patients in primary care, 2000–2009: a retrospective cohort study." "idioma" => "en" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ 0 => "James GD" 1 => "Donaldson GC" 2 => "Wedzicha JA" 3 => "Nazareth I." ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:3 [ "tituloSerie" => "NPJ Prim Care Respir Med. " "fecha" => "2014" "volumen" => "24:14015." ] ] ] ] ] ] 39 => array:3 [ "identificador" => "bib137" "etiqueta" => "40" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "The ADMIT series – Issues in inhalation therapy. 4) How to choose inhaler devices for the treatment of COPD. Prim Care Respir J. 2010; 19:10-20. " "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "The ADMIT series – Issues in inhalation therapy. 4) How to choose inhaler devices for the treatment of COPD." "idioma" => "en" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => "Vincken W" 1 => "Dekhuijzen PR" 2 => "Barnes P." ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:3 [ "tituloSerie" => "Prim Care Respir J. " "fecha" => "2010" "volumen" => "19:10-20." ] ] ] ] ] ] 40 => array:3 [ "identificador" => "bib138" "etiqueta" => "41" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Delivery characteristics and patients’ handling of two single-dose dry-powder inhalers used in COPD. Int J Chron Obstruct Pulmon Dis. 2011; 6:353-63. " "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "Delivery characteristics and patients’ handling of two single-dose dry-powder inhalers used in COPD." "idioma" => "en" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:7 [ 0 => "Chapman KR" 1 => "Fogarty CM" 2 => "Peckitt C" 3 => "Lassen C" 4 => "Jadayel D" 5 => "Dederichs J" 6 => "et-al." ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:3 [ "tituloSerie" => "Int J Chron Obstruct Pulmon Dis. " "fecha" => "2011" "volumen" => "6:353-63." ] ] ] ] ] ] 41 => array:3 [ "identificador" => "bib139" "etiqueta" => "42" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Delivery characteristics of a low-resistance dry-powder inhaler used to deliver the longacting muscarinic antagonist glycopyrronium. J Drug Assess. 2013; 2:11-6. " "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "Delivery characteristics of a low-resistance dry-powder inhaler used to deliver the longacting muscarinic antagonist glycopyrronium." "idioma" => "en" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ 0 => "Colthorpe P" 1 => "Voshaar T" 2 => "Kieckbusch T" 3 => "Cuoghi E" 4 => "Jauernig J." ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:3 [ "tituloSerie" => "J Drug Assess. " "fecha" => "2013" "volumen" => "2:11-6." ] ] ] ] ] ] 42 => array:3 [ "identificador" => "bib140" "etiqueta" => "43" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Dual-pharmacology muscarinic antagonist and beta(2) agonist molecules for the treatment of chronic obstructive pulmonary disease. Future Med Chem. 2011; 3:1585-605. " "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "Dual-pharmacology muscarinic antagonist and beta(2) agonist molecules for the treatment of chronic obstructive pulmonary disease." "idioma" => "en" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "Hughes AD" 1 => "Jones LH." ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:3 [ "tituloSerie" => "Future Med Chem. " "fecha" => "2011" "volumen" => "3:1585-605." ] ] ] ] ] ] 43 => array:3 [ "identificador" => "bib141" "etiqueta" => "44" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Study to Determine the Pharmacokinetics of GSK961081 and Fluticasone Furoate When Administered Alone or in Combination. 2014. <inter-ref>https://www.clinicaltrials.gov/ct2/show/study/NCT02064504?term=MABA&rank=1</inter-ref>. " "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "Study to Determine the Pharmacokinetics of GSK961081 and Fluticasone Furoate When Administered Alone or in Combination. 2014. https://www. " "idioma" => "en" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ 0 => "GlaxoSmithKline." ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:1 [ "tituloSerie" => "clinicaltrials. " ] ] ] ] ] ] 44 => array:3 [ "identificador" => "bib142" "etiqueta" => "45" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Doenças Respiratórias em Números. Portugal. 2014. " "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "Doenças Respiratórias em Números. Portugal." "idioma" => "pt" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ 0 => "Direcção Geral de Saúde." ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:1 [ "tituloSerie" => "2014. " ] ] ] ] ] ] 45 => array:3 [ "identificador" => "bib143" "etiqueta" => "46" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Effect of carbocisteine on acute exacerbation of chronic obstructive pulmonary disease (PEACE Study): a randomised placebo-controlled study. Lancet. 2008; 371:2013-8. " "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "Effect of carbocisteine on acute exacerbation of chronic obstructive pulmonary disease (PEACE Study): a randomised placebo-controlled study." "idioma" => "en" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:7 [ 0 => "Zheng JP" 1 => "Kang J" 2 => "Huang SG" 3 => "Chen P" 4 => "Yao WZ" 5 => "Yang L" 6 => "et-al." ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:3 [ "tituloSerie" => "Lancet. " "fecha" => "2008" "volumen" => "371:2013-8." ] ] ] ] ] ] 46 => array:3 [ "identificador" => "bib144" "etiqueta" => "47" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "High-dose N-acetylcysteine in stable COPD: the 1-year, double-blind, randomized, placebo-controlled HIACE study. Chest. 2013; 144:106-18. " "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "High-dose N-acetylcysteine in stable COPD: the 1-year, double-blind, randomized, placebo-controlled HIACE study." "idioma" => "en" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:7 [ 0 => "Tse HN" 1 => "Raiteri L" 2 => "Wong KY" 3 => "Yee KS" 4 => "Ng LY" 5 => "Wai KY" 6 => "et-al." ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:3 [ "tituloSerie" => "Chest. " "fecha" => "2013" "volumen" => "144:106-18." ] ] ] ] ] ] 47 => array:3 [ "identificador" => "bib145" "etiqueta" => "48" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Antioxidants and mucolytics in COPD management: when (if ever) and in whom. Curr Drug Targets. 2013; 14:225-34. " "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "Antioxidants and mucolytics in COPD management: when (if ever) and in whom." "idioma" => "en" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ 0 => "Hillas G" 1 => "Nikolakopoulou S" 2 => "Hussain S" 3 => "Vassilakopoulos T." ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:3 [ "tituloSerie" => "Curr Drug Targets. " "fecha" => "2013" "volumen" => "14:225-34." ] ] ] ] ] ] 48 => array:3 [ "identificador" => "bib146" "etiqueta" => "49" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Effect of high/low dose N-acetylcysteine on chronic obstructive pulmonary disease: a systematic review and meta-analysis. COPD. 2014; 11:351-8. " "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "Effect of high/low dose N-acetylcysteine on chronic obstructive pulmonary disease: a systematic review and meta-analysis." "idioma" => "en" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ 0 => "Shen Y" 1 => "Cai W" 2 => "Lei S" 3 => "Zhang Z." ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:3 [ "tituloSerie" => "COPD. " "fecha" => "2014" "volumen" => "11:351-8." ] ] ] ] ] ] 49 => array:3 [ "identificador" => "bib147" "etiqueta" => "50" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Benefits of high-dose N-acetylcysteine to exacerbation-prone patients with COPD. Chest. 2014; 146:611-23. " "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "Benefits of high-dose N-acetylcysteine to exacerbation-prone patients with COPD." "idioma" => "en" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ 0 => "Tse HN" 1 => "Raiteri L" 2 => "Wong KY" 3 => "Ng LY" 4 => "Yee KS" 5 => "Tseng CZ." ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:3 [ "tituloSerie" => "Chest. " "fecha" => "2014" "volumen" => "146:611-23." ] ] ] ] ] ] 50 => array:3 [ "identificador" => "bib148" "etiqueta" => "51" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Twice daily N-acetylcysteine 600\u{A0}mg for exacerbations of chronic obstructive pulmonary disease (PANTHEON): a randomised, double-blind placebo-controlled trial. Lancet Respir Med. 2014; 2:187-94. " "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "Twice daily N-acetylcysteine 600 mg for exacerbations of chronic obstructive pulmonary disease (PANTHEON): a randomised, double-blind placebo-controlled trial." "idioma" => "en" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:7 [ 0 => "Zheng JP" 1 => "Wen FQ" 2 => "Bai CX" 3 => "Wan HY" 4 => "Kang J" 5 => "Chen P" 6 => "et-al." ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:3 [ "tituloSerie" => "Lancet Respir Med. " "fecha" => "2014" "volumen" => "2:187-94." ] ] ] ] ] ] 51 => array:3 [ "identificador" => "bib149" "etiqueta" => "52" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "N-acetylcysteine for COPD: the evidence remains inconclusive. Lancet Respir Med. 2014; 2:e3. " "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "N-acetylcysteine for COPD: the evidence remains inconclusive." "idioma" => "en" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "Turner RD" 1 => "Bothamley GH." ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:3 [ "tituloSerie" => "Lancet Respir Med. " "fecha" => "2014" "volumen" => "2:e3." ] ] ] ] ] ] 52 => array:3 [ "identificador" => "bib150" "etiqueta" => "53" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "N-acetylcysteine in COPD may be beneficial, but for whom. Lancet Respir Med. 2014; 2:166-7. " "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "N-acetylcysteine in COPD may be beneficial, but for whom." "idioma" => "en" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "Cazzola M" 1 => "Matera MG." ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:3 [ "tituloSerie" => "Lancet Respir Med. " "fecha" => "2014" "volumen" => "2:166-7." ] ] ] ] ] ] 53 => array:3 [ "identificador" => "bib151" "etiqueta" => "54" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "N-acetylcysteine in patients with COPD exacerbations associated with increased sputum. Wien Klin Wochenschr. 2015. " "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "N-acetylcysteine in patients with COPD exacerbations associated with increased sputum. Wien Klin Wochenschr." "idioma" => "en" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ 0 => "Ayfer Aytemur Z" 1 => "Baysak A" 2 => "Ozdemir O" 3 => "Kose T" 4 => "Sayiner A." ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:1 [ "tituloSerie" => "2015. " ] ] ] ] ] ] 54 => array:3 [ "identificador" => "bib152" "etiqueta" => "55" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Effects of N-acetylcysteine on outcomes in chronic obstructive pulmonary disease (Bronchitis Randomized on NAC Cost-Utility Study, BRONCUS): a randomised placebo-controlled trial. Lancet. 2005; 365:1552-60. " "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "Effects of N-acetylcysteine on outcomes in chronic obstructive pulmonary disease (Bronchitis Randomized on NAC Cost-Utility Study, BRONCUS): a randomised placebo-controlled trial." "idioma" => "en" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:7 [ 0 => "Decramer M" 1 => "Rutten-van Molken M" 2 => "Dekhuijzen PN" 3 => "Troosters T" 4 => "van Herwaarden C" 5 => "Pellegrino R" 6 => "et-al." ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:3 [ "tituloSerie" => "Lancet. " "fecha" => "2005" "volumen" => "365:1552-60." ] ] ] ] ] ] 55 => array:3 [ "identificador" => "bib153" "etiqueta" => "56" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "The therapeutic efficacy of erdosteine in the treatment of chronic obstructive bronchitis: a meta-analysis of individual patient data. Pulm Pharmacol Ther. 2010; 23:135-44. " "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "The therapeutic efficacy of erdosteine in the treatment of chronic obstructive bronchitis: a meta-analysis of individual patient data." "idioma" => "en" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => "Cazzola M" 1 => "Floriani I" 2 => "Page CP." ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:3 [ "tituloSerie" => "Pulm Pharmacol Ther. " "fecha" => "2010" "volumen" => "23:135-44." ] ] ] ] ] ] 56 => array:3 [ "identificador" => "bib154" "etiqueta" => "57" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Database of Abstracts of Reviews of Effects (DARE): Quality-assessed Reviews. The therapeutic efficacy of erdosteine in the treatment of chronic obstructive bronchitis: a meta-analysis of individual patient data. 2011. <inter-ref>http://wwwncbinlmnihgov/pubmedhealth/PMH0029749/</inter-ref>. " "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Database of Abstracts of Reviews of Effects (DARE): Quality-assessed Reviews. The therapeutic efficacy of erdosteine in the treatment of chronic obstructive bronchitis: a meta-analysis of individual patient data." "idioma" => "en" ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:1 [ "tituloSerie" => "2011. " ] ] ] ] ] ] 57 => array:3 [ "identificador" => "bib155" "etiqueta" => "58" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Antibiotic prophylaxis in COPD: why, when, and for whom?. Pulm Pharmacol Ther. 2014. " "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "Antibiotic prophylaxis in COPD: why, when, and for whom?. Pulm Pharmacol Ther." "idioma" => "en" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "Miravitlles M" 1 => "Anzueto A." ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:1 [ "tituloSerie" => "2014. " ] ] ] ] ] ] 58 => array:3 [ "identificador" => "bib156" "etiqueta" => "59" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Prophylactic antibiotic therapy for chronic obstructive pulmonary disease (COPD). CDS Rev. 2013; 11:CD009764. " "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "Prophylactic antibiotic therapy for chronic obstructive pulmonary disease (COPD)." "idioma" => "en" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "Herath SC" 1 => "Poole P." ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:3 [ "tituloSerie" => "CDS Rev. " "fecha" => "2013" "volumen" => "11:CD009764." ] ] ] ] ] ] 59 => array:3 [ "identificador" => "bib157" "etiqueta" => "60" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Azithromycin maintenance treatment in patients with frequent exacerbations of chronic obstructive pulmonary disease (COLUMBUS): a randomised, double-blind, placebo-controlled trial. Lancet Respir Med. 2014; 2:361-8. " "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "Azithromycin maintenance treatment in patients with frequent exacerbations of chronic obstructive pulmonary disease (COLUMBUS): a randomised, double-blind, placebo-controlled trial." "idioma" => "en" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:7 [ 0 => "Uzun S" 1 => "Djamin RS" 2 => "Kluytmans JA" 3 => "Mulder PG" 4 => "van’t Veer NE" 5 => "Ermens AA" 6 => "et-al." ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:3 [ "tituloSerie" => "Lancet Respir Med. " "fecha" => "2014" "volumen" => "2:361-8." ] ] ] ] ] ] 60 => array:3 [ "identificador" => "bib158" "etiqueta" => "61" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Predictors of chronic obstructive pulmonary disease exacerbation reduction in response to daily azithromycin therapy. Am J Respir Crit Care Med. 2014; 189:1503-8. " "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "Predictors of chronic obstructive pulmonary disease exacerbation reduction in response to daily azithromycin therapy." "idioma" => "en" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:7 [ 0 => "Han MK" 1 => "Tayob N" 2 => "Murray S" 3 => "Dransfield MT" 4 => "Washko G" 5 => "Scanlon PD" 6 => "et-al." ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:3 [ "tituloSerie" => "Am J Respir Crit Care Med. " "fecha" => "2014" "volumen" => "189:1503-8." ] ] ] ] ] ] 61 => array:3 [ "identificador" => "bib159" "etiqueta" => "62" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "exacerbations with macrolides: a review and budget impact analysis. Respir Med. 2013; 107:637-48. " "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "exacerbations with macrolides: a review and budget impact analysis." "idioma" => "en" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ 0 => "Simoens S" 1 => "Laekeman G" 2 => "Decramer M" 3 => "Preventing COPD." ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:3 [ "tituloSerie" => "Respir Med. " "fecha" => "2013" "volumen" => "107:637-48." ] ] ] ] ] ] 62 => array:3 [ "identificador" => "bib160" "etiqueta" => "63" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Reply: azithromycin we’re there!. Am J Respir Crit Care Med. 2014; 190:1075-6. " "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "Reply: azithromycin we’re there!." "idioma" => "en" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "Restrepo MI" 1 => "Anzueto A." ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:3 [ "tituloSerie" => "Am J Respir Crit Care Med. " "fecha" => "2014" "volumen" => "190:1075-6." ] ] ] ] ] ] 63 => array:3 [ "identificador" => "bib161" "etiqueta" => "64" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Preventing COPD exacerbations: budget impact of a respiratory day hospital and long-term azithromycin therapy. Respir Med. 2014; 108:1064. " "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "Preventing COPD exacerbations: budget impact of a respiratory day hospital and long-term azithromycin therapy." "idioma" => "en" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "Pomares Amigo X" 1 => "Monton Soler C." ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:3 [ "tituloSerie" => "Respir Med. " "fecha" => "2014" "volumen" => "108:1064." ] ] ] ] ] ] 64 => array:3 [ "identificador" => "bib162" "etiqueta" => "65" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Preventing COPD exacerbations with macrolides: a review and budget impact analysis – author response to letter to the editor. Respir Med. 2014; 108:1065. " "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "Preventing COPD exacerbations with macrolides: a review and budget impact analysis – author response to letter to the editor." "idioma" => "en" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => "Simoens S" 1 => "Laekeman G" 2 => "Decramer M." ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:3 [ "tituloSerie" => "Respir Med. " "fecha" => "2014" "volumen" => "108:1065." ] ] ] ] ] ] 65 => array:3 [ "identificador" => "bib163" "etiqueta" => "66" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Azithromycin for patients with frequent COPD exacerbations. Lancet Respir Med. 2014; 2:340-1. " "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "Azithromycin for patients with frequent COPD exacerbations." "idioma" => "en" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "Wong C" 1 => "Herath S." ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:3 [ "tituloSerie" => "Lancet Respir Med. " "fecha" => "2014" "volumen" => "2:340-1." ] ] ] ] ] ] 66 => array:3 [ "identificador" => "bib164" "etiqueta" => "67" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Phosphodiesterase 4 inhibitors for chronic obstructive pulmonary disease. CDS Rev. 2013; 11:CD002309. " "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "Phosphodiesterase 4 inhibitors for chronic obstructive pulmonary disease." "idioma" => "en" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => "Chong J" 1 => "Leung B" 2 => "Poole P." ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:3 [ "tituloSerie" => "CDS Rev. " "fecha" => "2013" "volumen" => "11:CD002309." ] ] ] ] ] ] 67 => array:3 [ "identificador" => "bib165" "etiqueta" => "68" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Efficacy and safety of roflumilast in patients with chronic obstructive pulmonary disease: a systematic review and meta-analysis. Ther Adv Respir Dis. 2013; 7:13-24. " "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "Efficacy and safety of roflumilast in patients with chronic obstructive pulmonary disease: a systematic review and meta-analysis." "idioma" => "en" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "Oba Y" 1 => "Lone NA." ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:3 [ "tituloSerie" => "Ther Adv Respir Dis. " "fecha" => "2013" "volumen" => "7:13-24." ] ] ] ] ] ] 68 => array:3 [ "identificador" => "bib166" "etiqueta" => "69" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Response. Chest. 2014; 145:428. " "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "Response." "idioma" => "fr" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:7 [ 0 => "Wedzicha JA" 1 => "Rabe KF" …5 ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:3 [ "tituloSerie" => "Chest. " "fecha" => "2014" "volumen" => "145:428." ] ] ] ] ] ] 69 => array:3 [ "identificador" => "bib167" "etiqueta" => "70" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Point: were industry-sponsored roflumilast trials appropriate? Yes. Chest. 2014; 145:937-9. " "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "Point: were industry-sponsored roflumilast trials appropriate? Yes." "idioma" => "en" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ …2] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:3 [ "tituloSerie" => "Chest. " "fecha" => "2014" "volumen" => "145:937-9." ] ] ] ] ] ] 70 => array:3 [ "identificador" => "bib168" "etiqueta" => "71" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Counterpoint: were industry-sponsored roflumilast trials appropriate? No. Chest. 2014; 145:939-42. " "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "Counterpoint: were industry-sponsored roflumilast trials appropriate? No." "idioma" => "en" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ …3] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:3 [ "tituloSerie" => "Chest. " "fecha" => "2014" "volumen" => "145:939-42." ] ] ] ] ] ] 71 => array:3 [ "identificador" => "bib169" "etiqueta" => "72" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Effect of roflumilast on exacerbations in patients with severe chronic obstructive pulmonary disease uncontrolled by combination therapy (REACT): a multicentre randomised controlled trial. Lancet. 2015; 385:857-66. " "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "Effect of roflumilast on exacerbations in patients with severe chronic obstructive pulmonary disease uncontrolled by combination therapy (REACT): a multicentre randomised controlled trial." "idioma" => "en" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ …6] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:3 [ "tituloSerie" => "Lancet. " "fecha" => "2015" "volumen" => "385:857-66." ] ] ] ] ] ] 72 => array:3 [ "identificador" => "bib170" "etiqueta" => "73" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Roflumilast added to triple therapy in patients with severe COPD: a real life study. Pulm Pharmacol Ther. 2015; 30:16-21. " "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "Roflumilast added to triple therapy in patients with severe COPD: a real life study." "idioma" => "en" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:7 [ …7] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:3 [ "tituloSerie" => "Pulm Pharmacol Ther. " "fecha" => "2015" "volumen" => "30:16-21." ] ] ] ] ] ] 73 => array:3 [ "identificador" => "bib171" "etiqueta" => "74" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Am J Respir Crit Care Med. 2013; 188:901-6. " "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "Am J Respir Crit Care Med." "idioma" => "en" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ …2] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:2 [ "fecha" => "2013" "volumen" => "188:901-6." ] ] ] ] ] ] 74 => array:3 [ "identificador" => "bib172" "etiqueta" => "75" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "A meta-analysis on the efficacy of oral theophylline in patients with stable COPD. Int J Chron Obstruct Pulmon Dis. 2006; 1:261-6. " "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "A meta-analysis on the efficacy of oral theophylline in patients with stable COPD." "idioma" => "en" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ …2] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:3 [ "tituloSerie" => "Int J Chron Obstruct Pulmon Dis. " "fecha" => "2006" "volumen" => "1:261-6." ] ] ] ] ] ] 75 => array:3 [ "identificador" => "bib173" "etiqueta" => "76" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Efficacy of theophylline in people with stable chronic obstructive pulmonary disease: a systematic review and meta-analysis. Respir Med. 2005; 99:135-44. " "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "Efficacy of theophylline in people with stable chronic obstructive pulmonary disease: a systematic review and meta-analysis." "idioma" => "en" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:7 [ …7] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:3 [ "tituloSerie" => "Respir Med. " "fecha" => "2005" "volumen" => "99:135-44." ] ] ] ] ] ] 76 => array:3 [ "identificador" => "bib174" "etiqueta" => "77" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Methylxanthines for exacerbations of chronic obstructive pulmonary disease. CDS Rev. 2003; CD002168. " "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "Methylxanthines for exacerbations of chronic obstructive pulmonary disease." "idioma" => "en" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ …3] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:3 [ "tituloSerie" => "CDS Rev. " "fecha" => "2003" "volumen" => "CD002168." ] ] ] ] ] ] 77 => array:3 [ "identificador" => "bib175" "etiqueta" => "78" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Effects of an immunostimulating agent on acute exacerbations and hospitalizations in patients with chronic obstructive pulmonary disease. The PARI-IS Study Steering Committee and Research Group. Prevention of Acute Respiratory Infection by an Immunostimulant. Am J Respir Crit Care Med. 1997; 156:1719-24. " "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "Effects of an immunostimulating agent on acute exacerbations and hospitalizations in patients with chronic obstructive pulmonary disease. The PARI-IS Study Steering Committee and Research Group. Prevention of Acute Respiratory Infection by an Immunostimulant." "idioma" => "en" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ …6] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:3 [ "tituloSerie" => "Am J Respir Crit Care Med. " "fecha" => "1997" "volumen" => "156:1719-24." ] ] ] ] ] ] 78 => array:3 [ "identificador" => "bib176" "etiqueta" => "79" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Protective effect of a bacterial extract against acute exacerbation in patients with chronic bronchitis accompanied by chronic obstructive pulmonary disease. Chin Med J (Engl). 2004; 117:828-34. " "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "Protective effect of a bacterial extract against acute exacerbation in patients with chronic bronchitis accompanied by chronic obstructive pulmonary disease." "idioma" => "en" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ …6] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:3 [ "tituloSerie" => "Chin Med J (Engl). " "fecha" => "2004" "volumen" => "117:828-34." ] ] ] ] ] ] 79 => array:3 [ "identificador" => "bib177" "etiqueta" => "80" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Double-blind study of OM-85 in patients with chronic bronchitis or mild chronic obstructive pulmonary disease. Respiration. 2007; 74:26-32. " "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "Double-blind study of OM-85 in patients with chronic bronchitis or mild chronic obstructive pulmonary disease." "idioma" => "en" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ …3] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:3 [ "tituloSerie" => "Respiration. " "fecha" => "2007" "volumen" => "74:26-32." ] ] ] ] ] ] 80 => array:3 [ "identificador" => "bib178" "etiqueta" => "81" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Reduction of morbidity and mortality by statins, angiotensin-converting enzyme inhibitors, and angiotensin receptor blockers in patients with chronic obstructive pulmonary disease. J Am Coll Cardiol. 2006; 47:2554-60. " "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "Reduction of morbidity and mortality by statins, angiotensin-converting enzyme inhibitors, and angiotensin receptor blockers in patients with chronic obstructive pulmonary disease." "idioma" => "en" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ …6] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:3 [ "tituloSerie" => "J Am Coll Cardiol. " "fecha" => "2006" "volumen" => "47:2554-60." ] ] ] ] ] ] 81 => array:3 [ "identificador" => "bib179" "etiqueta" => "82" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Reducing mortality for chronic obstructive pulmonary disease: role of statins and angiotensin-converting enzyme inhibitors. Expert Rev Pharmacoecon Outcomes Res. 2009; 9:523-5. " "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "Reducing mortality for chronic obstructive pulmonary disease: role of statins and angiotensin-converting enzyme inhibitors." "idioma" => "en" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ …1] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:3 [ "tituloSerie" => "Expert Rev Pharmacoecon Outcomes Res. " "fecha" => "2009" "volumen" => "9:523-5." ] ] ] ] ] ] 82 => array:3 [ "identificador" => "bib180" "etiqueta" => "83" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Statins reduce all-cause mortality in chronic obstructive pulmonary disease: a systematic review and meta-analysis of observational studies. Respir Res. 2014; 15:80. " "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "Statins reduce all-cause mortality in chronic obstructive pulmonary disease: a systematic review and meta-analysis of observational studies." "idioma" => "en" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:7 [ …7] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:3 [ "tituloSerie" => "Respir Res. " "fecha" => "2014" "volumen" => "15:80." ] ] ] ] ] ] 83 => array:3 [ "identificador" => "bib181" "etiqueta" => "84" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Statins as emerging treatments for asthma and chronic obstructive pulmonary disease. Expert Rev Respir Med. 2008; 2:329-35. " "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "Statins as emerging treatments for asthma and chronic obstructive pulmonary disease." "idioma" => "en" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ …1] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:3 [ "tituloSerie" => "Expert Rev Respir Med. " "fecha" => "2008" "volumen" => "2:329-35." ] ] ] ] ] ] 84 => array:3 [ "identificador" => "bib182" "etiqueta" => "85" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Potential benefits of statins on morbidity and mortality in chronic obstructive pulmonary disease: a review of the evidence. Postgrad Med J. 2009; 85:414-21. " "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "Potential benefits of statins on morbidity and mortality in chronic obstructive pulmonary disease: a review of the evidence." "idioma" => "en" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ …3] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:3 [ "tituloSerie" => "Postgrad Med J. " "fecha" => "2009" "volumen" => "85:414-21." ] ] ] ] ] ] 85 => array:3 [ "identificador" => "bib183" "etiqueta" => "86" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Update on the potential role of statins in chronic obstructive pulmonary disease and its co-morbidities. Expert Rev Respir Med. 2013; 7:533-44. " "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "Update on the potential role of statins in chronic obstructive pulmonary disease and its co-morbidities." "idioma" => "en" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ …2] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:3 [ "tituloSerie" => "Expert Rev Respir Med. " "fecha" => "2013" "volumen" => "7:533-44." ] ] ] ] ] ] 86 => array:3 [ "identificador" => "bib184" "etiqueta" => "87" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Simvastatin Therapy for Moderate and Severe COPD (STATCOPE). 2015. <inter-ref>https://wwwclinicaltrialsgov/ct2/show?cond=copd&intr=statin&rank=8</inter-ref>. " "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "Simvastatin Therapy for Moderate and Severe COPD (STATCOPE)." "idioma" => "en" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ …1] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:1 [ "tituloSerie" => "2015. " ] ] ] ] ] ] 87 => array:3 [ "identificador" => "bib185" "etiqueta" => "88" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "A randomized controlled trial of angiotensin-converting enzyme inhibition for skeletal muscle dysfunction in COPD. Chest. 2014; 146:932-40. " "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "A randomized controlled trial of angiotensin-converting enzyme inhibition for skeletal muscle dysfunction in COPD." "idioma" => "en" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:7 [ …7] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:3 [ "tituloSerie" => "Chest. " "fecha" => "2014" "volumen" => "146:932-40." ] ] ] ] ] ] 88 => array:3 [ "identificador" => "bib186" "etiqueta" => "89" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Angiotensin II blockers in obstructive pulmonary disease: a randomised controlled trial. Eur Respir J. 2006; 27:972-9. " "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "Angiotensin II blockers in obstructive pulmonary disease: a randomised controlled trial." "idioma" => "en" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:7 [ …7] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:3 [ "tituloSerie" => "Eur Respir J. " "fecha" => "2006" "volumen" => "27:972-9." ] ] ] ] ] ] 89 => array:3 [ "identificador" => "bib187" "etiqueta" => "90" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Impact of cardioselective beta-blockers on mortality in patients with chronic obstructive pulmonary disease and atherosclerosis. Am J Respir Crit Care Med. 2008; 178:695-700. " "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "Impact of cardioselective beta-blockers on mortality in patients with chronic obstructive pulmonary disease and atherosclerosis." "idioma" => "en" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:7 [ …7] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:3 [ "tituloSerie" => "Am J Respir Crit Care Med. " "fecha" => "2008" "volumen" => "178:695-700." ] ] ] ] ] ] 90 => array:3 [ "identificador" => "bib188" "etiqueta" => "91" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Cardioselective beta blockers do not produce adverse respiratory effects in COPD. Evid Based Med. 2006; 11:84. " "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "Cardioselective beta blockers do not produce adverse respiratory effects in COPD." "idioma" => "en" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ …1] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:3 [ "tituloSerie" => "Evid Based Med. " "fecha" => "2006" "volumen" => "11:84." ] ] ] ] ] ] 91 => array:3 [ "identificador" => "bib189" "etiqueta" => "92" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Beta-blockers reduced the risk of mortality and exacerbation in patients with COPD: a meta-analysis of observational studies. PLOS ONE. 2014; 9:e113048. " "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "Beta-blockers reduced the risk of mortality and exacerbation in patients with COPD: a meta-analysis of observational studies." "idioma" => "en" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ …5] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:3 [ "tituloSerie" => "PLOS ONE. " "fecha" => "2014" "volumen" => "9:e113048." ] ] ] ] ] ] 92 => array:3 [ "identificador" => "bib190" "etiqueta" => "93" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Use of beta blockers and the risk of death in hospitalised patients with acute exacerbations of COPD. Thorax. 2008; 63:301-5. " "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "Use of beta blockers and the risk of death in hospitalised patients with acute exacerbations of COPD." "idioma" => "en" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ …5] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:3 [ "tituloSerie" => "Thorax. " "fecha" => "2008" "volumen" => "63:301-5." ] ] ] ] ] ] 93 => array:3 [ "identificador" => "bib191" "etiqueta" => "94" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Impact of gastro-oesophageal reflux disease symptoms on COPD exacerbation. Thorax. 2008; 63:951-5. " "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "Impact of gastro-oesophageal reflux disease symptoms on COPD exacerbation." "idioma" => "en" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:7 [ …7] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:3 [ "tituloSerie" => "Thorax. " "fecha" => "2008" "volumen" => "63:951-5." ] ] ] ] ] ] 94 => array:3 [ "identificador" => "bib192" "etiqueta" => "95" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Association between chronic obstructive pulmonary disease and gastroesophageal reflux disease: a national cross-sectional cohort study. BMC Pulm Med. 2013; 13:51. " "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "Association between chronic obstructive pulmonary disease and gastroesophageal reflux disease: a national cross-sectional cohort study." "idioma" => "en" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:7 [ …7] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:3 [ "tituloSerie" => "BMC Pulm Med. " "fecha" => "2013" "volumen" => "13:51." ] ] ] ] ] ] 95 => array:3 [ "identificador" => "bib193" "etiqueta" => "96" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Gastro-esophageal reflux disease and exacerbations in chronic obstructive pulmonary disease. Respirology. 2015; 20:101-7. " "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "Gastro-esophageal reflux disease and exacerbations in chronic obstructive pulmonary disease." "idioma" => "en" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ …6] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:3 [ "tituloSerie" => "Respirology. " "fecha" => "2015" "volumen" => "20:101-7." ] ] ] ] ] ] 96 => array:3 [ "identificador" => "bib194" "etiqueta" => "97" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "A randomized, single-blind study of lansoprazole for the prevention of exacerbations of chronic obstructive pulmonary disease in older patients. J Am Geriatr Soc. 2009; 57:1453-7. " "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "A randomized, single-blind study of lansoprazole for the prevention of exacerbations of chronic obstructive pulmonary disease in older patients." "idioma" => "en" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:7 [ …7] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:3 [ "tituloSerie" => "J Am Geriatr Soc. " "fecha" => "2009" "volumen" => "57:1453-7." ] ] ] ] ] ] ] ] ] ] ] "idiomaDefecto" => "en" "url" => "/08732159/0000002200000001/v0_201604141139/X0873215916479478/v0_201604141140/en/main.assets" "Apartado" => array:4 [ "identificador" => "50812" "tipo" => "SECCION" "es" => array:2 [ "titulo" => "Thematic Series-COPD" "idiomaDefecto" => true ] "idiomaDefecto" => "es" ] "PDF" => "https://static.elsevier.es/multimedia/08732159/0000002200000001/v0_201604141139/X0873215916479478/v0_201604141140/en/320v22n01a90447947pdf001.pdf?idApp=UINPBA00004E&text.app=https://journalpulmonology.org/" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/X0873215916479478?idApp=UINPBA00004E"]

Statistics

J.. Ferreiraa, M.. Drummondb,c, N.. Piresd, G.. Reise, C.. Alvesf, C.. Robalo-Cordeirog,

a Pulmonology Department, Unidade Local de Saúde de Matosinhos, Portugal

b Pulmonology Department, Centro Hospitalar de São João, Porto, Portugal

c Porto Medical School, Porto University, Portugal

d Pulmonology Department, Hospital Santa Maria Maior, Barcelos, Portugal

e Pulmonology Department, Hospital Distrital de Santarém, Portugal

f Pulmonology Department, Hospital de Nossa Senhora do Rosário, Barreiro, Portugal

g Pulmonology Department, University Hospital, Coimbra, Portugal

h Coimbra Medical School, Coimbra University, Portugal

Read

2140

Times
was read the article

816

Total PDF

1324

Total HTML

Share statistics

 array:20 [
  "pii" => "X0873215916479478"
  "issn" => "08732159"
  "doi" => "10.1016/j.rppnen.2015.10.009"
  "estado" => "S300"
  "fechaPublicacion" => "2016-01-01"
  "documento" => "article"
  "licencia" => "http://www.elsevier.com/open-access/userlicense/1.0/"
  "subdocumento" => "fla"
  "cita" => "Rev Port Pneumol. 2016;22:39-49"
  "abierto" => array:3 [
    "ES" => true
    "ES2" => true
    "LATM" => true
  ]
  "gratuito" => true
  "lecturas" => array:2 [
    "total" => 749
    "formatos" => array:2 [
      "HTML" => 468
      "PDF" => 281
    ]
  ]
  "itemSiguiente" => array:16 [
    "pii" => "X0873215916479486"
    "issn" => "08732159"
    "doi" => "10.1016/j.rppnen.2015.08.006"
    "estado" => "S300"
    "fechaPublicacion" => "2016-01-01"
    "documento" => "article"
    "licencia" => "http://www.elsevier.com/open-access/userlicense/1.0/"
    "subdocumento" => "fla"
    "cita" => "Rev Port Pneumol. 2016;22:50-2"
    "abierto" => array:3 [
      "ES" => true
      "ES2" => true
      "LATM" => true
    ]
    "gratuito" => true
    "lecturas" => array:2 [
      "total" => 395
      "formatos" => array:2 [
        "HTML" => 245
        "PDF" => 150
      ]
    ]
    "en" => array:9 [
      "idiomaDefecto" => true
      "titulo" => "Social profile of the highest tuberculosis incidence areas in Portugal"
      "tienePdf" => "en"
      "tieneTextoCompleto" => "en"
      "paginas" => array:1 [
        0 => array:2 [
          "paginaInicial" => "50"
          "paginaFinal" => "52"
        ]
      ]
      "contieneTextoCompleto" => array:1 [
        "en" => true
      ]
      "contienePdf" => array:1 [
        "en" => true
      ]
      "resumenGrafico" => array:2 [
        "original" => 0
        "multimedia" => array:8 [
          "identificador" => "fig1"
          "etiqueta" => "Figure 1"
          "tipo" => "MULTIMEDIAFIGURA"
          "mostrarFloat" => true
          "mostrarDisplay" => false
          "copyright" => "Elsevier Espa&#241;a"
          "figura" => array:1 [
            0 => array:4 [
              "imagen" => "320v22n01-90447948fig1.jpg"
              "Alto" => 2198
              "Ancho" => 1785
              "Tamanyo" => 861112
            ]
          ]
          "descripcion" => array:1 [
            "en" => "Variation of tuberculosis incidence rate&#44; population density&#44; proportion of people at working age and unemployment rate between 2002 and 2012&#44; and proportion of immigrants between 2008 and 2012&#44; in Greater Oporto&#44; Greater Lisbon and Set&#250;bal Peninsula&#46;"
          ]
        ]
      ]
      "autores" => array:1 [
        0 => array:2 [
          "autoresLista" => "I. Franco, P. Sousa, M. Gomes, A. Oliveira, A.R. Gaio, R. Duarte"
          "autores" => array:6 [
            0 => array:2 [
              "Iniciales" => "I."
              "apellidos" => "Franco"
            ]
            1 => array:2 [
              "Iniciales" => "P."
              "apellidos" => "Sousa"
            ]
            2 => array:2 [
              "Iniciales" => "M."
              "apellidos" => "Gomes"
            ]
            3 => array:2 [
              "Iniciales" => "A."
              "apellidos" => "Oliveira"
            ]
            4 => array:2 [
              "Iniciales" => "A.R."
              "apellidos" => "Gaio"
            ]
            5 => array:2 [
              "Iniciales" => "R."
              "apellidos" => "Duarte"
            ]
          ]
        ]
      ]
    ]
    "idiomaDefecto" => "en"
    "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/X0873215916479486?idApp=UINPBA00004E"
    "url" => "/08732159/0000002200000001/v0_201604141139/X0873215916479486/v0_201604141140/en/main.assets"
  ]
  "itemAnterior" => array:16 [
    "pii" => "X087321591647946X"
    "issn" => "08732159"
    "doi" => "10.1016/j.rppnen.2015.09.001"
    "estado" => "S300"
    "fechaPublicacion" => "2016-01-01"
    "documento" => "article"
    "licencia" => "http://www.elsevier.com/open-access/userlicense/1.0/"
    "subdocumento" => "fla"
    "cita" => "Rev Port Pneumol. 2016;22:34-8"
    "abierto" => array:3 [
      "ES" => true
      "ES2" => true
      "LATM" => true
    ]
    "gratuito" => true
    "lecturas" => array:2 [
      "total" => 499
      "formatos" => array:2 [
        "HTML" => 318
        "PDF" => 181
      ]
    ]
    "en" => array:10 [
      "idiomaDefecto" => true
      "titulo" => "Bronchial artery embolisation in management of hemoptysis &#8211; A retrospective analysis in a tertiary university hospital"
      "tienePdf" => "en"
      "tieneTextoCompleto" => "en"
      "tieneResumen" => "en"
      "paginas" => array:1 [
        0 => array:2 [
          "paginaInicial" => "34"
          "paginaFinal" => "38"
        ]
      ]
      "contieneResumen" => array:1 [
        "en" => true
      ]
      "contieneTextoCompleto" => array:1 [
        "en" => true
      ]
      "contienePdf" => array:1 [
        "en" => true
      ]
      "autores" => array:1 [
        0 => array:2 [
          "autoresLista" => "H. Dab&#243;, R. Gomes, A. Marinho, M. Madureira, J. Paquete, P. Morgado"
          "autores" => array:6 [
            0 => array:2 [
              "Iniciales" => "H."
              "apellidos" => "Dab&#243;"
            ]
            1 => array:2 [
              "Iniciales" => "R."
              "apellidos" => "Gomes"
            ]
            2 => array:2 [
              "Iniciales" => "A."
              "apellidos" => "Marinho"
            ]
            3 => array:2 [
              "Iniciales" => "M."
              "apellidos" => "Madureira"
            ]
            4 => array:2 [
              "Iniciales" => "J."
              "apellidos" => "Paquete"
            ]
            5 => array:2 [
              "Iniciales" => "P."
              "apellidos" => "Morgado"
            ]
          ]
        ]
      ]
    ]
    "idiomaDefecto" => "en"
    "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/X087321591647946X?idApp=UINPBA00004E"
    "url" => "/08732159/0000002200000001/v0_201604141139/X087321591647946X/v0_201604141139/en/main.assets"
  ]
  "en" => array:14 [
    "idiomaDefecto" => true
    "titulo" => "Optimal treatment sequence in COPD&#58; Can a consensus be found&#63;"
    "tieneTextoCompleto" => true
    "paginas" => array:1 [
      0 => array:2 [
        "paginaInicial" => "39"
        "paginaFinal" => "49"
      ]
    ]
    "autores" => array:1 [
      0 => array:4 [
        "autoresLista" => "J. Ferreira, M. Drummond, N. Pires, G. Reis, C. Alves, C. Robalo-Cordeiro"
        "autores" => array:6 [
          0 => array:3 [
            "Iniciales" => "J."
            "apellidos" => "Ferreira"
            "referencia" => array:1 [
              0 => array:2 [
                "etiqueta" => "<span class="elsevierStyleSup">a</span>"
                "identificador" => "affa"
              ]
            ]
          ]
          1 => array:3 [
            "Iniciales" => "M."
            "apellidos" => "Drummond"
            "referencia" => array:2 [
              0 => array:2 [
                "etiqueta" => "<span class="elsevierStyleSup">b</span>"
                "identificador" => "affb"
              ]
              1 => array:2 [
                "etiqueta" => "<span class="elsevierStyleSup">c</span>"
                "identificador" => "affc"
              ]
            ]
          ]
          2 => array:3 [
            "Iniciales" => "N."
            "apellidos" => "Pires"
            "referencia" => array:1 [
              0 => array:2 [
                "etiqueta" => "<span class="elsevierStyleSup">d</span>"
                "identificador" => "affd"
              ]
            ]
          ]
          3 => array:3 [
            "Iniciales" => "G."
            "apellidos" => "Reis"
            "referencia" => array:1 [
              0 => array:2 [
                "etiqueta" => "<span class="elsevierStyleSup">e</span>"
                "identificador" => "affe"
              ]
            ]
          ]
          4 => array:3 [
            "Iniciales" => "C."
            "apellidos" => "Alves"
            "referencia" => array:1 [
              0 => array:2 [
                "etiqueta" => "<span class="elsevierStyleSup">f</span>"
                "identificador" => "afff"
              ]
            ]
          ]
          5 => array:4 [
            "Iniciales" => "C."
            "apellidos" => "Robalo-Cordeiro"
            "email" => array:1 [
              0 => "carlos&#46;crobalo&#64;gmail&#46;com"
            ]
            "referencia" => array:3 [
              0 => array:2 [
                "etiqueta" => "<span class="elsevierStyleSup">g</span>"
                "identificador" => "affg"
              ]
              1 => array:2 [
                "etiqueta" => "<span class="elsevierStyleSup">&#42;</span>"
                "identificador" => "cor1"
              ]
              2 => array:2 [
                "etiqueta" => "<span class="elsevierStyleSup">h</span>"
                "identificador" => "affh"
              ]
            ]
          ]
        ]
        "afiliaciones" => array:8 [
          0 => array:3 [
            "entidad" => "Pulmonology Department, Unidade Local de Saúde de Matosinhos, Portugal"
            "etiqueta" => "<span class="elsevierStyleSup">a</span>"
            "identificador" => "affa"
          ]
          1 => array:3 [
            "entidad" => "Pulmonology Department, Centro Hospitalar de São João, Porto, Portugal"
            "etiqueta" => "<span class="elsevierStyleSup">b</span>"
            "identificador" => "affb"
          ]
          2 => array:3 [
            "entidad" => "Porto Medical School, Porto University, Portugal"
            "etiqueta" => "<span class="elsevierStyleSup">c</span>"
            "identificador" => "affc"
          ]
          3 => array:3 [
            "entidad" => "Pulmonology Department, Hospital Santa Maria Maior, Barcelos, Portugal"
            "etiqueta" => "<span class="elsevierStyleSup">d</span>"
            "identificador" => "affd"
          ]
          4 => array:3 [
            "entidad" => "Pulmonology Department, Hospital Distrital de Santarém, Portugal"
            "etiqueta" => "<span class="elsevierStyleSup">e</span>"
            "identificador" => "affe"
          ]
          5 => array:3 [
            "entidad" => "Pulmonology Department, Hospital de Nossa Senhora do Rosário, Barreiro, Portugal"
            "etiqueta" => "<span class="elsevierStyleSup">f</span>"
            "identificador" => "afff"
          ]
          6 => array:3 [
            "entidad" => "Pulmonology Department, University Hospital, Coimbra, Portugal"
            "etiqueta" => "<span class="elsevierStyleSup">g</span>"
            "identificador" => "affg"
          ]
          7 => array:3 [
            "entidad" => "Coimbra Medical School, Coimbra University, Portugal"
            "etiqueta" => "<span class="elsevierStyleSup">h</span>"
            "identificador" => "affh"
          ]
        ]
        "correspondencia" => array:1 [
          0 => array:3 [
            "identificador" => "cor1"
            "etiqueta" => "<span class="elsevierStyleSup">&#42;</span>"
            "correspondencia" => "Corresponding author. carlos.crobalo@gmail.com"
          ]
        ]
      ]
    ]
    "resumenGrafico" => array:2 [
      "original" => 0
      "multimedia" => array:8 [
        "identificador" => "fig1"
        "etiqueta" => "Figure 1"
        "tipo" => "MULTIMEDIAFIGURA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "copyright" => "Elsevier Espa&#241;a"
        "figura" => array:1 [
          0 => array:4 [
            "imagen" => "320v22n01-90447947fig1.jpg"
            "Alto" => 1979
            "Ancho" => 3091
            "Tamanyo" => 539936
          ]
        ]
        "descripcion" => array:1 [
          "en" => "Proposed therapeutic scheme&#46; From top to bottom&#58; asthma component predominant to COPD component predominant&#46;"
        ]
      ]
    ]
    "textoCompleto" => "<a name="sec0005" class="elsevierStyleCrossRefs"></a><span class="elsevierStyleSectionTitle">Introduction</span><p class="elsevierStylePara">One of the main reasons that has precluded the establishment of a consensus treatment sequence in chronic obstructive pulmonary disease &#40;COPD&#41; is that patient stratification is not consensual across guidelines&#46;<a href="&#35;bib98" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">1</span></a><span class="elsevierStyleSup">&#44; </span><a href="&#35;bib99" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">2</span></a><span class="elsevierStyleSup">&#44; </span><a href="&#35;bib100" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">3</span></a><span class="elsevierStyleSup">&#44; </span><a href="&#35;bib101" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">4</span></a> The first problem emerges with the classification by the Global Initiative for Chronic Obstructive Lung Disease &#40;GOLD&#41; only distinguishing two issues&#44; symptoms and risk&#44;<a href="&#35;bib98" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">1</span></a> which are clearly not sufficient to define a patient with COPD&#44; an extremely heterogeneous disease&#46; The Spanish guidelines propose treatment based on four clinically relevant phenotypes&#44;<a href="&#35;bib99" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">2</span></a> but even this approach presents heterogeneity&#46; Although it is fairly consensual that initial treatment should begin with an inhaled short-acting beta agonist &#40;SABA&#41;&#44; a short-acting muscarinic antagonist &#40;SAMA&#41;&#44; a long-acting beta-agonist &#40;LABA&#41; or a long-acting muscarinic antagonist &#40;LAMA&#41;&#44;<a href="&#35;bib98" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">1</span></a><span class="elsevierStyleSup">&#44; </span><a href="&#35;bib99" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">2</span></a><span class="elsevierStyleSup">&#44; </span><a href="&#35;bib101" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">4</span></a><span class="elsevierStyleSup">&#44; </span><a href="&#35;bib102" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">5</span></a> when and in which patients to use dual bronchodilation&#44; inhaled corticosteroids &#40;ICS&#41; in combination with bronchodilation&#44; or triple therapy&#44; remains controversial&#44;<a href="&#35;bib103" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">6</span></a> except in patients with the Asthma-COPD overlap syndrome &#40;ACOS&#41;&#44; who should be initially treated with ICS&#46;<a href="&#35;bib104" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">7</span></a> ICS have been shown to have side effects&#44; namely pneumonia&#44;<a href="&#35;bib103" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">6</span></a> and tuberculosis and the risk increases dose-dependently with ICS use&#46;<a href="&#35;bib105" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">8</span></a></p><p class="elsevierStylePara">Apart from the above mentioned molecules&#44; other potentially useful non-inhaled therapies such as mucolytic agents&#44; antibiotics&#44; phosphodiesterase-4 inhibitors &#40;PDE4i&#41;&#44; methylxanthines and immunostimulating agents&#44; are available&#44; but again their use is not consensual&#46;<a href="&#35;bib98" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">1</span></a><span class="elsevierStyleSup">&#44; </span><a href="&#35;bib99" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">2</span></a><span class="elsevierStyleSup">&#44; </span><a href="&#35;bib100" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">3</span></a><span class="elsevierStyleSup">&#44; </span><a href="&#35;bib101" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">4</span></a> Although increasingly relevant and important to the management of COPD&#44; this paper does not include a section on non-pharmacological measures&#44; which are duly addressed by Guimar&#227;es et al&#46;<a href="&#35;bib106" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">9</span></a></p><p class="elsevierStylePara">This paper reviews current guidelines and available evidence and proposes a therapeutic scheme for COPD patients&#46;</p><a name="sec0010" class="elsevierStyleCrossRefs"></a><span class="elsevierStyleSectionTitle">Methods</span><p class="elsevierStylePara">The GI DPOC-Grupo de Interesse na Doen&#231;a Pulmonar Obstrutiva Cr&#243;nica convened on December 2014 to review and discuss previously distributed papers&#44; scientific meeting presentations&#44; current guidelines and practices related to the management of COPD&#46; Papers had been identified through searching PubMed with the search terms &#8220;chronic obstructive pulmonary disease dual bronchodilation&#8221; and &#8220;chronic obstructive pulmonary disease triple therapy&#8221; with no date limits&#46; Papers identified as described were searched manually&#46; Distributed guidelines were GOLD 2014&#44;<a href="&#35;bib107" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">10</span></a> GesEPOC 2014&#44;<a href="&#35;bib99" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">2</span></a> NICE 2010<a href="&#35;bib100" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">3</span></a> and The Canadian Thoracic Society recommendations for management of COPD 2007&#46;<a href="&#35;bib101" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">4</span></a> Additional new evidence was distributed after the meeting&#44; including articles identified through searches of the authors&#8217; own files&#46; Subsequent discussions by email led to the preparation of the first draft of this paper&#46; On February 2015 the GI-DPOC convened again&#44; and discussed the first draft of the paper in light of GOLD 2015&#46;<a href="&#35;bib98" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">1</span></a> Additional new evidence was distributed after the meeting&#44; including recent articles identified through searches of the authors&#8217; own files&#46; Subsequent discussions by email led to the preparation of the final text of this paper&#46; The final reference list was generated on the basis of originality and relevance to the scope of this paper&#46;</p><a name="sec0015" class="elsevierStyleCrossRefs"></a><span class="elsevierStyleSectionTitle">Should therapy be initiated early&#63;</span><p class="elsevierStylePara">A clinical diagnosis of COPD should be considered in any patient who has dyspnea&#44; chronic cough or sputum production&#44; and a history of exposure to risk factors for the disease&#46; Spirometry is required to establish a diagnosis of COPD&#46;<a href="&#35;bib98" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">1</span></a> The presence of a post-bronchodilator ratio of Forced Expiratory Volume in 1 second by Forced Vital Capacity &#40;FEV<span class="elsevierStyleInf">1</span>&#47;FVC&#41;&#160;&#60;&#160;0&#46;70 confirms the presence of persistent airflow limitation and thus of COPD and a normal value for spirometry effectively excludes the diagnosis of clinically relevant COPD&#46;<a href="&#35;bib98" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">1</span></a> Spirometric screening of asymptomatic individuals is not supported by evidence&#46; However&#44; in individuals over 40 years old with a smoking history &#40;&#62;10 pack-years&#41;&#44; spirometry may be performed with the aim of early diagnosis&#46;<a href="&#35;bib102" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">5</span></a></p><p class="elsevierStylePara">A correct diagnosis is mandatory to decide the best treatment approach&#46;<a href="&#35;bib108" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">11</span></a> Therapy should be initiated in early stages of the disease as even patients in GOLD stage 1 &#40;as defined by GOLD prior to 2011&#41; may respond to bronchodilators with physiological and symptomatic improvements&#46;<a href="&#35;bib109" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">12</span></a><span class="elsevierStyleSup">&#44; </span><a href="&#35;bib110" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">13</span></a> Also&#44; several studies have reported improvement with bronchodilators in GOLD stage 2 patients &#40;as defined by GOLD prior to 2011&#41;&#46;<a href="&#35;bib111" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">14</span></a><span class="elsevierStyleSup">&#44; </span><a href="&#35;bib112" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">15</span></a><span class="elsevierStyleSup">&#44; </span><a href="&#35;bib113" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">16</span></a> A study assessing the ability of the GOLD 2011 stratification<a href="&#35;bib114" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">17</span></a> to predict the clinical course of COPD showed that group B had significantly poorer survival than group C&#44; concluding that this group warrants special attention&#44; requiring additional assessment and treatment&#46;<a href="&#35;bib115" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">18</span></a></p><p class="elsevierStylePara">The Canadian Thoracic Society recommends therapy should be guided by the degree of disability&#44; lung function and exacerbations<a href="&#35;bib101" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">4</span></a> whereas the National Institute for Health and Care Excellence &#40;NICE&#41; guidelines propose therapy based on a variety of parameters such as lung function&#44; improvement in symptoms&#44; activities of daily living&#44; exercise capacity&#44; rapidity of symptom relief&#44; exacerbations&#44; patient preference&#44; side effects and cost&#46;<a href="&#35;bib100" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">3</span></a> According to the GOLD guideliness&#44; LAMA or LABA are alternative choices for group A patients and the recommended first choice for group B patients&#44; with alternative choice of LAMA&#160;&#43;&#160;LABA&#46;<a href="&#35;bib98" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">1</span></a> However&#44; dual bronchodilation with a fixed-dose combination of indacaterol&#47;glycopyrronium &#40;IND&#47;GLY&#41; has been reported to have clinically meaningful and symptomatic improvement in moderate to severe non-exacerbating COPD patients&#44; who by definition fall within the B category&#46;<a href="&#35;bib116" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">19</span></a><span class="elsevierStyleSup">&#44; </span><a href="&#35;bib117" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">20</span></a> On the other hand&#44; there are several potential advantages and beneficial effects of having a LABA&#160;&#43;&#160;LAMA combination on the same device&#46;<a href="&#35;bib118" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">21</span></a></p><p class="elsevierStylePara">The Spanish guidelines propose that COPD treatment should be based on four clinical phenotypes &#40;non-exacerbator&#44; exacerbator with emphysema&#44; exacerbator with chronic bronchitis&#44; mixed COPD-asthma&#41; and disease severity&#44; and recommend LABA&#160;&#43;&#160;LAMA as an option for all phenotypes with severity level&#160;&#62;&#160;II &#40;on a scale of I to IV&#41;&#46;<a href="&#35;bib99" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">2</span></a></p><p class="elsevierStylePara"><a href="&#35;t0005" class="elsevierStyleCrossRefs">Table 1</a> summarizes our proposals&#44; suggestions and recommendations on diagnosis and early therapy&#46;</p><p class="elsevierStylePara">Table 1&#46; Should therapy be initiated early&#63;</p><a name="t0005" class="elsevierStyleCrossRefs"></a><p class="elsevierStylePara"></p><table><tr align="left"><td>Diagnosis</td><td>&#8226; early diagnosis is of paramount importance to initiate treatment in the early stages of the disease</td></tr><tr align="left"><td>Therapy GOLD A patients</td><td>&#8226; monotherapy with a long-acting bronchodilator should be the first treatment choice</td></tr><tr align="left"><td>Therapy GOLD B patients</td><td>&#8226; in highly symptomatic GOLD B patients&#44; dual bronchodilation should be initiated as soon as possible</td></tr><tr align="left"><td rowspan="3">Therapy in patients with bronchitic COPD</td><td>&#8226; the choice of single or dual bronchodilation will depend on the symptoms</td></tr><tr align="left"><td>&#8226; if the patient is a frequent exacerbator &#40;&#8805;2 exacerbations&#47;year or 1 exacerbation requiring hospitalization&#41;&#44; ICS should be added</td></tr><tr align="left"><td>&#8226; in these patients&#44; mucolytic agents are also drugs to consider</td></tr></table><a name="sec0020" class="elsevierStyleCrossRefs"></a><span class="elsevierStyleSectionTitle">ICS and triple therapy</span><p class="elsevierStylePara">ICS use has unequivocal benefits in asthma&#44; but its position in COPD treatment is controversial&#46;<a href="&#35;bib108" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">11</span></a> Different guidelines recommend the use of ICS or triple therapy in different patient categories given that patient stratification is not consensual across guidelines&#46;<a href="&#35;bib98" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">1</span></a><span class="elsevierStyleSup">&#44; </span><a href="&#35;bib99" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">2</span></a><span class="elsevierStyleSup">&#44; </span><a href="&#35;bib100" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">3</span></a><span class="elsevierStyleSup">&#44; </span><a href="&#35;bib101" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">4</span></a> The only apparent consensus is that ICS therapy alone is not recommended in COPD patients&#44;<a href="&#35;bib98" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">1</span></a><span class="elsevierStyleSup">&#44; </span><a href="&#35;bib99" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">2</span></a><span class="elsevierStyleSup">&#44; </span><a href="&#35;bib100" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">3</span></a><span class="elsevierStyleSup">&#44; </span><a href="&#35;bib101" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">4</span></a><span class="elsevierStyleSup">&#44; </span><a href="&#35;bib102" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">5</span></a><span class="elsevierStyleSup">&#44; </span><a href="&#35;bib119" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">22</span></a> and even in the treatment of exacerbations&#44; the recommendation is to add oral or intravenous corticosteroids and&#47;or antibiotics&#44; depending on symptom severity and the existence of infection&#46;<a href="&#35;bib98" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">1</span></a> Regardless of GOLD stage&#44; severe exacerbations must be managed properly&#44; since mortality increases as they become more frequent&#44; particularly when these require hospital admission&#46;<a href="&#35;bib120" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">23</span></a></p><p class="elsevierStylePara">Several recent studies have investigated the benefits of ICS on COPD&#44;<a href="&#35;bib112" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">15</span></a><span class="elsevierStyleSup">&#44; </span><a href="&#35;bib116" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">19</span></a><span class="elsevierStyleSup">&#44; </span><a href="&#35;bib117" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">20</span></a><span class="elsevierStyleSup">&#44; </span><a href="&#35;bib118" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">21</span></a><span class="elsevierStyleSup">&#44; </span><a href="&#35;bib121" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">24</span></a><span class="elsevierStyleSup">&#44; </span><a href="&#35;bib122" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">25</span></a><span class="elsevierStyleSup">&#44; </span><a href="&#35;bib123" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">26</span></a><span class="elsevierStyleSup">&#44; </span><a href="&#35;bib124" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">27</span></a><span class="elsevierStyleSup">&#44; </span><a href="&#35;bib125" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">28</span></a> and the majority do not support the use of ICS in all patients&#46; Two specific groups of patients may benefit from ICS&#58; ACOS&#44;<a href="&#35;bib104" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">7</span></a> with a reported prevalence ranging from 15&#37; to 55&#37;&#44; depending on age and gender&#44;<a href="&#35;bib126" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">29</span></a> whose patients cannot be treated with monotherapy LABA&#44; and COPD with frequent exacerbations &#40;&#8805;2&#47;year&#41; regardless of treatment with bronchodilators&#46;<a href="&#35;bib108" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">11</span></a> A very recent review of available studies strongly recommends limiting use of ICS to a minority of COPD patients who might benefit from it&#44; and suggests some indicators of likelihood of ICS patients&#8217; response&#46;<a href="&#35;bib103" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">6</span></a></p><p class="elsevierStylePara">Several questions remain regarding the use of ICS in COPD patients&#58; &#40;a&#41; do all ICSs increase the risk of pneumonia in COPD patients&#44; or is it dependent on drug class&#63;&#59;<a href="&#35;bib108" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">11</span></a><span class="elsevierStyleSup">&#44; </span><a href="&#35;bib109" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">12</span></a><span class="elsevierStyleSup">&#44; </span><a href="&#35;bib112" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">15</span></a><span class="elsevierStyleSup">&#44; </span><a href="&#35;bib122" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">25</span></a><span class="elsevierStyleSup">&#44; </span><a href="&#35;bib127" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">30</span></a> &#40;b&#41; treatment with ICS for 3 years has been reported to be safe&#44;<a href="&#35;bib112" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">15</span></a> but for more prolonged treatment the safety profile is still unknown&#59;<a href="&#35;bib109" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">12</span></a> &#40;c&#41; is the use of a specific ICS and its dose relevant to the efficacy&#47;safety ratio&#63;&#59;<a href="&#35;bib128" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">31</span></a> &#40;d&#41; Randomized Clinical Trials &#40;RCTs&#41; use very high doses of ICS &#8211; do they have the same safety and efficacy profile in lower doses&#63;&#59; and &#40;e&#41; should ICS be used only in patients for whom the benefits outweigh the risks&#63;<a href="&#35;bib108" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">11</span></a> Risks associated to ICS use should be clearly established and balanced against its clinical benefits such as exacerbation control&#46;</p><p class="elsevierStylePara">As for triple therapy&#44; its recommendation in COPD patients at risk of exacerbations is generally accepted<a href="&#35;bib128" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">31</span></a><span class="elsevierStyleSup">&#44; </span><a href="&#35;bib129" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">32</span></a><span class="elsevierStyleSup">&#44; </span><a href="&#35;bib130" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">33</span></a><span class="elsevierStyleSup">&#44; </span><a href="&#35;bib131" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">34</span></a><span class="elsevierStyleSup">&#44; </span><a href="&#35;bib132" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">35</span></a> &#40;one or more exacerbations per year&#44; on average&#44; for 2 consecutive years&#41;&#46;<a href="&#35;bib132" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">35</span></a> Triple therapy seems to improve lung function&#44; Quality of Life &#40;QoL&#41;&#44;<a href="&#35;bib125" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">28</span></a><span class="elsevierStyleSup">&#44; </span><a href="&#35;bib130" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">33</span></a> and hospitalization rates&#44;<a href="&#35;bib125" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">28</span></a> to provide greater reduction in airway wall thickness<a href="&#35;bib130" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">33</span></a> and seems to confer benefits on cardiovascular mortality&#46;<a href="&#35;bib133" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">36</span></a> On the other hand&#44; a National Health Service &#40;NHS&#41; review concluded that&#44; although triple therapy decreased the hospitalization rate due to severe&#47;acute COPD exacerbations compared with LAMA monotherapy&#44; there was insufficient evidence to determine whether triple therapy was superior to dual bronchodilation&#46;<a href="&#35;bib134" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">37</span></a> Several authors pointed out that evidence in favor of triple therapy use is scarce&#44; study results heterogeneous&#44;<a href="&#35;bib119" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">22</span></a><span class="elsevierStyleSup">&#44; </span><a href="&#35;bib127" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">30</span></a><span class="elsevierStyleSup">&#44; </span><a href="&#35;bib131" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">34</span></a> and the studies were too short to lead to any strong recommendations&#46;<a href="&#35;bib131" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">34</span></a> However&#44; it should be noted that future triple therapy&#44; with all drugs in the same device&#44; may have added advantages compared to triple therapy in different devices&#44; given the possible synergism between molecules&#44; as already shown for LABA&#160;&#43;&#160;LAMA<a href="&#35;bib123" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">26</span></a> and ICS&#160;&#43;&#160;LABA&#46;<a href="&#35;bib135" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">38</span></a></p><p class="elsevierStylePara">Also&#44; it has to be taken into account that triple therapy is expensive and has its own inherent risks&#46;<a href="&#35;bib129" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">32</span></a> A recent review from UK general practice showed that&#44; from 2004 to 2009&#44; the use of triple therapy in all COPD degrees increased&#58; from 25&#37; to 59&#37; in patients with very severe COPD&#44; and as much as 14&#37; and 19&#37; in patients with mild and moderate COPD&#44; respectively&#46; Up to a third of patients with mild or moderate COPD were on triple therapy&#44; and the authors raise the question of whether these patients are indeed frequent exacerbators&#44; and thus are being treated according to current guidelines&#46;<a href="&#35;bib136" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">39</span></a> These numbers are somewhat worrying given the available evidence&#44; and may indicate that ICSs are being over-prescribed and&#44; consequently&#44; patients are being overtreated&#46; Some authors propose that ICS should be withdrawn from patients who do not benefit from it&#46; Gradual ICS withdrawal in moderate COPD patients does not increase moderate to severe exacerbations&#44; although a greater decrease in lung function during the final step of withdrawal was shown&#46;<a href="&#35;bib121" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">24</span></a></p><p class="elsevierStylePara">Some authors defend the position that&#44; given the risks associated with ICS therapy&#44; and the overall safety and effectiveness of long-acting bronchodilators&#44; bronchodilators without ICS should be favored at all levels of COPD severity&#44; except if there is an asthma component associated with COPD&#46;<a href="&#35;bib103" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">6</span></a> Dual bronchodilation with IND&#47;GLY may be preferable&#44; since it has demonstrated superiority versus treatment with its monocomponents&#44; indacaterol and glycopyrronium&#44;<a href="&#35;bib123" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">26</span></a> suggesting the existence of synergistic activity&#46; The potential advantages and beneficial effects of having a combination of LABA&#160;&#43;&#160;LAMA on the same device are&#58; &#40;1&#41; prevention of disease progression&#44; &#40;2&#41; increased efficacy compared to single agents given their different mechanisms of action&#44; &#40;3&#41; health status improvement by reducing symptoms and increasing physical activity&#44; and &#40;4&#41; increased compliance &#8211; once daily&#44; same device&#46;<a href="&#35;bib118" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">21</span></a></p><p class="elsevierStylePara">GOLD recommends dual bronchodilation for symptom optimization as the second treatment choice in B&#44; C and D patients&#46;<a href="&#35;bib98" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">1</span></a></p><p class="elsevierStylePara"><a href="&#35;t0010" class="elsevierStyleCrossRefs">Table 2</a> and <a href="&#35;f0005" class="elsevierStyleCrossRefs">Figure 1</a> summarize our proposals&#44; suggestions and recommendations on COPD treatment sequence&#46;</p><p class="elsevierStylePara">Table 2&#46; ICS and triple therapy&#46;</p><a name="t0010" class="elsevierStyleCrossRefs"></a><p class="elsevierStylePara"></p><table><tr align="left"><td>ICS and triple therapy</td><td>&#8226; proposal of therapeutic scheme depicted in  Fig&#46; 1 </td></tr><tr align="left"><td>Recommendation</td><td>&#8226; strong recommendation for a personalized&#44; patient-oriented approach&#44; taking into account each patient&#39;s clinical and personal characteristics and preferences</td></tr></table><a name="f0005" class="elsevierStyleCrossRefs"></a><p class="elsevierStylePara"><img src="320v22n01-90447947fig1.jpg" alt="Proposed therapeutic scheme&#46; From top to bottom&#58; asthma component predominant to COPD component predominant&#46;"></img></p><p class="elsevierStylePara">Figure 1&#46; Proposed therapeutic scheme&#46; From top to bottom&#58; asthma component predominant to COPD component predominant&#46;</p><a name="sec0025" class="elsevierStyleCrossRefs"></a><span class="elsevierStyleSectionTitle">Compliance and new molecules</span><p class="elsevierStylePara">Difficulties in early interventions &#40;GOLD stage 1 and 2&#41; are mainly due to low compliance&#44; with increased mortality rate regardless of the type of therapy&#46;<a href="&#35;bib109" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">12</span></a> A patient with dyspnea and fatigue will be more likely to comply with treatment whereas a less symptomatic patient will tend to be non-compliant&#46; Focus should be given to informing patients<a href="&#35;bib109" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">12</span></a><span class="elsevierStyleSup">&#44; </span><a href="&#35;bib116" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">19</span></a><span class="elsevierStyleSup">&#44; </span><a href="&#35;bib117" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">20</span></a> about therapy benefits&#46; As previously mentioned&#44; one of the potential advantages and beneficial effects of having a combination LABA&#160;&#43;&#160;LAMA therapy on the same device is an increased compliance &#8211; once daily&#46;<a href="&#35;bib116" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">19</span></a><span class="elsevierStyleSup">&#44; </span><a href="&#35;bib117" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">20</span></a><span class="elsevierStyleSup">&#44; </span><a href="&#35;bib118" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">21</span></a> However&#44; the choice of an inhaler should consider a range of different factors&#44; including price and availability&#44; similarity to other inhalers the patient uses&#44; ability for the health care provider to correctly train the patient&#44; ability of the patient to handle the inhaler&#44; and patient preference&#46;<a href="&#35;bib137" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">40</span></a> In this regard&#44; studies have shown some advantages of the Breezhaler in comparison to the Handihaler in COPD patients with different disease severities&#58; &#40;1&#41; Breezhaler has mechanisms that assure the drug is completely inhaled by the patient&#59;<a href="&#35;bib138" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">41</span></a> &#40;2&#41; it delivers a higher fine particle fraction and generates a greater and more consistent intrathoracic deposition<a href="&#35;bib139" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">42</span></a> and &#40;3&#41; patients seem to prefer the Breezhaler because it is easier and more comfortable to use&#46;<a href="&#35;bib138" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">41</span></a></p><p class="elsevierStylePara">As for the development of new drugs&#44; the combination of a muscarinic antagonist with a beta<span class="elsevierStyleInf">2</span> agonist &#40;MABA&#41; is an interesting new approach&#44; since it has the potential to demonstrate additive or synergistic bronchodilation over either component alone&#46;<a href="&#35;bib140" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">43</span></a> A phase I trial to determine the pharmacokinetics of a MABA has already been completed&#44; but the results are not yet available&#46;<a href="&#35;bib141" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">44</span></a></p><p class="elsevierStylePara"><a href="&#35;t0015" class="elsevierStyleCrossRefs">Table 3</a> summarizes our proposals&#44; suggestions and recommendations on compliance and new molecules&#46;</p><p class="elsevierStylePara">Table 3&#46; Compliance and new molecules&#46;</p><a name="t0015" class="elsevierStyleCrossRefs"></a><p class="elsevierStylePara"></p><table><tr align="left"><td rowspan="2">Compliance</td><td>&#8226; proposal of focusing on patient information and education to increase compliance</td></tr><tr align="left"><td>&#8226; having a combination of drugs on the same device increases compliance&#44; and the choice of an inhaler should be based on several factors</td></tr><tr align="left"><td>New Molecules &#40;MABA&#41;</td><td>&#8226; results not available</td></tr></table><a name="sec0030" class="elsevierStyleCrossRefs"></a><span class="elsevierStyleSectionTitle">Additional useful non-inhaled therapies</span><p class="elsevierStylePara">There are a few useful non-inhaled therapies that can be used in the management of COPD&#44; namely mucolytic agents&#44; macrolides&#44; PDE4i&#44; xanthine derivatives and immunostimulating agents&#46; Some guidelines have already incorporated these additional therapies&#44;<a href="&#35;bib98" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">1</span></a><span class="elsevierStyleSup">&#44; </span><a href="&#35;bib99" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">2</span></a><span class="elsevierStyleSup">&#44; </span><a href="&#35;bib100" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">3</span></a><span class="elsevierStyleSup">&#44; </span><a href="&#35;bib142" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">45</span></a> but which therapy to use in which group of patients remains controversial&#46;</p><a name="sec0035" class="elsevierStyleCrossRefs"></a><span class="elsevierStyleSectionTitle">Mucolytic agents</span><p class="elsevierStylePara">Carbocysteine&#44; N-acetylcysteine &#40;NAC&#41; and erdosteine are the most common mucolytic agents used in COPD&#46; They all exhibit antioxidant activity&#44;<a href="&#35;bib98" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">1</span></a> with carbocysteine and NAC being also anti-inflammatory&#46;<a href="&#35;bib143" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">46</span></a><span class="elsevierStyleSup">&#44; </span><a href="&#35;bib144" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">47</span></a> Carbocysteine seems to decrease exacerbations in frequent exacerbators not receiving ICS&#46;<a href="&#35;bib143" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">46</span></a><span class="elsevierStyleSup">&#44; </span><a href="&#35;bib145" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">48</span></a> High-dose NAC seems to decrease exacerbation frequency regardless of ICS therapy&#44;<a href="&#35;bib144" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">47</span></a><span class="elsevierStyleSup">&#44; </span><a href="&#35;bib146" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">49</span></a> but only in patients at high risk of exacerbations&#46;<a href="&#35;bib147" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">50</span></a> This effect appears to be particularly evident in patients with moderate COPD&#44;<a href="&#35;bib148" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">51</span></a> but limitations due to study population may preclude generalization of these conclusions&#46;<a href="&#35;bib149" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">52</span></a><span class="elsevierStyleSup">&#44; </span><a href="&#35;bib150" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">53</span></a> Low-dose NAC has no effect on exacerbation frequency<a href="&#35;bib146" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">49</span></a><span class="elsevierStyleSup">&#44; </span><a href="&#35;bib151" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">54</span></a><span class="elsevierStyleSup">&#44; </span><a href="&#35;bib152" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">55</span></a> or clinical outcomes&#46;<a href="&#35;bib151" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">54</span></a><span class="elsevierStyleSup">&#44; </span><a href="&#35;bib152" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">55</span></a> Data from a meta-analysis supports the use of erdosteine in COPD&#44; given the significant symptom improvement&#44;<a href="&#35;bib153" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">56</span></a> but the reliability of this conclusion is disputed&#46;<a href="&#35;bib154" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">57</span></a> The Spanish guidelines consider the addition of carbocysteine in the exacerbator patient with chronic bronchitis phenotype and severity level&#160;&#62;&#160;II&#46;<a href="&#35;bib99" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">2</span></a> GOLD considers carbocysteine as an option for GOLD D patients&#44;<a href="&#35;bib98" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">1</span></a> and the NICE guidelines consider mucolytic therapy for patients with a chronic cough productive of sputum&#44; but do not recommend routine use of mucolytic drugs to prevent exacerbations in patients with stable COPD&#46;<a href="&#35;bib100" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">3</span></a></p><a name="sec0040" class="elsevierStyleCrossRefs"></a><span class="elsevierStyleSectionTitle">Macrolides</span><p class="elsevierStylePara">Macrolides are the most widely studied antibiotics for continuous long-term or intermittent use in COPD&#46;<a href="&#35;bib155" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">58</span></a> Available evidence supports the continuous use of macrolides to prevent exacerbations<a href="&#35;bib156" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">59</span></a><span class="elsevierStyleSup">&#44; </span><a href="&#35;bib157" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">60</span></a><span class="elsevierStyleSup">&#44; </span><a href="&#35;bib158" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">61</span></a><span class="elsevierStyleSup">&#44; </span><a href="&#35;bib159" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">62</span></a> and hospitalizations&#44;<a href="&#35;bib159" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">62</span></a> but which patient population would benefit the most&#44; as well as optimal dose and duration of treatment&#44; remain unknown&#46;<a href="&#35;bib155" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">58</span></a><span class="elsevierStyleSup">&#44; </span><a href="&#35;bib159" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">62</span></a><span class="elsevierStyleSup">&#44; </span><a href="&#35;bib160" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">63</span></a> A small study in patients with 3 or more exacerbations in the previous year showed that 500&#160;mg azithromycin 3 times per week for 12 months significantly decreased exacerbation rate and suggested that this regimen should be considered for use in patients with the frequent exacerbator phenotype who are refractory to standard care&#46;<a href="&#35;bib157" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">60</span></a> However&#44; a large study where 250&#160;mg azithromycin was given to patients daily for 12 months concluded that azithromycin was most effective in preventing exacerbations requiring both antibiotic and steroid treatment&#44; and reported a greater efficacy in older patients and in those with less severe COPD&#46;<a href="&#35;bib158" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">61</span></a> A systematic review including only trials with patients who were frequent exacerbators and who needed treatment with antibiotics or systemic steroids for those events&#44; or who were on supplemental oxygen&#44; concluded that the impact of intermittent use of macrolides &#40;either 5 days every two months or 3 consecutive days per month&#41; on exacerbation frequency and quality of life remains uncertain&#46;<a href="&#35;bib156" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">59</span></a> A recent literature review concluded that&#44; in Belgium&#44; beyond the positive impact on exacerbations and related hospitalizations&#44; the prevention of COPD exacerbations with azithromycin would not only be cost saving<a href="&#35;bib159" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">62</span></a> but also cost-effective&#46;<a href="&#35;bib161" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">64</span></a><span class="elsevierStyleSup">&#44; </span><a href="&#35;bib162" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">65</span></a></p><p class="elsevierStylePara">Two additional concerns regarding prophylactic long-term antibiotic treatment are the possibility of developing antibiotic resistance<a href="&#35;bib155" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">58</span></a><span class="elsevierStyleSup">&#44; </span><a href="&#35;bib156" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">59</span></a><span class="elsevierStyleSup">&#44; </span><a href="&#35;bib159" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">62</span></a><span class="elsevierStyleSup">&#44; </span><a href="&#35;bib160" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">63</span></a><span class="elsevierStyleSup">&#44; </span><a href="&#35;bib163" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">66</span></a> and the unknown potential adverse effects&#46;<a href="&#35;bib155" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">58</span></a><span class="elsevierStyleSup">&#44; </span><a href="&#35;bib156" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">59</span></a><span class="elsevierStyleSup">&#44; </span><a href="&#35;bib160" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">63</span></a><span class="elsevierStyleSup">&#44; </span><a href="&#35;bib163" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">66</span></a></p><p class="elsevierStylePara">All current guidelines recommend the use of antibiotics only for the treatment of infectious or severe exacerbations&#44; and do not support the use of prophylactic antibiotic therapy&#46;<a href="&#35;bib98" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">1</span></a><span class="elsevierStyleSup">&#44; </span><a href="&#35;bib99" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">2</span></a><span class="elsevierStyleSup">&#44; </span><a href="&#35;bib100" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">3</span></a><span class="elsevierStyleSup">&#44; </span><a href="&#35;bib101" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">4</span></a><span class="elsevierStyleSup">&#44; </span><a href="&#35;bib102" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">5</span></a> The Spanish guidelines also consider the addition of antibiotics in the exacerbator with chronic bronchitis phenotype with severity level IV&#46;<a href="&#35;bib99" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">2</span></a> Macrolides are one of the first choice class of antibiotics to be used when necessary&#44;<a href="&#35;bib98" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">1</span></a><span class="elsevierStyleSup">&#44; </span><a href="&#35;bib100" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">3</span></a><span class="elsevierStyleSup">&#44; </span><a href="&#35;bib101" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">4</span></a><span class="elsevierStyleSup">&#44; </span><a href="&#35;bib102" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">5</span></a> but teophylline dose should be reduced during macrolide treatment<a href="&#35;bib100" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">3</span></a><span class="elsevierStyleSup">&#44; </span><a href="&#35;bib102" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">5</span></a> since macrolides increase the serum concentration of theophylline&#46;<a href="&#35;bib98" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">1</span></a></p><a name="sec0045" class="elsevierStyleCrossRefs"></a><span class="elsevierStyleSectionTitle">Phosphodiesterase-4 inhibitors</span><p class="elsevierStylePara">Although PDE4i are currently not available in Portugal&#44; its use in COPD is already considered in the Spanish<a href="&#35;bib99" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">2</span></a> and GOLD<a href="&#35;bib98" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">1</span></a> guidelines&#46; PDE4i are thought to reduce airway inflammation and bronchoconstriction&#46; A very large systematic review concluded that PDE4i improve short-term lung function and reduce exacerbations&#44; but have minimal or no impact on daily symptoms&#44; QoL or life expectancy&#46; Moreover&#44; they are associated with gastrointestinal adverse effects and headaches&#44; with roflumilast in particular being associated with significant weight loss and some psychiatric symptoms&#46; These authors suggest that use of PDE4i should be limited to add-on therapy in a subgroup of patients with persistent symptoms or exacerbations despite optimal COPD management&#44; and recognize that the role of PDE4i and its positioning in COPD management remains to be defined&#46;<a href="&#35;bib164" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">67</span></a> Another very large systematic review of roflumilast reached the same overall conclusions&#44; and further reported that roflumilast significantly reduced moderate to severe exacerbations&#44; but not severe exacerbations alone&#46;<a href="&#35;bib165" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">68</span></a> Both reviews agree that longer-term trials are needed to determine the actual benefits of PDE4i and their long-term safety&#46; A more recent study confirmed these results by reporting a borderline statistical significance in the reduction of severe COPD exacerbations with roflumilast versus placebo in patients with severe to very severe COPD&#46;<a href="&#35;bib166" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">69</span></a> However&#44; all roflumilast results derived from industry-sponsored trials have been disputed&#44; with some authors defending that these trials were appropriate<a href="&#35;bib167" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">70</span></a> and others criticizing them&#46;<a href="&#35;bib168" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">71</span></a> A very recent study concluded that&#44; in patients with severe chronic obstructive pulmonary disease at risk for exacerbations&#44; already receiving ICS&#160;&#43;&#160;LABA&#44; with or without tiotropium&#44; roflumilast reduces exacerbations and hospital admissions&#44;<a href="&#35;bib169" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">72</span></a> and these results were corroborated in a small &#8220;real-life&#8221; population of severe COPD patients with frequent exacerbations already receiving triple therapy&#46;<a href="&#35;bib170" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">73</span></a> Roflumilast showed particular benefit in patients with 4 or more exacerbations prior to initiating therapy&#46;<a href="&#35;bib170" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">73</span></a></p><p class="elsevierStylePara">The Spanish guidelines consider the addition of PDE4i in the ACOS phenotype with severity level IV if associated with exacerbations and sputum&#44; and in the exacerbator with chronic bronchitis phenotype with severity level&#160;&#62;&#160;I PDE4i are one of the recommended choices&#46;<a href="&#35;bib99" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">2</span></a> GOLD guidelines recommend PDE4i as alternative choice treatments for GOLD C and D patients&#44; and state that they may be useful to reduce exacerbations in patients with FEV<span class="elsevierStyleInf">1</span>&#160;&#60;&#160;50&#37; predicted&#44; chronic bronchitis&#44; and frequent exacerbations&#46; Despite this&#44; PDE4i should always be used in combination with at least one long-acting bronchodilator&#46;<a href="&#35;bib98" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">1</span></a></p><a name="sec0050" class="elsevierStyleCrossRefs"></a><span class="elsevierStyleSectionTitle">Methylxanthines</span><p class="elsevierStylePara">Methylxanthines are nonspecific inhibitors of all phosphodiesterase enzyme subsets&#44; and have a wide range of adverse effects<a href="&#35;bib98" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">1</span></a> related to plasma concentrations&#44; including nausea&#44; vomiting&#44; and headaches and&#44; at higher concentrations&#44; cardiac arrhythmias and seizures&#46;<a href="&#35;bib171" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">74</span></a> Theophylline&#44; the most widely used methylxanthine&#44; has shown clinically relevant results in patients with stable COPD&#44; namely FEV<span class="elsevierStyleInf">1</span> and FVC improvement&#44;<a href="&#35;bib172" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">75</span></a><span class="elsevierStyleSup">&#44; </span><a href="&#35;bib173" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">76</span></a> as well as improvements in maximal O<span class="elsevierStyleInf">2</span> uptake &#40;VO<span class="elsevierStyleInf">2max</span>&#41;&#44; O<span class="elsevierStyleInf">2</span> partial pressure &#40;PaO<span class="elsevierStyleInf">2</span>&#41; and CO<span class="elsevierStyleInf">2</span> partial pressure &#40;PaCO<span class="elsevierStyleInf">2</span>&#41;&#46;<a href="&#35;bib173" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">76</span></a> Theophylline has a role in the management of stable COPD&#44; and is currently used as add-on therapy in severe COPD patients not controlled by bronchodilator therapy&#46;<a href="&#35;bib171" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">74</span></a> However&#44; its wider use is hampered by the fact that blood levels need to be closely monitored due to serious&#44; even potentially life-threatening side-effects&#46;<a href="&#35;bib172" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">75</span></a><span class="elsevierStyleSup">&#44; </span><a href="&#35;bib173" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">76</span></a> As for the use of methylxanthines in the management of COPD exacerbations&#44; current evidence does not support it&#44; given that the possible beneficial effects in lung function and clinical endpoints are modest and inconsistent&#44; whereas adverse effects are significant&#46;<a href="&#35;bib174" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">77</span></a> All current guidelines stand by this point of view&#46;</p><p class="elsevierStylePara">The Spanish guidelines consider the addition of theophylline in all phenotypes&#44; but only with severity level IV&#46;<a href="&#35;bib99" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">2</span></a> GOLD recommends theophylline as an alternative choice treatment for all GOLD classes&#44; but only if other long-term treatment bronchodilators are unavailable or unaffordable&#46;<a href="&#35;bib98" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">1</span></a> The NICE guidelines propose that theophylline should only be used after a trial of short-acting bronchodilators and long-acting bronchodilators&#44; or in patients who are unable to use inhaled therapy&#46;<a href="&#35;bib100" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">3</span></a> The Canadian guidelines only recommend trying theophylline in patients with severe symptoms and frequent exacerbations despite use of both tiotropium and a LABA&#47;ICS&#46;<a href="&#35;bib101" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">4</span></a> In the management of exacerbations&#44; intravenous methylxanthines &#40;theophylline or aminophylline&#41; are considered second-line therapy&#44; only to be used in selected cases when there is insufficient response to short-acting bronchodilators&#46;<a href="&#35;bib98" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">1</span></a><span class="elsevierStyleSup">&#44; </span><a href="&#35;bib100" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">3</span></a><span class="elsevierStyleSup">&#44; </span><a href="&#35;bib102" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">5</span></a> When using theophylline&#44; it is necessary to monitor blood levels&#44; side effects and potential drug interactions&#46;<a href="&#35;bib101" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">4</span></a></p><a name="sec0055" class="elsevierStyleCrossRefs"></a><span class="elsevierStyleSectionTitle">Immunostimulating agents</span><p class="elsevierStylePara">A few small studies have reported a potential benefit of the immunostimulating agent OM-85 in the prevention of severe respiratory events&#44; risk of hospitalization and duration of hospital stay in severe and very severe COPD patients&#44;<a href="&#35;bib175" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">78</span></a> and in the decrease of acute exacerbations&#44; symptoms&#44; and need for antibiotics and symptomatic relief medications&#44; in patients with chronic bronchitis and COPD&#46;<a href="&#35;bib176" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">79</span></a> OM-85 was well tolerated&#46;<a href="&#35;bib176" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">79</span></a> In patients with chronic bronchitis or mild COPD&#44; a decrease in exacerbation frequency was observed after 6 months of intermittent OM-85 administration &#40;30 days followed by three 10-day courses for months 3&#44; 4 and 5&#41;&#44; and OM-85 was also well tolerated&#46;<a href="&#35;bib177" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">80</span></a> However&#44; these studies were small and the longest follow-up period lasted for only 1 year&#46;</p><p class="elsevierStylePara">GOLD does not recommend regular use of immunostimulating agents due to the lack of studies on their long-term effects&#46;<a href="&#35;bib98" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">1</span></a></p><p class="elsevierStylePara"><a href="&#35;t0020" class="elsevierStyleCrossRefs">Table 4</a> summarizes our proposals&#44; suggestions and recommendations on additional non-inhaled therapies&#46;</p><p class="elsevierStylePara">Table 4&#46; Additional useful non-inhaled therapies&#46;</p><a name="t0020" class="elsevierStyleCrossRefs"></a><p class="elsevierStylePara"></p><table><tr align="left"><td rowspan="2">Mucolytic agents</td><td>&#8226; seem to prevent exacerbations in certain subtypes of COPD patients</td></tr><tr align="left"><td>&#8226; suggestion to use in a patient-oriented manner</td></tr><tr align="left"><td rowspan="3">Macrolides</td><td>&#8226; current uncertainties of long-term macrolide use</td></tr><tr align="left"><td>&#8226; proposal of&#44; when considering this approach&#44; continuous use is preferable to intermittent use and severe frequent exacerbators are the phenotype of choice</td></tr><tr align="left"><td>&#8226; decision should be patient-oriented&#44; considering the risk&#47;benefit ratio for each individual</td></tr><tr align="left"><td rowspan="3">Phosphodiesterase-4 inhibitors &#40;PDE4i&#41;</td><td>&#8226; identification of the group of patients that could benefit the most from PDE4i remains elusive</td></tr><tr align="left"><td>&#8226; proposal that this alternative should be offered to more severe patients&#44; frequent exacerbators or with chronic bronchitis&#44; without low BMI</td></tr><tr align="left"><td>&#8226; weight loss and gastrointestinal adverse effects should be monitored closely</td></tr><tr align="left"><td rowspan="4">Methylxanthines in COPD exacerbations</td><td>&#8226; current evidence does not support their use in the management of COPD exacerbations</td></tr><tr align="left"><td>&#8226; possible beneficial effects in lung function and clinical endpoints are modest and inconsistent&#44; whereas adverse effects are significant</td></tr><tr align="left"><td>&#8226; intravenous methylxanthines &#40;theophylline or aminophylline&#41; are considered second-line therapy&#44; only to be used in selected cases when there is insufficient response to short-acting bronchodilators</td></tr><tr align="left"><td>&#8226; when using theophylline&#44; it is necessary to monitor blood levels&#44; side effects and potential drug interactions</td></tr><tr align="left"><td rowspan="4">Theophylline for Stable COPD</td><td>&#8226; to be considered in all phenotypes&#44; but only with severity level IV</td></tr><tr align="left"><td>&#8226; recommended as an alternative choice treatment for all GOLD classes&#44; but only if other long-term treatment bronchodilators are unavailable or unaffordable</td></tr><tr align="left"><td>&#8226; should only be used after a trial of short-acting bronchodilators and long-acting bronchodilators&#44; or in patients who are unable to use inhaled therapy</td></tr><tr align="left"><td>&#8226; only recommended to try in patients with severe symptoms and frequent exacerbations despite use of both tiotropium and a LABA&#47;ICS</td></tr><tr align="left"><td>Immunostimulating agents</td><td>&#8226; not recommended due to lack of studies on their long-term effects</td></tr></table><a name="sec0060" class="elsevierStyleCrossRefs"></a><span class="elsevierStyleSectionTitle">Treatment of co-morbidities</span><p class="elsevierStylePara">There are no conclusive data establishing that treatment of COPD co-morbidities will reduce morbidity and mortality rates in patients&#46; The fact that patients with clinically relevant co-morbidities are usually excluded from clinical trials of COPD&#44; and that patients with COPD are also usually excluded from clinical trials on other pathologies&#44; has prevented evidence-based clinical treatment guidelines in these patients&#46; However&#44; co-morbidities should be adequately controlled due to their potential negative impact on COPD prognosis&#46;<a href="&#35;bib98" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">1</span></a></p><a name="sec0065" class="elsevierStyleCrossRefs"></a><span class="elsevierStyleSectionTitle">Cardiovascular co-morbidities</span><a name="sec0070" class="elsevierStyleCrossRefs"></a><span class="elsevierStyleSectionTitle"><span class="elsevierStyleItalic">Cardiovascular medications</span></span><p class="elsevierStylePara">A large retrospective study reported that statins&#44; angiotensin-converting-enzyme inhibitors &#40;ACEi&#41;&#44; and angiotensin-receptor blockers &#40;ARBs&#41; could have cardioprotective properties in patients with COPD&#44; substantially altering their prognosis&#46; Also&#44; COPD hospitalization and total mortality rates were reduced&#44; as well as the myocardial infarction rate in COPD patients with high cardiovascular risk&#44; independently of the concomitant use of steroids&#46; The largest benefits were observed with the combination of statins and either ACEi or ARBs&#46;<a href="&#35;bib178" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">81</span></a> Several further studies were conducted to assess the potential effect of statins and ACEi on COPD&#44; and reviews of those studies concluded that they were beneficial&#46;<a href="&#35;bib179" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">82</span></a><span class="elsevierStyleSup">&#44; </span><a href="&#35;bib180" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">83</span></a><span class="elsevierStyleSup">&#44; </span><a href="&#35;bib181" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">84</span></a><span class="elsevierStyleSup">&#44; </span><a href="&#35;bib182" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">85</span></a><span class="elsevierStyleSup">&#44; </span><a href="&#35;bib183" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">86</span></a> However&#44; all these studies were observational&#44; and a very recent large RCT on the effects of simvastatin on exacerbations and FEV<span class="elsevierStyleInf">1</span> in COPD patients was terminated due to futility&#46;<a href="&#35;bib184" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">87</span></a> Other RCTs also failed to prove the benefits of ACEi<a href="&#35;bib185" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">88</span></a> or ARBs<a href="&#35;bib186" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">89</span></a> in different COPD outcomes&#46; GOLD guidelines do not mention the use of these medications and state that cardiovascular co-morbidities should be treated according to their specific guidelines&#46;<a href="&#35;bib98" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">1</span></a></p><a name="sec0075" class="elsevierStyleCrossRefs"></a><span class="elsevierStyleSectionTitle"><span class="elsevierStyleItalic">&#946;-Blockers</span></span><p class="elsevierStylePara">There has been concern that prescription of &#946;-blockers for patients with COPD might cause bronchoconstriction and worsen respiratory symptoms&#46;<a href="&#35;bib109" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">12</span></a> However&#44; cardioselective &#946;-blockers have been shown to be associated with reduced mortality in patients with COPD undergoing vascular surgery&#44;<a href="&#35;bib187" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">90</span></a> and a meta-analysis did not find significant differences in FEV<span class="elsevierStyleInf">1</span> or respiratory symptoms between patients treated with a cardioselective &#946;-blocker and those treated with placebo&#44; even in patients with severe COPD&#46;<a href="&#35;bib188" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">91</span></a> Another very recent meta-analysis concluded that the use of &#946;-blockers in patients with COPD with or without co-morbid cardiovascular diseases&#44; may not only decrease the risk of overall mortality but also reduce the risk of exacerbations&#44; concluding that&#44; given the benefits of &#946;-blockers in conditions such as hypertension&#44; heart failure and coronary artery disease&#44; these drugs should not be withheld because of COPD&#46;<a href="&#35;bib189" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">92</span></a> In a fairly large population &#40;<span class="elsevierStyleItalic">n</span>&#160;&#61;&#160;825&#41; of inpatients admitted for acute exacerbations of COPD&#44; the use of &#946;-blockers was well tolerated and associated with reduced mortality&#46;<a href="&#35;bib190" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">93</span></a> Current guidelines recommend the use of &#946;-blockers to treat specific associated co-morbidities&#44;<a href="&#35;bib98" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">1</span></a><span class="elsevierStyleSup">&#44; </span><a href="&#35;bib99" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">2</span></a> preferably cardioselective &#946;-blockers&#44;<a href="&#35;bib98" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">1</span></a> with the added advantage of reducing exacerbations and mortality associated with some cardiovascular co-morbidities&#46;<a href="&#35;bib99" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">2</span></a></p><a name="sec0080" class="elsevierStyleCrossRefs"></a><span class="elsevierStyleSectionTitle">Gastroesophageal reflux disease &#40;GERD&#41;</span><p class="elsevierStylePara">GERD is one of the most common causes of chronic cough and is a frequent co-morbidity in COPD patients&#44; also being associated with exacerbations&#46;<a href="&#35;bib191" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">94</span></a><span class="elsevierStyleSup">&#44; </span><a href="&#35;bib192" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">95</span></a><span class="elsevierStyleSup">&#44; </span><a href="&#35;bib193" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">96</span></a> Older age and female gender<a href="&#35;bib192" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">95</span></a> are associated with GERD in COPD patients&#44; and the association between GERD and obesity is well known&#46; A very recent large study reported that COPD patients with GERD were at increased risk of medically treated COPD exacerbations&#44; defined as a short course treatment with oral corticosteroids alone or in combination with antibiotics&#44; only if they did not use acid inhibitory treatment regularly&#46;<a href="&#35;bib193" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">96</span></a> These results are in accordance with a small study that reported that proton pump inhibitor use was associated with a significant decrease in COPD exacerbations in older patients&#46;<a href="&#35;bib194" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">97</span></a> Also&#44; it has been reported that most of COPD medications except LAMA are associated with GERD&#46;<a href="&#35;bib192" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">95</span></a> GOLD guidelines state that proton pump inhibitors are often used for treatment of GERD&#44; but the most effective treatment for this condition in patients with COPD has yet to be established&#46;<a href="&#35;bib98" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">1</span></a></p><p class="elsevierStylePara"><a href="&#35;t0025" class="elsevierStyleCrossRefs">Table 5</a> summarizes our proposals&#44; suggestions and recommendations on the treatment of cardiovascular co-morbidities and GERD&#46;</p><p class="elsevierStylePara">Table 5&#46; Treatment of co-morbidities&#46;</p><a name="t0025" class="elsevierStyleCrossRefs"></a><p class="elsevierStylePara"></p><table><tr align="left"><td rowspan="2">Cardiovascular</td><td>&#8226; cardiovascular co-morbidities should be treated according to their specific guidelines</td></tr><tr align="left"><td>&#8226; in the presence of some cardiovascular co-morbidities&#44; cardioselective beta-blockers are not only safe but also beneficial in the control of COPD</td></tr><tr align="left"><td rowspan="2">Gastroesophageal reflux disease &#40;GERD&#41;</td><td>&#8226; special attention should be given to older patients&#44; women&#44; and obese patients</td></tr><tr align="left"><td>&#8226; a proton pump inhibitor is advisable</td></tr></table><a name="sec0085" class="elsevierStyleCrossRefs"></a><span class="elsevierStyleSectionTitle">Conclusions</span><p class="elsevierStylePara">Although this paper proposes a therapeutic scheme for COPD patients&#44; a full consensus on optimal treatment sequence in COPD cannot be found at present&#46; There are still too many unknown variables&#44; no reliable biomarkers to guide treatment&#44; and a poor definition of clinically relevant COPD phenotypes&#46; It is imperative that active research continues in order not only to identify specific groups of patients that can benefit from specific treatments&#44; but also to develop new molecules or combinations of molecules&#44; that are more effective in symptom control&#46; The ultimate goal would be to stop disease progression&#44; but this goal may not be attainable&#46; At present&#44; COPD should be treated in a personalized&#44; tailor-made&#44; patient-oriented manner&#46;</p><a name="sec0090" class="elsevierStyleCrossRefs"></a><span class="elsevierStyleSectionTitle">Ethical responsibilities</span><a name="sec0095" class="elsevierStyleCrossRefs"></a><span class="elsevierStyleSectionTitle">Protection of human and animal subjects</span><p class="elsevierStylePara">The authors declare that no experiments were performed on humans or animals for this study&#46;</p><a name="sec0100" class="elsevierStyleCrossRefs"></a><span class="elsevierStyleSectionTitle">Confidentiality of data</span><p class="elsevierStylePara">The authors declare that no patient data appear in this article&#46;</p><a name="sec0105" class="elsevierStyleCrossRefs"></a><span class="elsevierStyleSectionTitle">Right to privacy and informed consent</span><p class="elsevierStylePara">The authors declare that no patient data appear in this article&#46;</p><a name="sec0110" class="elsevierStyleCrossRefs"></a><span class="elsevierStyleSectionTitle">Conflict of interest</span><p class="elsevierStylePara">The authors declare collaborating and receiving fees from pharmaceutical companies other than Novartis either through participation in advisory board or consultancy meetings&#44; congress symposia&#44; clinical trial conduct or investigator-initiated trials&#46;</p><a name="sec0115" class="elsevierStyleCrossRefs"></a><span class="elsevierStyleSectionTitle">Role of funding source</span><p class="elsevierStylePara">Funding for this paper was provided by Novartis Portugal&#46; Funding was used to access all necessary scientific bibliography and cover meeting expenses&#46; Novartis Portugal had no role in the collection&#44; analysis and interpretation of data&#44; in the writing of the paper and in the decision to submit the paper for publication&#46;</p><p class="elsevierStylePara">Acknowledgements</p><p class="elsevierStylePara">The authors wish to thank Novartis Portugal for the funding for this paper&#44; which was used to access all necessary scientific bibliography and cover meeting expenses&#46;</p><p class="elsevierStylePara">Received 8 August 2015 <br></br>Accepted 20 October 2015 </p><p class="elsevierStylePara">Corresponding author&#46; carlos&#46;crobalo&#64;gmail&#46;com</p>"
    "pdfFichero" => "320v22n01a90447947pdf001.pdf"
    "tienePdf" => true
    "PalabrasClave" => array:1 [
      "en" => array:1 [
        0 => array:4 [
          "clase" => "keyword"
          "titulo" => "Keywords"
          "identificador" => "xpalclavsec640961"
          "palabras" => array:9 [
            0 => "COPD"
            1 => "Treatment sequence"
            2 => "SABA"
            3 => "SAMA"
            4 => "LABA"
            5 => "LAMA"
            6 => "ICS"
            7 => "Triple therapy"
            8 => "Non-inhaled therapies"
          ]
        ]
      ]
    ]
    "tieneResumen" => true
    "resumen" => array:1 [
      "en" => array:1 [
        "resumen" => "<span class="elsevierStyleSectionTitle"> Abstract</span><br/><p class="elsevierStylePara"> There is currently no consensus on the treatment sequence in chronic obstructive pulmonary disease &#40;COPD&#41;&#44; although it is recognized that early diagnosis is of paramount importance to start treatment in the early stages of the disease&#46; Although it is fairly consensual that initial treatment should be with an inhaled short-acting beta agonist&#44; a short-acting muscarinic antagonist&#44; a long-acting beta-agonist or a long-acting muscarinic antagonist&#46; As the disease progresses&#44; several therapeutic options are available&#44; and which to choose at each disease stage remains controversial&#46; When and in which patients to use dual bronchodilation&#63; When to use inhaled corticosteroids&#63; And triple therapy&#63; Are the existing non-inhaled therapies&#44; such as mucolytic agents&#44; antibiotics&#44; phosphodiesterase-4 inhibitors&#44; methylxanthines and immunostimulating agents&#44; useful&#63; If so&#44; which patients would benefit&#63; Should co-morbitities be taken into account when choosing COPD therapy for a patient&#63;</p><p class="elsevierStylePara"> This paper reviews current guidelines and available evidence and proposes a therapeutic scheme for COPD patients&#46; We also propose a treatment algorithm in the hope that it will help physicians to decide the best approach for their patients&#46; The authors conclude that&#44; at present&#44; a full consensus on optimal treatment sequence in COPD cannot be found&#44; mainly due to disease heterogeneity and lack of biomarkers to guide treatment&#46; For the time being&#44; and although some therapeutic approaches are consensual&#44; treatment of COPD should be patient-oriented&#46;</p>"
      ]
    ]
    "multimedia" => array:2 [
      0 => array:8 [
        "identificador" => "fig1"
        "etiqueta" => "Figure 1"
        "tipo" => "MULTIMEDIAFIGURA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "copyright" => "Elsevier Espa&#241;a"
        "figura" => array:1 [
          0 => array:4 [
            "imagen" => "320v22n01-90447947fig1.jpg"
            "Alto" => 1979
            "Ancho" => 3091
            "Tamanyo" => 539936
          ]
        ]
        "descripcion" => array:1 [
          "en" => "Proposed therapeutic scheme&#46; From top to bottom&#58; asthma component predominant to COPD component predominant&#46;"
        ]
      ]
      1 => array:6 [
        "identificador" => "fig2"
        "tipo" => "MULTIMEDIAFIGURA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "copyright" => "Elsevier Espa&#241;a"
        "descripcion" => array:1 [
          "en" => "Proposed therapeutic scheme&#46; From top to bottom&#58; asthma component predominant to COPD component predominant&#46;"
        ]
      ]
    ]
    "bibliografia" => array:2 [
      "titulo" => "Bibliography"
      "seccion" => array:1 [
        0 => array:1 [
          "bibliografiaReferencia" => array:97 [
            0 => array:3 [
              "identificador" => "bib98"
              "etiqueta" => "1"
              "referencia" => array:1 [
                0 => array:3 [
                  "referenciaCompleta" => "Global Strategy for the Diagnosis, Management and Prevention of Chronic Obstructive Pulmonary Disease (Updated). 2015. "
                  "contribucion" => array:1 [
                    0 => array:3 [
                      "titulo" => "Global Strategy for the Diagnosis&#44; Management and Prevention of Chronic Obstructive Pulmonary Disease &#40;Updated&#41;&#46;"
                      "idioma" => "en"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:1 [
                            0 => "Global Initiative for Chronic Obstructive Lung Disease&#46;"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:1 [
                        "tituloSerie" => "2015. "
                      ]
                    ]
                  ]
                ]
              ]
            ]
            1 => array:3 [
              "identificador" => "bib99"
              "etiqueta" => "2"
              "referencia" => array:1 [
                0 => array:3 [
                  "referenciaCompleta" => "Spanish guideline for COPD (GesEPOC). Update 2014. Arch Bronconeumol. 2014; 50(Suppl. 1):1-16. "
                  "contribucion" => array:1 [
                    0 => array:3 [
                      "titulo" => "Spanish guideline for COPD &#40;GesEPOC&#41;&#46; Update 2014&#46;"
                      "idioma" => "en"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:7 [
                            0 => "Miravitlles M"
                            1 => "Soler-Cataluna JJ"
                            2 => "Calle M"
                            3 => "Molina J"
                            4 => "Almagro P"
                            5 => "Quintano JA"
                            6 => "et-al&#46;"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:3 [
                        "tituloSerie" => "Arch Bronconeumol. "
                        "fecha" => "2014"
                        "volumen" => "50"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            2 => array:3 [
              "identificador" => "bib100"
              "etiqueta" => "3"
              "referencia" => array:1 [
                0 => array:3 [
                  "referenciaCompleta" => "Chronic obstructive pulmonary disease: management of chronic obstructive pulmonary disease in adults in primary and secondary care (partial update). 2010. <inter-ref>http://www.nice.org.uk/guidance/CG101</inter-ref>. "
                  "contribucion" => array:1 [
                    0 => array:3 [
                      "titulo" => "Chronic obstructive pulmonary disease&#58; management of chronic obstructive pulmonary disease in adults in primary and secondary care &#40;partial update&#41;&#46; 2010&#46;  http&#58;&#47;&#47;www&#46;nice&#46; "
                      "idioma" => "en"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:1 [
                            0 => "National Institute for Health and Care Excellence&#46;"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:2 [
                        "tituloSerie" => "org. "
                        "fecha" => "uk/guidance/CG101</inter-ref>"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            3 => array:3 [
              "identificador" => "bib101"
              "etiqueta" => "4"
              "referencia" => array:1 [
                0 => array:3 [
                  "referenciaCompleta" => "Canadian Thoracic Society recommendations for management of chronic obstructive pulmonary disease – 2007 update. Can Respir J. 2007; 14(Suppl. B):5B-32B. "
                  "contribucion" => array:1 [
                    0 => array:3 [
                      "titulo" => "Canadian Thoracic Society recommendations for management of chronic obstructive pulmonary disease – 2007 update&#46;"
                      "idioma" => "en"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:7 [
                            0 => "O’Donnell DE"
                            1 => "Aaron S"
                            2 => "Bourbeau J"
                            3 => "Hernandez P"
                            4 => "Marciniuk DD"
                            5 => "Balter M"
                            6 => "et-al&#46;"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:3 [
                        "tituloSerie" => "Can Respir J. "
                        "fecha" => "2007"
                        "volumen" => "14"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            4 => array:3 [
              "identificador" => "bib102"
              "etiqueta" => "5"
              "referencia" => array:1 [
                0 => array:3 [
                  "referenciaCompleta" => "Norma nr 028/2011 – Diagnóstico e Tratamento da Doença Pulmonar Obstrutiva Crónica. Portugal. 2013. "
                  "contribucion" => array:1 [
                    0 => array:3 [
                      "titulo" => "Norma nr 028&#47;2011 – Diagn&#243;stico e Tratamento da Doen&#231;a Pulmonar Obstrutiva Cr&#243;nica&#46; Portugal&#46;"
                      "idioma" => "pt"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:1 [
                            0 => "Direc&#231;&#227;o Geral de Sa&#250;de&#46;"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:1 [
                        "tituloSerie" => "2013. "
                      ]
                    ]
                  ]
                ]
              ]
            ]
            5 => array:3 [
              "identificador" => "bib103"
              "etiqueta" => "6"
              "referencia" => array:1 [
                0 => array:3 [
                  "referenciaCompleta" => "Inhaled corticosteroids in COPD: the clinical evidence. Eur Respir J. 2015; 45:525-37. "
                  "contribucion" => array:1 [
                    0 => array:3 [
                      "titulo" => "Inhaled corticosteroids in COPD&#58; the clinical evidence&#46;"
                      "idioma" => "en"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [
                            0 => "Ernst P"
                            1 => "Saad N"
                            2 => "Suissa S&#46;"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:3 [
                        "tituloSerie" => "Eur Respir J. "
                        "fecha" => "2015"
                        "volumen" => "45:525-37."
                      ]
                    ]
                  ]
                ]
              ]
            ]
            6 => array:3 [
              "identificador" => "bib104"
              "etiqueta" => "7"
              "referencia" => array:1 [
                0 => array:3 [
                  "referenciaCompleta" => "The asthma-chronic obstructive pulmonary disease overlap syndrome (ACOS): opportunities and challenges. Curr Opin Pulm Med. 2015; 21:74-9. "
                  "contribucion" => array:1 [
                    0 => array:3 [
                      "titulo" => "The asthma-chronic obstructive pulmonary disease overlap syndrome &#40;ACOS&#41;&#58; opportunities and challenges&#46;"
                      "idioma" => "en"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [
                            0 => "Barrecheguren M"
                            1 => "Esquinas C"
                            2 => "Miravitlles M&#46;"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:3 [
                        "tituloSerie" => "Curr Opin Pulm Med. "
                        "fecha" => "2015"
                        "volumen" => "21:74-9."
                      ]
                    ]
                  ]
                ]
              ]
            ]
            7 => array:3 [
              "identificador" => "bib105"
              "etiqueta" => "8"
              "referencia" => array:1 [
                0 => array:3 [
                  "referenciaCompleta" => "Use of inhaled corticosteroids and the risk of tuberculosis. Thorax. 2013; 68:1105-13. "
                  "contribucion" => array:1 [
                    0 => array:3 [
                      "titulo" => "Use of inhaled corticosteroids and the risk of tuberculosis&#46;"
                      "idioma" => "en"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:6 [
                            0 => "Lee CH"
                            1 => "Kim K"
                            2 => "Hyun MK"
                            3 => "Jang EJ"
                            4 => "Lee NR"
                            5 => "Yim JJ&#46;"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:3 [
                        "tituloSerie" => "Thorax. "
                        "fecha" => "2013"
                        "volumen" => "68:1105-13."
                      ]
                    ]
                  ]
                ]
              ]
            ]
            8 => array:3 [
              "identificador" => "bib106"
              "etiqueta" => "9"
              "referencia" => array:1 [
                0 => array:3 [
                  "referenciaCompleta" => "Guimarães M, Bugalho A, Oliveira AS, Moita J, Marques M. COPD symptoms control: can a consensus be found? submitted for publication. "
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Guimar&#227;es M&#44; Bugalho A&#44; Oliveira AS&#44; Moita J&#44; Marques M&#46;"
                      "idioma" => "pt"
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:1 [
                        "tituloSerie" => "COPD symptoms control: can a consensus be found? submitted for publication. "
                      ]
                    ]
                  ]
                ]
              ]
            ]
            9 => array:3 [
              "identificador" => "bib107"
              "etiqueta" => "10"
              "referencia" => array:1 [
                0 => array:3 [
                  "referenciaCompleta" => "Global Strategy for the Diagnosis, Management and Prevention of Chronic Obstructive Pulmonary Disease (Updated). 2014. "
                  "contribucion" => array:1 [
                    0 => array:3 [
                      "titulo" => "Global Strategy for the Diagnosis&#44; Management and Prevention of Chronic Obstructive Pulmonary Disease &#40;Updated&#41;&#46;"
                      "idioma" => "en"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:1 [
                            0 => "Global Initiative for Chronic Obstructive Lung Disease&#46;"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:1 [
                        "tituloSerie" => "2014. "
                      ]
                    ]
                  ]
                ]
              ]
            ]
            10 => array:3 [
              "identificador" => "bib108"
              "etiqueta" => "11"
              "referencia" => array:1 [
                0 => array:3 [
                  "referenciaCompleta" => "Risk-to-benefit ratio of inhaled corticosteroids in patients with COPD. Prim Care Respir J. 2013; 22:92-100. "
                  "contribucion" => array:1 [
                    0 => array:3 [
                      "titulo" => "Risk-to-benefit ratio of inhaled corticosteroids in patients with COPD&#46;"
                      "idioma" => "en"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:4 [
                            0 => "Price D"
                            1 => "Yawn B"
                            2 => "Brusselle G"
                            3 => "Rossi A&#46;"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:3 [
                        "tituloSerie" => "Prim Care Respir J. "
                        "fecha" => "2013"
                        "volumen" => "22:92-100."
                      ]
                    ]
                  ]
                ]
              ]
            ]
            11 => array:3 [
              "identificador" => "bib109"
              "etiqueta" => "12"
              "referencia" => array:1 [
                0 => array:3 [
                  "referenciaCompleta" => "Controversies in treatment of chronic obstructive pulmonary disease. Lancet. 2011; 378:1038-47. "
                  "contribucion" => array:1 [
                    0 => array:3 [
                      "titulo" => "Controversies in treatment of chronic obstructive pulmonary disease&#46;"
                      "idioma" => "en"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "Rabe KF"
                            1 => "Wedzicha JA&#46;"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:3 [
                        "tituloSerie" => "Lancet. "
                        "fecha" => "2011"
                        "volumen" => "378:1038-47."
                      ]
                    ]
                  ]
                ]
              ]
            ]
            12 => array:3 [
              "identificador" => "bib110"
              "etiqueta" => "13"
              "referencia" => array:1 [
                0 => array:3 [
                  "referenciaCompleta" => "Tiotropium versus salmeterol for the prevention of exacerbations of COPD. N Engl J Med. 2011; 364:1093-103. "
                  "contribucion" => array:1 [
                    0 => array:3 [
                      "titulo" => "Tiotropium versus salmeterol for the prevention of exacerbations of COPD&#46;"
                      "idioma" => "en"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:7 [
                            0 => "Vogelmeier C"
                            1 => "Hederer B"
                            2 => "Glaab T"
                            3 => "Schmidt H"
                            4 => "Rutten-van Molken MP"
                            5 => "Beeh KM"
                            6 => "et-al&#46;"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:3 [
                        "tituloSerie" => "N Engl J Med. "
                        "fecha" => "2011"
                        "volumen" => "364:1093-103."
                      ]
                    ]
                  ]
                ]
              ]
            ]
            13 => array:3 [
              "identificador" => "bib111"
              "etiqueta" => "14"
              "referencia" => array:1 [
                0 => array:3 [
                  "referenciaCompleta" => "Susceptibility to exacerbation in chronic obstructive pulmonary disease. N Engl J Med. 2010; 363:1128-38. "
                  "contribucion" => array:1 [
                    0 => array:3 [
                      "titulo" => "Susceptibility to exacerbation in chronic obstructive pulmonary disease&#46;"
                      "idioma" => "en"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:7 [
                            0 => "Hurst JR"
                            1 => "Vestbo J"
                            2 => "Anzueto A"
                            3 => "Locantore N"
                            4 => "Mullerova H"
                            5 => "Tal-Singer R"
                            6 => "et-al&#46;"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:3 [
                        "tituloSerie" => "N Engl J Med. "
                        "fecha" => "2010"
                        "volumen" => "363:1128-38."
                      ]
                    ]
                  ]
                ]
              ]
            ]
            14 => array:3 [
              "identificador" => "bib112"
              "etiqueta" => "15"
              "referencia" => array:1 [
                0 => array:3 [
                  "referenciaCompleta" => "Salmeterol and fluticasone propionate and survival in chronic obstructive pulmonary disease. N Engl J Med. 2007; 356:775-89. "
                  "contribucion" => array:1 [
                    0 => array:3 [
                      "titulo" => "Salmeterol and fluticasone propionate and survival in chronic obstructive pulmonary disease&#46;"
                      "idioma" => "en"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:7 [
                            0 => "Calverley PM"
                            1 => "Anderson JA"
                            2 => "Celli B"
                            3 => "Ferguson GT"
                            4 => "Jenkins C"
                            5 => "Jones PW"
                            6 => "et-al&#46;"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:3 [
                        "tituloSerie" => "N Engl J Med. "
                        "fecha" => "2007"
                        "volumen" => "356:775-89."
                      ]
                    ]
                  ]
                ]
              ]
            ]
            15 => array:3 [
              "identificador" => "bib113"
              "etiqueta" => "16"
              "referencia" => array:1 [
                0 => array:3 [
                  "referenciaCompleta" => "Effect of tiotropium on outcomes in patients with moderate chronic obstructive pulmonary disease (UPLIFT): a prespecified subgroup analysis of a randomised controlled trial. Lancet. 2009; 374:1171-8. "
                  "contribucion" => array:1 [
                    0 => array:3 [
                      "titulo" => "Effect of tiotropium on outcomes in patients with moderate chronic obstructive pulmonary disease &#40;UPLIFT&#41;&#58; a prespecified subgroup analysis of a randomised controlled trial&#46;"
                      "idioma" => "en"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:6 [
                            0 => "Decramer M"
                            1 => "Celli B"
                            2 => "Kesten S"
                            3 => "Lystig T"
                            4 => "Mehra S"
                            5 => "Tashkin DP&#46;"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:3 [
                        "tituloSerie" => "Lancet. "
                        "fecha" => "2009"
                        "volumen" => "374:1171-8."
                      ]
                    ]
                  ]
                ]
              ]
            ]
            16 => array:3 [
              "identificador" => "bib114"
              "etiqueta" => "17"
              "referencia" => array:1 [
                0 => array:3 [
                  "referenciaCompleta" => "Global Strategy for the Diagnosis, Management and Prevention of Chronic Obstructive Pulmonary Disease (Revised). 2011. "
                  "contribucion" => array:1 [
                    0 => array:3 [
                      "titulo" => "Global Strategy for the Diagnosis&#44; Management and Prevention of Chronic Obstructive Pulmonary Disease &#40;Revised&#41;&#46;"
                      "idioma" => "en"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:1 [
                            0 => "Global Initiative for Chronic Obstructive Lung Disease&#46;"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:1 [
                        "tituloSerie" => "2011. "
                      ]
                    ]
                  ]
                ]
              ]
            ]
            17 => array:3 [
              "identificador" => "bib115"
              "etiqueta" => "18"
              "referencia" => array:1 [
                0 => array:3 [
                  "referenciaCompleta" => "Prediction of the clinical course of chronic obstructive pulmonary disease, using the new GOLD classification: a study of the general population. Am J Respir Crit Care Med. 2012; 186:975-81. "
                  "contribucion" => array:1 [
                    0 => array:3 [
                      "titulo" => "Prediction of the clinical course of chronic obstructive pulmonary disease&#44; using the new GOLD classification&#58; a study of the general population&#46;"
                      "idioma" => "en"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:7 [
                            0 => "Lange P"
                            1 => "Marott JL"
                            2 => "Vestbo J"
                            3 => "Olsen KR"
                            4 => "Ingebrigtsen TS"
                            5 => "Dahl M"
                            6 => "et-al&#46;"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:3 [
                        "tituloSerie" => "Am J Respir Crit Care Med. "
                        "fecha" => "2012"
                        "volumen" => "186:975-81."
                      ]
                    ]
                  ]
                ]
              ]
            ]
            18 => array:3 [
              "identificador" => "bib116"
              "etiqueta" => "19"
              "referencia" => array:1 [
                0 => array:3 [
                  "referenciaCompleta" => "Efficacy and safety of once-daily QVA149 compared with twice-daily salmeterol-fluticasone in patients with chronic obstructive pulmonary disease (ILLUMINATE): a randomised, double-blind, parallel group study. Lancet Respir Med. 2013; 1:51-60. "
                  "contribucion" => array:1 [
                    0 => array:3 [
                      "titulo" => "Efficacy and safety of once-daily QVA149 compared with twice-daily salmeterol-fluticasone in patients with chronic obstructive pulmonary disease &#40;ILLUMINATE&#41;&#58; a randomised&#44; double-blind&#44; parallel group study&#46;"
                      "idioma" => "en"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:7 [
                            0 => "Vogelmeier CF"
                            1 => "Bateman ED"
                            2 => "Pallante J"
                            3 => "Alagappan VK"
                            4 => "D’Andrea P"
                            5 => "Chen H"
                            6 => "et-al&#46;"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:3 [
                        "tituloSerie" => "Lancet Respir Med. "
                        "fecha" => "2013"
                        "volumen" => "1:51-60."
                      ]
                    ]
                  ]
                ]
              ]
            ]
            19 => array:3 [
              "identificador" => "bib117"
              "etiqueta" => "20"
              "referencia" => array:1 [
                0 => array:3 [
                  "referenciaCompleta" => "Efficacy and safety of once-daily QVA149 compared with twice-daily salmeterol/fluticasone combination (SFC) in patients with COPD: the LANTERN study. Poster Presented at the European Respiratory Society Annual Congress. 6-10 September 2014, Munich, Germany. 2014. A2331. "
                  "contribucion" => array:1 [
                    0 => array:3 [
                      "titulo" => "Efficacy and safety of once-daily QVA149 compared with twice-daily salmeterol&#47;fluticasone combination &#40;SFC&#41; in patients with COPD&#58; the LANTERN study&#46; Poster Presented at the European Respiratory Society Annual Congress&#46; 6-10 September 2014&#44; Munich&#44; Germany&#46; 2014&#46;"
                      "idioma" => "en"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:7 [
                            0 => "Zhong N"
                            1 => "Wang C"
                            2 => "Zhou X"
                            3 => "Zhang N"
                            4 => "Patalano F"
                            5 => "Humphries M"
                            6 => "et-al&#46;"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:1 [
                        "tituloSerie" => "A2331. "
                      ]
                    ]
                  ]
                ]
              ]
            ]
            20 => array:3 [
              "identificador" => "bib118"
              "etiqueta" => "21"
              "referencia" => array:1 [
                0 => array:3 [
                  "referenciaCompleta" => "Analysis of chronic obstructive pulmonary disease exacerbations with the dual bronchodilator QVA149 compared with glycopyrronium and tiotropium (SPARK): a randomised, double-blind, parallel-group study. Lancet Respir Med. 2013; 1:199-209. "
                  "contribucion" => array:1 [
                    0 => array:3 [
                      "titulo" => "Analysis of chronic obstructive pulmonary disease exacerbations with the dual bronchodilator QVA149 compared with glycopyrronium and tiotropium &#40;SPARK&#41;&#58; a randomised&#44; double-blind&#44; parallel-group study&#46;"
                      "idioma" => "en"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:7 [
                            0 => "Wedzicha JA"
                            1 => "Decramer M"
                            2 => "Ficker JH"
                            3 => "Niewoehner DE"
                            4 => "Sandstrom T"
                            5 => "Taylor AF"
                            6 => "et-al&#46;"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:3 [
                        "tituloSerie" => "Lancet Respir Med. "
                        "fecha" => "2013"
                        "volumen" => "1:199-209."
                      ]
                    ]
                  ]
                ]
              ]
            ]
            21 => array:3 [
              "identificador" => "bib119"
              "etiqueta" => "22"
              "referencia" => array:1 [
                0 => array:3 [
                  "referenciaCompleta" => "Tailoring of corticosteroids in COPD management. Curr Respir Care Rep. 2014; 3:121-32. "
                  "contribucion" => array:1 [
                    0 => array:3 [
                      "titulo" => "Tailoring of corticosteroids in COPD management&#46;"
                      "idioma" => "en"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "De Coster DA"
                            1 => "Jones M&#46;"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:3 [
                        "tituloSerie" => "Curr Respir Care Rep. "
                        "fecha" => "2014"
                        "volumen" => "3:121-32."
                      ]
                    ]
                  ]
                ]
              ]
            ]
            22 => array:3 [
              "identificador" => "bib120"
              "etiqueta" => "23"
              "referencia" => array:1 [
                0 => array:3 [
                  "referenciaCompleta" => "Severe acute exacerbations and mortality in patients with chronic obstructive pulmonary disease. Thorax. 2005; 60:925-31. "
                  "contribucion" => array:1 [
                    0 => array:3 [
                      "titulo" => "Severe acute exacerbations and mortality in patients with chronic obstructive pulmonary disease&#46;"
                      "idioma" => "en"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:6 [
                            0 => "Soler-Cataluna JJ"
                            1 => "Martinez-Garcia MA"
                            2 => "Roman Sanchez P"
                            3 => "Salcedo E"
                            4 => "Navarro M"
                            5 => "Ochando R&#46;"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:3 [
                        "tituloSerie" => "Thorax. "
                        "fecha" => "2005"
                        "volumen" => "60:925-31."
                      ]
                    ]
                  ]
                ]
              ]
            ]
            23 => array:3 [
              "identificador" => "bib121"
              "etiqueta" => "24"
              "referencia" => array:1 [
                0 => array:3 [
                  "referenciaCompleta" => "Withdrawal of inhaled glucocorticoids and exacerbations of COPD. N Engl J Med. 2014; 371:1285-94. "
                  "contribucion" => array:1 [
                    0 => array:3 [
                      "titulo" => "Withdrawal of inhaled glucocorticoids and exacerbations of COPD&#46;"
                      "idioma" => "en"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:7 [
                            0 => "Magnussen H"
                            1 => "Disse B"
                            2 => "Rodriguez-Roisin R"
                            3 => "Kirsten A"
                            4 => "Watz H"
                            5 => "Tetzlaff K"
                            6 => "et-al&#46;"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:3 [
                        "tituloSerie" => "N Engl J Med. "
                        "fecha" => "2014"
                        "volumen" => "371:1285-94."
                      ]
                    ]
                  ]
                ]
              ]
            ]
            24 => array:3 [
              "identificador" => "bib122"
              "etiqueta" => "25"
              "referencia" => array:1 [
                0 => array:3 [
                  "referenciaCompleta" => "The prevention of chronic obstructive pulmonary disease exacerbations by salmeterol/fluticasone propionate or tiotropium bromide. Am J Respir Crit Care Med. 2008; 177:19-26. "
                  "contribucion" => array:1 [
                    0 => array:3 [
                      "titulo" => "The prevention of chronic obstructive pulmonary disease exacerbations by salmeterol&#47;fluticasone propionate or tiotropium bromide&#46;"
                      "idioma" => "en"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:6 [
                            0 => "Wedzicha JA"
                            1 => "Calverley PM"
                            2 => "Seemungal TA"
                            3 => "Hagan G"
                            4 => "Ansari Z"
                            5 => "Stockley RA&#46;"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:3 [
                        "tituloSerie" => "Am J Respir Crit Care Med. "
                        "fecha" => "2008"
                        "volumen" => "177:19-26."
                      ]
                    ]
                  ]
                ]
              ]
            ]
            25 => array:3 [
              "identificador" => "bib123"
              "etiqueta" => "26"
              "referencia" => array:1 [
                0 => array:3 [
                  "referenciaCompleta" => "Dual bronchodilation with QVA149 versus single bronchodilator therapy: the SHINE study. Eur Respir J. 2013; 42:1484-94. "
                  "contribucion" => array:1 [
                    0 => array:3 [
                      "titulo" => "Dual bronchodilation with QVA149 versus single bronchodilator therapy&#58; the SHINE study&#46;"
                      "idioma" => "en"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:7 [
                            0 => "Bateman ED"
                            1 => "Ferguson GT"
                            2 => "Barnes N"
                            3 => "Gallagher N"
                            4 => "Green Y"
                            5 => "Henley M"
                            6 => "et-al&#46;"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:3 [
                        "tituloSerie" => "Eur Respir J. "
                        "fecha" => "2013"
                        "volumen" => "42:1484-94."
                      ]
                    ]
                  ]
                ]
              ]
            ]
            26 => array:3 [
              "identificador" => "bib124"
              "etiqueta" => "27"
              "referencia" => array:1 [
                0 => array:3 [
                  "referenciaCompleta" => "Dual bronchodilation with QVA149 reduces patient-reported dyspnoea in COPD: the BLAZE study. Eur Respir J. 2014; 43:1599-609. "
                  "contribucion" => array:1 [
                    0 => array:3 [
                      "titulo" => "Dual bronchodilation with QVA149 reduces patient-reported dyspnoea in COPD&#58; the BLAZE study&#46;"
                      "idioma" => "en"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:7 [
                            0 => "Mahler DA"
                            1 => "Decramer M"
                            2 => "D’Urzo A"
                            3 => "Worth H"
                            4 => "White T"
                            5 => "Alagappan VK"
                            6 => "et-al&#46;"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:3 [
                        "tituloSerie" => "Eur Respir J. "
                        "fecha" => "2014"
                        "volumen" => "43:1599-609."
                      ]
                    ]
                  ]
                ]
              ]
            ]
            27 => array:3 [
              "identificador" => "bib125"
              "etiqueta" => "28"
              "referencia" => array:1 [
                0 => array:3 [
                  "referenciaCompleta" => "Tiotropium in combination with placebo, salmeterol, or fluticasone-salmeterol for treatment of chronic obstructive pulmonary disease: a randomized trial. Ann Intern Med. 2007; 146:545-55. "
                  "contribucion" => array:1 [
                    0 => array:3 [
                      "titulo" => "Tiotropium in combination with placebo&#44; salmeterol&#44; or fluticasone-salmeterol for treatment of chronic obstructive pulmonary disease&#58; a randomized trial&#46;"
                      "idioma" => "en"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:7 [
                            0 => "Aaron SD"
                            1 => "Vandemheen KL"
                            2 => "Fergusson D"
                            3 => "Maltais F"
                            4 => "Bourbeau J"
                            5 => "Goldstein R"
                            6 => "et-al&#46;"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:3 [
                        "tituloSerie" => "Ann Intern Med. "
                        "fecha" => "2007"
                        "volumen" => "146:545-55."
                      ]
                    ]
                  ]
                ]
              ]
            ]
            28 => array:3 [
              "identificador" => "bib126"
              "etiqueta" => "29"
              "referencia" => array:1 [
                0 => array:3 [
                  "referenciaCompleta" => "GINA Global Strategy for Asthma Management and Prevention. 2014. "
                  "contribucion" => array:1 [
                    0 => array:3 [
                      "titulo" => "GINA Global Strategy for Asthma Management and Prevention&#46;"
                      "idioma" => "en"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:1 [
                            0 => "Global Initiative for Asthma &#40;GINA&#41;&#46;"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:1 [
                        "tituloSerie" => "2014. "
                      ]
                    ]
                  ]
                ]
              ]
            ]
            29 => array:3 [
              "identificador" => "bib127"
              "etiqueta" => "30"
              "referencia" => array:1 [
                0 => array:3 [
                  "referenciaCompleta" => "Management and prevention of exacerbations of COPD. BMJ. 2014; 349:g5237. "
                  "contribucion" => array:1 [
                    0 => array:3 [
                      "titulo" => "Management and prevention of exacerbations of COPD&#46;"
                      "idioma" => "en"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:1 [
                            0 => "Aaron SD&#46;"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:3 [
                        "tituloSerie" => "BMJ. "
                        "fecha" => "2014"
                        "volumen" => "349:g5237."
                      ]
                    ]
                  ]
                ]
              ]
            ]
            30 => array:3 [
              "identificador" => "bib128"
              "etiqueta" => "31"
              "referencia" => array:1 [
                0 => array:3 [
                  "referenciaCompleta" => "Inhaled steroids in COPD: when should they be used. Lancet Respir Med. 2014; 2:869-71. "
                  "contribucion" => array:1 [
                    0 => array:3 [
                      "titulo" => "Inhaled steroids in COPD&#58; when should they be used&#46;"
                      "idioma" => "en"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "Agusti A"
                            1 => "Fabbri LM&#46;"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:3 [
                        "tituloSerie" => "Lancet Respir Med. "
                        "fecha" => "2014"
                        "volumen" => "2:869-71."
                      ]
                    ]
                  ]
                ]
              ]
            ]
            31 => array:3 [
              "identificador" => "bib129"
              "etiqueta" => "32"
              "referencia" => array:1 [
                0 => array:3 [
                  "referenciaCompleta" => "Appropriateness of triple therapy after COPD exacerbation. Can J Hosp Pharm. 2013; 66:41-2. "
                  "contribucion" => array:1 [
                    0 => array:3 [
                      "titulo" => "Appropriateness of triple therapy after COPD exacerbation&#46;"
                      "idioma" => "en"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:1 [
                            0 => "Manderville JR&#46;"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:3 [
                        "tituloSerie" => "Can J Hosp Pharm. "
                        "fecha" => "2013"
                        "volumen" => "66:41-2."
                      ]
                    ]
                  ]
                ]
              ]
            ]
            32 => array:3 [
              "identificador" => "bib130"
              "etiqueta" => "33"
              "referencia" => array:1 [
                0 => array:3 [
                  "referenciaCompleta" => "Effects of tiotropium and salmeterol/fluticasone propionate on airway wall thickness in chronic obstructive pulmonary disease. Respiration. 2013; 86:280-7. "
                  "contribucion" => array:1 [
                    0 => array:3 [
                      "titulo" => "Effects of tiotropium and salmeterol&#47;fluticasone propionate on airway wall thickness in chronic obstructive pulmonary disease&#46;"
                      "idioma" => "en"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "Hoshino M"
                            1 => "Ohtawa J&#46;"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:3 [
                        "tituloSerie" => "Respiration. "
                        "fecha" => "2013"
                        "volumen" => "86:280-7."
                      ]
                    ]
                  ]
                ]
              ]
            ]
            33 => array:3 [
              "identificador" => "bib131"
              "etiqueta" => "34"
              "referencia" => array:1 [
                0 => array:3 [
                  "referenciaCompleta" => "Triple combinations in chronic obstructive pulmonary disease – is three better than two. Expert Opin Pharmacother. 2014; 15:2475-8. "
                  "contribucion" => array:1 [
                    0 => array:3 [
                      "titulo" => "Triple combinations in chronic obstructive pulmonary disease – is three better than two&#46;"
                      "idioma" => "en"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "Cazzola M"
                            1 => "Matera MG&#46;"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:3 [
                        "tituloSerie" => "Expert Opin Pharmacother. "
                        "fecha" => "2014"
                        "volumen" => "15:2475-8."
                      ]
                    ]
                  ]
                ]
              ]
            ]
            34 => array:3 [
              "identificador" => "bib132"
              "etiqueta" => "35"
              "referencia" => array:1 [
                0 => array:3 [
                  "referenciaCompleta" => "Management of chronic obstructive pulmonary disease in patients admitted to a tertiary care centre for exacerbation of their disease. Can J Hosp Pharm. 2012; 65:373-9. "
                  "contribucion" => array:1 [
                    0 => array:3 [
                      "titulo" => "Management of chronic obstructive pulmonary disease in patients admitted to a tertiary care centre for exacerbation of their disease&#46;"
                      "idioma" => "en"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:7 [
                            0 => "Dault R"
                            1 => "Dube AI"
                            2 => "Blais L"
                            3 => "Boileau R"
                            4 => "Larrivee P"
                            5 => "Dumas ME"
                            6 => "et-al&#46;"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:3 [
                        "tituloSerie" => "Can J Hosp Pharm. "
                        "fecha" => "2012"
                        "volumen" => "65:373-9."
                      ]
                    ]
                  ]
                ]
              ]
            ]
            35 => array:3 [
              "identificador" => "bib133"
              "etiqueta" => "36"
              "referencia" => array:1 [
                0 => array:3 [
                  "referenciaCompleta" => "Impact of long-acting bronchodilators and exposure to inhaled corticosteroids on mortality in COPD: a real-life retrospective cohort study. Lung. 2014; 192:649-52. "
                  "contribucion" => array:1 [
                    0 => array:3 [
                      "titulo" => "Impact of long-acting bronchodilators and exposure to inhaled corticosteroids on mortality in COPD&#58; a real-life retrospective cohort study&#46;"
                      "idioma" => "en"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:4 [
                            0 => "Manoharan A"
                            1 => "Short PM"
                            2 => "Anderson WJ"
                            3 => "Lipworth BJ&#46;"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:3 [
                        "tituloSerie" => "Lung. "
                        "fecha" => "2014"
                        "volumen" => "192:649-52."
                      ]
                    ]
                  ]
                ]
              ]
            ]
            36 => array:3 [
              "identificador" => "bib134"
              "etiqueta" => "37"
              "referencia" => array:1 [
                0 => array:3 [
                  "referenciaCompleta" => "Triple therapy for the management of COPD: a review. COPD. 2011; 8:206-43. "
                  "contribucion" => array:1 [
                    0 => array:3 [
                      "titulo" => "Triple therapy for the management of COPD&#58; a review&#46;"
                      "idioma" => "en"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:7 [
                            0 => "Gaebel K"
                            1 => "McIvor RA"
                            2 => "Xie F"
                            3 => "Blackhouse G"
                            4 => "Robertson D"
                            5 => "Assasi N"
                            6 => "et-al&#46;"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:3 [
                        "tituloSerie" => "COPD. "
                        "fecha" => "2011"
                        "volumen" => "8:206-43."
                      ]
                    ]
                  ]
                ]
              ]
            ]
            37 => array:3 [
              "identificador" => "bib135"
              "etiqueta" => "38"
              "referencia" => array:1 [
                0 => array:3 [
                  "referenciaCompleta" => "Advances in asthma and COPD treatment: combination therapy with inhaled corticosteroids and long-acting beta 2-agonists. Curr Pharm Des. 2006; 12:3261-79. "
                  "contribucion" => array:1 [
                    0 => array:3 [
                      "titulo" => "Advances in asthma and COPD treatment&#58; combination therapy with inhaled corticosteroids and long-acting beta 2-agonists&#46;"
                      "idioma" => "en"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "Miller-Larsson A"
                            1 => "Selroos O&#46;"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:3 [
                        "tituloSerie" => "Curr Pharm Des. "
                        "fecha" => "2006"
                        "volumen" => "12:3261-79."
                      ]
                    ]
                  ]
                ]
              ]
            ]
            38 => array:3 [
              "identificador" => "bib136"
              "etiqueta" => "39"
              "referencia" => array:1 [
                0 => array:3 [
                  "referenciaCompleta" => "Trends in management and outcomes of COPD patients in primary care, 2000–2009: a retrospective cohort study. NPJ Prim Care Respir Med. 2014; 24:14015. "
                  "contribucion" => array:1 [
                    0 => array:3 [
                      "titulo" => "Trends in management and outcomes of COPD patients in primary care&#44; 2000–2009&#58; a retrospective cohort study&#46;"
                      "idioma" => "en"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:4 [
                            0 => "James GD"
                            1 => "Donaldson GC"
                            2 => "Wedzicha JA"
                            3 => "Nazareth I&#46;"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:3 [
                        "tituloSerie" => "NPJ Prim Care Respir Med. "
                        "fecha" => "2014"
                        "volumen" => "24:14015."
                      ]
                    ]
                  ]
                ]
              ]
            ]
            39 => array:3 [
              "identificador" => "bib137"
              "etiqueta" => "40"
              "referencia" => array:1 [
                0 => array:3 [
                  "referenciaCompleta" => "The ADMIT series – Issues in inhalation therapy. 4) How to choose inhaler devices for the treatment of COPD. Prim Care Respir J. 2010; 19:10-20. "
                  "contribucion" => array:1 [
                    0 => array:3 [
                      "titulo" => "The ADMIT series – Issues in inhalation therapy&#46; 4&#41; How to choose inhaler devices for the treatment of COPD&#46;"
                      "idioma" => "en"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [
                            0 => "Vincken W"
                            1 => "Dekhuijzen PR"
                            2 => "Barnes P&#46;"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:3 [
                        "tituloSerie" => "Prim Care Respir J. "
                        "fecha" => "2010"
                        "volumen" => "19:10-20."
                      ]
                    ]
                  ]
                ]
              ]
            ]
            40 => array:3 [
              "identificador" => "bib138"
              "etiqueta" => "41"
              "referencia" => array:1 [
                0 => array:3 [
                  "referenciaCompleta" => "Delivery characteristics and patients’ handling of two single-dose dry-powder inhalers used in COPD. Int J Chron Obstruct Pulmon Dis. 2011; 6:353-63. "
                  "contribucion" => array:1 [
                    0 => array:3 [
                      "titulo" => "Delivery characteristics and patients’ handling of two single-dose dry-powder inhalers used in COPD&#46;"
                      "idioma" => "en"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:7 [
                            0 => "Chapman KR"
                            1 => "Fogarty CM"
                            2 => "Peckitt C"
                            3 => "Lassen C"
                            4 => "Jadayel D"
                            5 => "Dederichs J"
                            6 => "et-al&#46;"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:3 [
                        "tituloSerie" => "Int J Chron Obstruct Pulmon Dis. "
                        "fecha" => "2011"
                        "volumen" => "6:353-63."
                      ]
                    ]
                  ]
                ]
              ]
            ]
            41 => array:3 [
              "identificador" => "bib139"
              "etiqueta" => "42"
              "referencia" => array:1 [
                0 => array:3 [
                  "referenciaCompleta" => "Delivery characteristics of a low-resistance dry-powder inhaler used to deliver the longacting muscarinic antagonist glycopyrronium. J Drug Assess. 2013; 2:11-6. "
                  "contribucion" => array:1 [
                    0 => array:3 [
                      "titulo" => "Delivery characteristics of a low-resistance dry-powder inhaler used to deliver the longacting muscarinic antagonist glycopyrronium&#46;"
                      "idioma" => "en"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:5 [
                            0 => "Colthorpe P"
                            1 => "Voshaar T"
                            2 => "Kieckbusch T"
                            3 => "Cuoghi E"
                            4 => "Jauernig J&#46;"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:3 [
                        "tituloSerie" => "J Drug Assess. "
                        "fecha" => "2013"
                        "volumen" => "2:11-6."
                      ]
                    ]
                  ]
                ]
              ]
            ]
            42 => array:3 [
              "identificador" => "bib140"
              "etiqueta" => "43"
              "referencia" => array:1 [
                0 => array:3 [
                  "referenciaCompleta" => "Dual-pharmacology muscarinic antagonist and beta(2) agonist molecules for the treatment of chronic obstructive pulmonary disease. Future Med Chem. 2011; 3:1585-605. "
                  "contribucion" => array:1 [
                    0 => array:3 [
                      "titulo" => "Dual-pharmacology muscarinic antagonist and beta&#40;2&#41; agonist molecules for the treatment of chronic obstructive pulmonary disease&#46;"
                      "idioma" => "en"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "Hughes AD"
                            1 => "Jones LH&#46;"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:3 [
                        "tituloSerie" => "Future Med Chem. "
                        "fecha" => "2011"
                        "volumen" => "3:1585-605."
                      ]
                    ]
                  ]
                ]
              ]
            ]
            43 => array:3 [
              "identificador" => "bib141"
              "etiqueta" => "44"
              "referencia" => array:1 [
                0 => array:3 [
                  "referenciaCompleta" => "Study to Determine the Pharmacokinetics of GSK961081 and Fluticasone Furoate When Administered Alone or in Combination. 2014. <inter-ref>https://www.clinicaltrials.gov/ct2/show/study/NCT02064504?term=MABA&rank=1</inter-ref>. "
                  "contribucion" => array:1 [
                    0 => array:3 [
                      "titulo" => "Study to Determine the Pharmacokinetics of GSK961081 and Fluticasone Furoate When Administered Alone or in Combination&#46; 2014&#46;  https&#58;&#47;&#47;www&#46; "
                      "idioma" => "en"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:1 [
                            0 => "GlaxoSmithKline&#46;"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:1 [
                        "tituloSerie" => "clinicaltrials. "
                      ]
                    ]
                  ]
                ]
              ]
            ]
            44 => array:3 [
              "identificador" => "bib142"
              "etiqueta" => "45"
              "referencia" => array:1 [
                0 => array:3 [
                  "referenciaCompleta" => "Doenças Respiratórias em Números. Portugal. 2014. "
                  "contribucion" => array:1 [
                    0 => array:3 [
                      "titulo" => "Doen&#231;as Respirat&#243;rias em N&#250;meros&#46; Portugal&#46;"
                      "idioma" => "pt"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:1 [
                            0 => "Direc&#231;&#227;o Geral de Sa&#250;de&#46;"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:1 [
                        "tituloSerie" => "2014. "
                      ]
                    ]
                  ]
                ]
              ]
            ]
            45 => array:3 [
              "identificador" => "bib143"
              "etiqueta" => "46"
              "referencia" => array:1 [
                0 => array:3 [
                  "referenciaCompleta" => "Effect of carbocisteine on acute exacerbation of chronic obstructive pulmonary disease (PEACE Study): a randomised placebo-controlled study. Lancet. 2008; 371:2013-8. "
                  "contribucion" => array:1 [
                    0 => array:3 [
                      "titulo" => "Effect of carbocisteine on acute exacerbation of chronic obstructive pulmonary disease &#40;PEACE Study&#41;&#58; a randomised placebo-controlled study&#46;"
                      "idioma" => "en"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:7 [
                            0 => "Zheng JP"
                            1 => "Kang J"
                            2 => "Huang SG"
                            3 => "Chen P"
                            4 => "Yao WZ"
                            5 => "Yang L"
                            6 => "et-al&#46;"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:3 [
                        "tituloSerie" => "Lancet. "
                        "fecha" => "2008"
                        "volumen" => "371:2013-8."
                      ]
                    ]
                  ]
                ]
              ]
            ]
            46 => array:3 [
              "identificador" => "bib144"
              "etiqueta" => "47"
              "referencia" => array:1 [
                0 => array:3 [
                  "referenciaCompleta" => "High-dose N-acetylcysteine in stable COPD: the 1-year, double-blind, randomized, placebo-controlled HIACE study. Chest. 2013; 144:106-18. "
                  "contribucion" => array:1 [
                    0 => array:3 [
                      "titulo" => "High-dose N-acetylcysteine in stable COPD&#58; the 1-year&#44; double-blind&#44; randomized&#44; placebo-controlled HIACE study&#46;"
                      "idioma" => "en"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:7 [
                            0 => "Tse HN"
                            1 => "Raiteri L"
                            2 => "Wong KY"
                            3 => "Yee KS"
                            4 => "Ng LY"
                            5 => "Wai KY"
                            6 => "et-al&#46;"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:3 [
                        "tituloSerie" => "Chest. "
                        "fecha" => "2013"
                        "volumen" => "144:106-18."
                      ]
                    ]
                  ]
                ]
              ]
            ]
            47 => array:3 [
              "identificador" => "bib145"
              "etiqueta" => "48"
              "referencia" => array:1 [
                0 => array:3 [
                  "referenciaCompleta" => "Antioxidants and mucolytics in COPD management: when (if ever) and in whom. Curr Drug Targets. 2013; 14:225-34. "
                  "contribucion" => array:1 [
                    0 => array:3 [
                      "titulo" => "Antioxidants and mucolytics in COPD management&#58; when &#40;if ever&#41; and in whom&#46;"
                      "idioma" => "en"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:4 [
                            0 => "Hillas G"
                            1 => "Nikolakopoulou S"
                            2 => "Hussain S"
                            3 => "Vassilakopoulos T&#46;"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:3 [
                        "tituloSerie" => "Curr Drug Targets. "
                        "fecha" => "2013"
                        "volumen" => "14:225-34."
                      ]
                    ]
                  ]
                ]
              ]
            ]
            48 => array:3 [
              "identificador" => "bib146"
              "etiqueta" => "49"
              "referencia" => array:1 [
                0 => array:3 [
                  "referenciaCompleta" => "Effect of high/low dose N-acetylcysteine on chronic obstructive pulmonary disease: a systematic review and meta-analysis. COPD. 2014; 11:351-8. "
                  "contribucion" => array:1 [
                    0 => array:3 [
                      "titulo" => "Effect of high&#47;low dose N-acetylcysteine on chronic obstructive pulmonary disease&#58; a systematic review and meta-analysis&#46;"
                      "idioma" => "en"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:4 [
                            0 => "Shen Y"
                            1 => "Cai W"
                            2 => "Lei S"
                            3 => "Zhang Z&#46;"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:3 [
                        "tituloSerie" => "COPD. "
                        "fecha" => "2014"
                        "volumen" => "11:351-8."
                      ]
                    ]
                  ]
                ]
              ]
            ]
            49 => array:3 [
              "identificador" => "bib147"
              "etiqueta" => "50"
              "referencia" => array:1 [
                0 => array:3 [
                  "referenciaCompleta" => "Benefits of high-dose N-acetylcysteine to exacerbation-prone patients with COPD. Chest. 2014; 146:611-23. "
                  "contribucion" => array:1 [
                    0 => array:3 [
                      "titulo" => "Benefits of high-dose N-acetylcysteine to exacerbation-prone patients with COPD&#46;"
                      "idioma" => "en"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:6 [
                            0 => "Tse HN"
                            1 => "Raiteri L"
                            2 => "Wong KY"
                            3 => "Ng LY"
                            4 => "Yee KS"
                            5 => "Tseng CZ&#46;"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:3 [
                        "tituloSerie" => "Chest. "
                        "fecha" => "2014"
                        "volumen" => "146:611-23."
                      ]
                    ]
                  ]
                ]
              ]
            ]
            50 => array:3 [
              "identificador" => "bib148"
              "etiqueta" => "51"
              "referencia" => array:1 [
                0 => array:3 [
                  "referenciaCompleta" => "Twice daily N-acetylcysteine 600\u{A0}mg for exacerbations of chronic obstructive pulmonary disease (PANTHEON): a randomised, double-blind placebo-controlled trial. Lancet Respir Med. 2014; 2:187-94. "
                  "contribucion" => array:1 [
                    0 => array:3 [
                      "titulo" => "Twice daily N-acetylcysteine 600&#160;mg for exacerbations of chronic obstructive pulmonary disease &#40;PANTHEON&#41;&#58; a randomised&#44; double-blind placebo-controlled trial&#46;"
                      "idioma" => "en"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:7 [
                            0 => "Zheng JP"
                            1 => "Wen FQ"
                            2 => "Bai CX"
                            3 => "Wan HY"
                            4 => "Kang J"
                            5 => "Chen P"
                            6 => "et-al&#46;"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:3 [
                        "tituloSerie" => "Lancet Respir Med. "
                        "fecha" => "2014"
                        "volumen" => "2:187-94."
                      ]
                    ]
                  ]
                ]
              ]
            ]
            51 => array:3 [
              "identificador" => "bib149"
              "etiqueta" => "52"
              "referencia" => array:1 [
                0 => array:3 [
                  "referenciaCompleta" => "N-acetylcysteine for COPD: the evidence remains inconclusive. Lancet Respir Med. 2014; 2:e3. "
                  "contribucion" => array:1 [
                    0 => array:3 [
                      "titulo" => "N-acetylcysteine for COPD&#58; the evidence remains inconclusive&#46;"
                      "idioma" => "en"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "Turner RD"
                            1 => "Bothamley GH&#46;"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:3 [
                        "tituloSerie" => "Lancet Respir Med. "
                        "fecha" => "2014"
                        "volumen" => "2:e3."
                      ]
                    ]
                  ]
                ]
              ]
            ]
            52 => array:3 [
              "identificador" => "bib150"
              "etiqueta" => "53"
              "referencia" => array:1 [
                0 => array:3 [
                  "referenciaCompleta" => "N-acetylcysteine in COPD may be beneficial, but for whom. Lancet Respir Med. 2014; 2:166-7. "
                  "contribucion" => array:1 [
                    0 => array:3 [
                      "titulo" => "N-acetylcysteine in COPD may be beneficial&#44; but for whom&#46;"
                      "idioma" => "en"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "Cazzola M"
                            1 => "Matera MG&#46;"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:3 [
                        "tituloSerie" => "Lancet Respir Med. "
                        "fecha" => "2014"
                        "volumen" => "2:166-7."
                      ]
                    ]
                  ]
                ]
              ]
            ]
            53 => array:3 [
              "identificador" => "bib151"
              "etiqueta" => "54"
              "referencia" => array:1 [
                0 => array:3 [
                  "referenciaCompleta" => "N-acetylcysteine in patients with COPD exacerbations associated with increased sputum. Wien Klin Wochenschr. 2015. "
                  "contribucion" => array:1 [
                    0 => array:3 [
                      "titulo" => "N-acetylcysteine in patients with COPD exacerbations associated with increased sputum&#46; Wien Klin Wochenschr&#46;"
                      "idioma" => "en"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:5 [
                            0 => "Ayfer Aytemur Z"
                            1 => "Baysak A"
                            2 => "Ozdemir O"
                            3 => "Kose T"
                            4 => "Sayiner A&#46;"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:1 [
                        "tituloSerie" => "2015. "
                      ]
                    ]
                  ]
                ]
              ]
            ]
            54 => array:3 [
              "identificador" => "bib152"
              "etiqueta" => "55"
              "referencia" => array:1 [
                0 => array:3 [
                  "referenciaCompleta" => "Effects of N-acetylcysteine on outcomes in chronic obstructive pulmonary disease (Bronchitis Randomized on NAC Cost-Utility Study, BRONCUS): a randomised placebo-controlled trial. Lancet. 2005; 365:1552-60. "
                  "contribucion" => array:1 [
                    0 => array:3 [
                      "titulo" => "Effects of N-acetylcysteine on outcomes in chronic obstructive pulmonary disease &#40;Bronchitis Randomized on NAC Cost-Utility Study&#44; BRONCUS&#41;&#58; a randomised placebo-controlled trial&#46;"
                      "idioma" => "en"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:7 [
                            0 => "Decramer M"
                            1 => "Rutten-van Molken M"
                            2 => "Dekhuijzen PN"
                            3 => "Troosters T"
                            4 => "van Herwaarden C"
                            5 => "Pellegrino R"
                            6 => "et-al&#46;"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:3 [
                        "tituloSerie" => "Lancet. "
                        "fecha" => "2005"
                        "volumen" => "365:1552-60."
                      ]
                    ]
                  ]
                ]
              ]
            ]
            55 => array:3 [
              "identificador" => "bib153"
              "etiqueta" => "56"
              "referencia" => array:1 [
                0 => array:3 [
                  "referenciaCompleta" => "The therapeutic efficacy of erdosteine in the treatment of chronic obstructive bronchitis: a meta-analysis of individual patient data. Pulm Pharmacol Ther. 2010; 23:135-44. "
                  "contribucion" => array:1 [
                    0 => array:3 [
                      "titulo" => "The therapeutic efficacy of erdosteine in the treatment of chronic obstructive bronchitis&#58; a meta-analysis of individual patient data&#46;"
                      "idioma" => "en"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [
                            0 => "Cazzola M"
                            1 => "Floriani I"
                            2 => "Page CP&#46;"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:3 [
                        "tituloSerie" => "Pulm Pharmacol Ther. "
                        "fecha" => "2010"
                        "volumen" => "23:135-44."
                      ]
                    ]
                  ]
                ]
              ]
            ]
            56 => array:3 [
              "identificador" => "bib154"
              "etiqueta" => "57"
              "referencia" => array:1 [
                0 => array:3 [
                  "referenciaCompleta" => "Database of Abstracts of Reviews of Effects (DARE): Quality-assessed Reviews. The therapeutic efficacy of erdosteine in the treatment of chronic obstructive bronchitis: a meta-analysis of individual patient data. 2011. <inter-ref>http://wwwncbinlmnihgov/pubmedhealth/PMH0029749/</inter-ref>. "
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Database of Abstracts of Reviews of Effects &#40;DARE&#41;&#58; Quality-assessed Reviews&#46; The therapeutic efficacy of erdosteine in the treatment of chronic obstructive bronchitis&#58; a meta-analysis of individual patient data&#46;"
                      "idioma" => "en"
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:1 [
                        "tituloSerie" => "2011. "
                      ]
                    ]
                  ]
                ]
              ]
            ]
            57 => array:3 [
              "identificador" => "bib155"
              "etiqueta" => "58"
              "referencia" => array:1 [
                0 => array:3 [
                  "referenciaCompleta" => "Antibiotic prophylaxis in COPD: why, when, and for whom?. Pulm Pharmacol Ther. 2014. "
                  "contribucion" => array:1 [
                    0 => array:3 [
                      "titulo" => "Antibiotic prophylaxis in COPD&#58; why&#44; when&#44; and for whom&#63;&#46; Pulm Pharmacol Ther&#46;"
                      "idioma" => "en"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "Miravitlles M"
                            1 => "Anzueto A&#46;"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:1 [
                        "tituloSerie" => "2014. "
                      ]
                    ]
                  ]
                ]
              ]
            ]
            58 => array:3 [
              "identificador" => "bib156"
              "etiqueta" => "59"
              "referencia" => array:1 [
                0 => array:3 [
                  "referenciaCompleta" => "Prophylactic antibiotic therapy for chronic obstructive pulmonary disease (COPD). CDS Rev. 2013; 11:CD009764. "
                  "contribucion" => array:1 [
                    0 => array:3 [
                      "titulo" => "Prophylactic antibiotic therapy for chronic obstructive pulmonary disease &#40;COPD&#41;&#46;"
                      "idioma" => "en"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "Herath SC"
                            1 => "Poole P&#46;"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:3 [
                        "tituloSerie" => "CDS Rev. "
                        "fecha" => "2013"
                        "volumen" => "11:CD009764."
                      ]
                    ]
                  ]
                ]
              ]
            ]
            59 => array:3 [
              "identificador" => "bib157"
              "etiqueta" => "60"
              "referencia" => array:1 [
                0 => array:3 [
                  "referenciaCompleta" => "Azithromycin maintenance treatment in patients with frequent exacerbations of chronic obstructive pulmonary disease (COLUMBUS): a randomised, double-blind, placebo-controlled trial. Lancet Respir Med. 2014; 2:361-8. "
                  "contribucion" => array:1 [
                    0 => array:3 [
                      "titulo" => "Azithromycin maintenance treatment in patients with frequent exacerbations of chronic obstructive pulmonary disease &#40;COLUMBUS&#41;&#58; a randomised&#44; double-blind&#44; placebo-controlled trial&#46;"
                      "idioma" => "en"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:7 [
                            0 => "Uzun S"
                            1 => "Djamin RS"
                            2 => "Kluytmans JA"
                            3 => "Mulder PG"
                            4 => "van’t Veer NE"
                            5 => "Ermens AA"
                            6 => "et-al&#46;"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:3 [
                        "tituloSerie" => "Lancet Respir Med. "
                        "fecha" => "2014"
                        "volumen" => "2:361-8."
                      ]
                    ]
                  ]
                ]
              ]
            ]
            60 => array:3 [
              "identificador" => "bib158"
              "etiqueta" => "61"
              "referencia" => array:1 [
                0 => array:3 [
                  "referenciaCompleta" => "Predictors of chronic obstructive pulmonary disease exacerbation reduction in response to daily azithromycin therapy. Am J Respir Crit Care Med. 2014; 189:1503-8. "
                  "contribucion" => array:1 [
                    0 => array:3 [
                      "titulo" => "Predictors of chronic obstructive pulmonary disease exacerbation reduction in response to daily azithromycin therapy&#46;"
                      "idioma" => "en"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:7 [
                            0 => "Han MK"
                            1 => "Tayob N"
                            2 => "Murray S"
                            3 => "Dransfield MT"
                            4 => "Washko G"
                            5 => "Scanlon PD"
                            6 => "et-al&#46;"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:3 [
                        "tituloSerie" => "Am J Respir Crit Care Med. "
                        "fecha" => "2014"
                        "volumen" => "189:1503-8."
                      ]
                    ]
                  ]
                ]
              ]
            ]
            61 => array:3 [
              "identificador" => "bib159"
              "etiqueta" => "62"
              "referencia" => array:1 [
                0 => array:3 [
                  "referenciaCompleta" => "exacerbations with macrolides: a review and budget impact analysis. Respir Med. 2013; 107:637-48. "
                  "contribucion" => array:1 [
                    0 => array:3 [
                      "titulo" => "exacerbations with macrolides&#58; a review and budget impact analysis&#46;"
                      "idioma" => "en"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:4 [
                            0 => "Simoens S"
                            1 => "Laekeman G"
                            2 => "Decramer M"
                            3 => "Preventing COPD&#46;"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:3 [
                        "tituloSerie" => "Respir Med. "
                        "fecha" => "2013"
                        "volumen" => "107:637-48."
                      ]
                    ]
                  ]
                ]
              ]
            ]
            62 => array:3 [
              "identificador" => "bib160"
              "etiqueta" => "63"
              "referencia" => array:1 [
                0 => array:3 [
                  "referenciaCompleta" => "Reply: azithromycin we’re there!. Am J Respir Crit Care Med. 2014; 190:1075-6. "
                  "contribucion" => array:1 [
                    0 => array:3 [
                      "titulo" => "Reply&#58; azithromycin we’re there&#33;&#46;"
                      "idioma" => "en"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "Restrepo MI"
                            1 => "Anzueto A&#46;"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:3 [
                        "tituloSerie" => "Am J Respir Crit Care Med. "
                        "fecha" => "2014"
                        "volumen" => "190:1075-6."
                      ]
                    ]
                  ]
                ]
              ]
            ]
            63 => array:3 [
              "identificador" => "bib161"
              "etiqueta" => "64"
              "referencia" => array:1 [
                0 => array:3 [
                  "referenciaCompleta" => "Preventing COPD exacerbations: budget impact of a respiratory day hospital and long-term azithromycin therapy. Respir Med. 2014; 108:1064. "
                  "contribucion" => array:1 [
                    0 => array:3 [
                      "titulo" => "Preventing COPD exacerbations&#58; budget impact of a respiratory day hospital and long-term azithromycin therapy&#46;"
                      "idioma" => "en"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "Pomares Amigo X"
                            1 => "Monton Soler C&#46;"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:3 [
                        "tituloSerie" => "Respir Med. "
                        "fecha" => "2014"
                        "volumen" => "108:1064."
                      ]
                    ]
                  ]
                ]
              ]
            ]
            64 => array:3 [
              "identificador" => "bib162"
              "etiqueta" => "65"
              "referencia" => array:1 [
                0 => array:3 [
                  "referenciaCompleta" => "Preventing COPD exacerbations with macrolides: a review and budget impact analysis – author response to letter to the editor. Respir Med. 2014; 108:1065. "
                  "contribucion" => array:1 [
                    0 => array:3 [
                      "titulo" => "Preventing COPD exacerbations with macrolides&#58; a review and budget impact analysis – author response to letter to the editor&#46;"
                      "idioma" => "en"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [
                            0 => "Simoens S"
                            1 => "Laekeman G"
                            2 => "Decramer M&#46;"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:3 [
                        "tituloSerie" => "Respir Med. "
                        "fecha" => "2014"
                        "volumen" => "108:1065."
                      ]
                    ]
                  ]
                ]
              ]
            ]
            65 => array:3 [
              "identificador" => "bib163"
              "etiqueta" => "66"
              "referencia" => array:1 [
                0 => array:3 [
                  "referenciaCompleta" => "Azithromycin for patients with frequent COPD exacerbations. Lancet Respir Med. 2014; 2:340-1. "
                  "contribucion" => array:1 [
                    0 => array:3 [
                      "titulo" => "Azithromycin for patients with frequent COPD exacerbations&#46;"
                      "idioma" => "en"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "Wong C"
                            1 => "Herath S&#46;"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:3 [
                        "tituloSerie" => "Lancet Respir Med. "
                        "fecha" => "2014"
                        "volumen" => "2:340-1."
                      ]
                    ]
                  ]
                ]
              ]
            ]
            66 => array:3 [
              "identificador" => "bib164"
              "etiqueta" => "67"
              "referencia" => array:1 [
                0 => array:3 [
                  "referenciaCompleta" => "Phosphodiesterase 4 inhibitors for chronic obstructive pulmonary disease. CDS Rev. 2013; 11:CD002309. "
                  "contribucion" => array:1 [
                    0 => array:3 [
                      "titulo" => "Phosphodiesterase 4 inhibitors for chronic obstructive pulmonary disease&#46;"
                      "idioma" => "en"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [
                            0 => "Chong J"
                            1 => "Leung B"
                            2 => "Poole P&#46;"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:3 [
                        "tituloSerie" => "CDS Rev. "
                        "fecha" => "2013"
                        "volumen" => "11:CD002309."
                      ]
                    ]
                  ]
                ]
              ]
            ]
            67 => array:3 [
              "identificador" => "bib165"
              "etiqueta" => "68"
              "referencia" => array:1 [
                0 => array:3 [
                  "referenciaCompleta" => "Efficacy and safety of roflumilast in patients with chronic obstructive pulmonary disease: a systematic review and meta-analysis. Ther Adv Respir Dis. 2013; 7:13-24. "
                  "contribucion" => array:1 [
                    0 => array:3 [
                      "titulo" => "Efficacy and safety of roflumilast in patients with chronic obstructive pulmonary disease&#58; a systematic review and meta-analysis&#46;"
                      "idioma" => "en"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "Oba Y"
                            1 => "Lone NA&#46;"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:3 [
                        "tituloSerie" => "Ther Adv Respir Dis. "
                        "fecha" => "2013"
                        "volumen" => "7:13-24."
                      ]
                    ]
                  ]
                ]
              ]
            ]
            68 => array:3 [
              "identificador" => "bib166"
              "etiqueta" => "69"
              "referencia" => array:1 [
                0 => array:3 [
                  "referenciaCompleta" => "Response. Chest. 2014; 145:428. "
                  "contribucion" => array:1 [
                    0 => array:3 [
                      "titulo" => "Response&#46;"
                      "idioma" => "fr"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:7 [
                            0 => "Wedzicha JA"
                            1 => "Rabe KF"
                             …5
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:3 [
                        "tituloSerie" => "Chest. "
                        "fecha" => "2014"
                        "volumen" => "145:428."
                      ]
                    ]
                  ]
                ]
              ]
            ]
            69 => array:3 [
              "identificador" => "bib167"
              "etiqueta" => "70"
              "referencia" => array:1 [
                0 => array:3 [
                  "referenciaCompleta" => "Point: were industry-sponsored roflumilast trials appropriate? Yes. Chest. 2014; 145:937-9. "
                  "contribucion" => array:1 [
                    0 => array:3 [
                      "titulo" => "Point&#58; were industry-sponsored roflumilast trials appropriate&#63; Yes&#46;"
                      "idioma" => "en"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:3 [
                        "tituloSerie" => "Chest. "
                        "fecha" => "2014"
                        "volumen" => "145:937-9."
                      ]
                    ]
                  ]
                ]
              ]
            ]
            70 => array:3 [
              "identificador" => "bib168"
              "etiqueta" => "71"
              "referencia" => array:1 [
                0 => array:3 [
                  "referenciaCompleta" => "Counterpoint: were industry-sponsored roflumilast trials appropriate? No. Chest. 2014; 145:939-42. "
                  "contribucion" => array:1 [
                    0 => array:3 [
                      "titulo" => "Counterpoint&#58; were industry-sponsored roflumilast trials appropriate&#63; No&#46;"
                      "idioma" => "en"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [ …3]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:3 [
                        "tituloSerie" => "Chest. "
                        "fecha" => "2014"
                        "volumen" => "145:939-42."
                      ]
                    ]
                  ]
                ]
              ]
            ]
            71 => array:3 [
              "identificador" => "bib169"
              "etiqueta" => "72"
              "referencia" => array:1 [
                0 => array:3 [
                  "referenciaCompleta" => "Effect of roflumilast on exacerbations in patients with severe chronic obstructive pulmonary disease uncontrolled by combination therapy (REACT): a multicentre randomised controlled trial. Lancet. 2015; 385:857-66. "
                  "contribucion" => array:1 [
                    0 => array:3 [
                      "titulo" => "Effect of roflumilast on exacerbations in patients with severe chronic obstructive pulmonary disease uncontrolled by combination therapy &#40;REACT&#41;&#58; a multicentre randomised controlled trial&#46;"
                      "idioma" => "en"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:6 [ …6]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:3 [
                        "tituloSerie" => "Lancet. "
                        "fecha" => "2015"
                        "volumen" => "385:857-66."
                      ]
                    ]
                  ]
                ]
              ]
            ]
            72 => array:3 [
              "identificador" => "bib170"
              "etiqueta" => "73"
              "referencia" => array:1 [
                0 => array:3 [
                  "referenciaCompleta" => "Roflumilast added to triple therapy in patients with severe COPD: a real life study. Pulm Pharmacol Ther. 2015; 30:16-21. "
                  "contribucion" => array:1 [
                    0 => array:3 [
                      "titulo" => "Roflumilast added to triple therapy in patients with severe COPD&#58; a real life study&#46;"
                      "idioma" => "en"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:7 [ …7]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:3 [
                        "tituloSerie" => "Pulm Pharmacol Ther. "
                        "fecha" => "2015"
                        "volumen" => "30:16-21."
                      ]
                    ]
                  ]
                ]
              ]
            ]
            73 => array:3 [
              "identificador" => "bib171"
              "etiqueta" => "74"
              "referencia" => array:1 [
                0 => array:3 [
                  "referenciaCompleta" => "Am J Respir Crit Care Med. 2013; 188:901-6. "
                  "contribucion" => array:1 [
                    0 => array:3 [
                      "titulo" => "Am J Respir Crit Care Med&#46;"
                      "idioma" => "en"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:2 [
                        "fecha" => "2013"
                        "volumen" => "188:901-6."
                      ]
                    ]
                  ]
                ]
              ]
            ]
            74 => array:3 [
              "identificador" => "bib172"
              "etiqueta" => "75"
              "referencia" => array:1 [
                0 => array:3 [
                  "referenciaCompleta" => "A meta-analysis on the efficacy of oral theophylline in patients with stable COPD. Int J Chron Obstruct Pulmon Dis. 2006; 1:261-6. "
                  "contribucion" => array:1 [
                    0 => array:3 [
                      "titulo" => "A meta-analysis on the efficacy of oral theophylline in patients with stable COPD&#46;"
                      "idioma" => "en"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:3 [
                        "tituloSerie" => "Int J Chron Obstruct Pulmon Dis. "
                        "fecha" => "2006"
                        "volumen" => "1:261-6."
                      ]
                    ]
                  ]
                ]
              ]
            ]
            75 => array:3 [
              "identificador" => "bib173"
              "etiqueta" => "76"
              "referencia" => array:1 [
                0 => array:3 [
                  "referenciaCompleta" => "Efficacy of theophylline in people with stable chronic obstructive pulmonary disease: a systematic review and meta-analysis. Respir Med. 2005; 99:135-44. "
                  "contribucion" => array:1 [
                    0 => array:3 [
                      "titulo" => "Efficacy of theophylline in people with stable chronic obstructive pulmonary disease&#58; a systematic review and meta-analysis&#46;"
                      "idioma" => "en"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:7 [ …7]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:3 [
                        "tituloSerie" => "Respir Med. "
                        "fecha" => "2005"
                        "volumen" => "99:135-44."
                      ]
                    ]
                  ]
                ]
              ]
            ]
            76 => array:3 [
              "identificador" => "bib174"
              "etiqueta" => "77"
              "referencia" => array:1 [
                0 => array:3 [
                  "referenciaCompleta" => "Methylxanthines for exacerbations of chronic obstructive pulmonary disease. CDS Rev. 2003; CD002168. "
                  "contribucion" => array:1 [
                    0 => array:3 [
                      "titulo" => "Methylxanthines for exacerbations of chronic obstructive pulmonary disease&#46;"
                      "idioma" => "en"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [ …3]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:3 [
                        "tituloSerie" => "CDS Rev. "
                        "fecha" => "2003"
                        "volumen" => "CD002168."
                      ]
                    ]
                  ]
                ]
              ]
            ]
            77 => array:3 [
              "identificador" => "bib175"
              "etiqueta" => "78"
              "referencia" => array:1 [
                0 => array:3 [
                  "referenciaCompleta" => "Effects of an immunostimulating agent on acute exacerbations and hospitalizations in patients with chronic obstructive pulmonary disease. The PARI-IS Study Steering Committee and Research Group. Prevention of Acute Respiratory Infection by an Immunostimulant. Am J Respir Crit Care Med. 1997; 156:1719-24. "
                  "contribucion" => array:1 [
                    0 => array:3 [
                      "titulo" => "Effects of an immunostimulating agent on acute exacerbations and hospitalizations in patients with chronic obstructive pulmonary disease&#46; The PARI-IS Study Steering Committee and Research Group&#46; Prevention of Acute Respiratory Infection by an Immunostimulant&#46;"
                      "idioma" => "en"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:6 [ …6]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:3 [
                        "tituloSerie" => "Am J Respir Crit Care Med. "
                        "fecha" => "1997"
                        "volumen" => "156:1719-24."
                      ]
                    ]
                  ]
                ]
              ]
            ]
            78 => array:3 [
              "identificador" => "bib176"
              "etiqueta" => "79"
              "referencia" => array:1 [
                0 => array:3 [
                  "referenciaCompleta" => "Protective effect of a bacterial extract against acute exacerbation in patients with chronic bronchitis accompanied by chronic obstructive pulmonary disease. Chin Med J (Engl). 2004; 117:828-34. "
                  "contribucion" => array:1 [
                    0 => array:3 [
                      "titulo" => "Protective effect of a bacterial extract against acute exacerbation in patients with chronic bronchitis accompanied by chronic obstructive pulmonary disease&#46;"
                      "idioma" => "en"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:6 [ …6]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:3 [
                        "tituloSerie" => "Chin Med J (Engl). "
                        "fecha" => "2004"
                        "volumen" => "117:828-34."
                      ]
                    ]
                  ]
                ]
              ]
            ]
            79 => array:3 [
              "identificador" => "bib177"
              "etiqueta" => "80"
              "referencia" => array:1 [
                0 => array:3 [
                  "referenciaCompleta" => "Double-blind study of OM-85 in patients with chronic bronchitis or mild chronic obstructive pulmonary disease. Respiration. 2007; 74:26-32. "
                  "contribucion" => array:1 [
                    0 => array:3 [
                      "titulo" => "Double-blind study of OM-85 in patients with chronic bronchitis or mild chronic obstructive pulmonary disease&#46;"
                      "idioma" => "en"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [ …3]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:3 [
                        "tituloSerie" => "Respiration. "
                        "fecha" => "2007"
                        "volumen" => "74:26-32."
                      ]
                    ]
                  ]
                ]
              ]
            ]
            80 => array:3 [
              "identificador" => "bib178"
              "etiqueta" => "81"
              "referencia" => array:1 [
                0 => array:3 [
                  "referenciaCompleta" => "Reduction of morbidity and mortality by statins, angiotensin-converting enzyme inhibitors, and angiotensin receptor blockers in patients with chronic obstructive pulmonary disease. J Am Coll Cardiol. 2006; 47:2554-60. "
                  "contribucion" => array:1 [
                    0 => array:3 [
                      "titulo" => "Reduction of morbidity and mortality by statins&#44; angiotensin-converting enzyme inhibitors&#44; and angiotensin receptor blockers in patients with chronic obstructive pulmonary disease&#46;"
                      "idioma" => "en"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:6 [ …6]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:3 [
                        "tituloSerie" => "J Am Coll Cardiol. "
                        "fecha" => "2006"
                        "volumen" => "47:2554-60."
                      ]
                    ]
                  ]
                ]
              ]
            ]
            81 => array:3 [
              "identificador" => "bib179"
              "etiqueta" => "82"
              "referencia" => array:1 [
                0 => array:3 [
                  "referenciaCompleta" => "Reducing mortality for chronic obstructive pulmonary disease: role of statins and angiotensin-converting enzyme inhibitors. Expert Rev Pharmacoecon Outcomes Res. 2009; 9:523-5. "
                  "contribucion" => array:1 [
                    0 => array:3 [
                      "titulo" => "Reducing mortality for chronic obstructive pulmonary disease&#58; role of statins and angiotensin-converting enzyme inhibitors&#46;"
                      "idioma" => "en"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:1 [ …1]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:3 [
                        "tituloSerie" => "Expert Rev Pharmacoecon Outcomes Res. "
                        "fecha" => "2009"
                        "volumen" => "9:523-5."
                      ]
                    ]
                  ]
                ]
              ]
            ]
            82 => array:3 [
              "identificador" => "bib180"
              "etiqueta" => "83"
              "referencia" => array:1 [
                0 => array:3 [
                  "referenciaCompleta" => "Statins reduce all-cause mortality in chronic obstructive pulmonary disease: a systematic review and meta-analysis of observational studies. Respir Res. 2014; 15:80. "
                  "contribucion" => array:1 [
                    0 => array:3 [
                      "titulo" => "Statins reduce all-cause mortality in chronic obstructive pulmonary disease&#58; a systematic review and meta-analysis of observational studies&#46;"
                      "idioma" => "en"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:7 [ …7]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:3 [
                        "tituloSerie" => "Respir Res. "
                        "fecha" => "2014"
                        "volumen" => "15:80."
                      ]
                    ]
                  ]
                ]
              ]
            ]
            83 => array:3 [
              "identificador" => "bib181"
              "etiqueta" => "84"
              "referencia" => array:1 [
                0 => array:3 [
                  "referenciaCompleta" => "Statins as emerging treatments for asthma and chronic obstructive pulmonary disease. Expert Rev Respir Med. 2008; 2:329-35. "
                  "contribucion" => array:1 [
                    0 => array:3 [
                      "titulo" => "Statins as emerging treatments for asthma and chronic obstructive pulmonary disease&#46;"
                      "idioma" => "en"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:1 [ …1]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:3 [
                        "tituloSerie" => "Expert Rev Respir Med. "
                        "fecha" => "2008"
                        "volumen" => "2:329-35."
                      ]
                    ]
                  ]
                ]
              ]
            ]
            84 => array:3 [
              "identificador" => "bib182"
              "etiqueta" => "85"
              "referencia" => array:1 [
                0 => array:3 [
                  "referenciaCompleta" => "Potential benefits of statins on morbidity and mortality in chronic obstructive pulmonary disease: a review of the evidence. Postgrad Med J. 2009; 85:414-21. "
                  "contribucion" => array:1 [
                    0 => array:3 [
                      "titulo" => "Potential benefits of statins on morbidity and mortality in chronic obstructive pulmonary disease&#58; a review of the evidence&#46;"
                      "idioma" => "en"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [ …3]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:3 [
                        "tituloSerie" => "Postgrad Med J. "
                        "fecha" => "2009"
                        "volumen" => "85:414-21."
                      ]
                    ]
                  ]
                ]
              ]
            ]
            85 => array:3 [
              "identificador" => "bib183"
              "etiqueta" => "86"
              "referencia" => array:1 [
                0 => array:3 [
                  "referenciaCompleta" => "Update on the potential role of statins in chronic obstructive pulmonary disease and its co-morbidities. Expert Rev Respir Med. 2013; 7:533-44. "
                  "contribucion" => array:1 [
                    0 => array:3 [
                      "titulo" => "Update on the potential role of statins in chronic obstructive pulmonary disease and its co-morbidities&#46;"
                      "idioma" => "en"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:3 [
                        "tituloSerie" => "Expert Rev Respir Med. "
                        "fecha" => "2013"
                        "volumen" => "7:533-44."
                      ]
                    ]
                  ]
                ]
              ]
            ]
            86 => array:3 [
              "identificador" => "bib184"
              "etiqueta" => "87"
              "referencia" => array:1 [
                0 => array:3 [
                  "referenciaCompleta" => "Simvastatin Therapy for Moderate and Severe COPD (STATCOPE). 2015. <inter-ref>https://wwwclinicaltrialsgov/ct2/show?cond=copd&intr=statin&rank=8</inter-ref>. "
                  "contribucion" => array:1 [
                    0 => array:3 [
                      "titulo" => "Simvastatin Therapy for Moderate and Severe COPD &#40;STATCOPE&#41;&#46;"
                      "idioma" => "en"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:1 [ …1]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:1 [
                        "tituloSerie" => "2015. "
                      ]
                    ]
                  ]
                ]
              ]
            ]
            87 => array:3 [
              "identificador" => "bib185"
              "etiqueta" => "88"
              "referencia" => array:1 [
                0 => array:3 [
                  "referenciaCompleta" => "A randomized controlled trial of angiotensin-converting enzyme inhibition for skeletal muscle dysfunction in COPD. Chest. 2014; 146:932-40. "
                  "contribucion" => array:1 [
                    0 => array:3 [
                      "titulo" => "A randomized controlled trial of angiotensin-converting enzyme inhibition for skeletal muscle dysfunction in COPD&#46;"
                      "idioma" => "en"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:7 [ …7]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:3 [
                        "tituloSerie" => "Chest. "
                        "fecha" => "2014"
                        "volumen" => "146:932-40."
                      ]
                    ]
                  ]
                ]
              ]
            ]
            88 => array:3 [
              "identificador" => "bib186"
              "etiqueta" => "89"
              "referencia" => array:1 [
                0 => array:3 [
                  "referenciaCompleta" => "Angiotensin II blockers in obstructive pulmonary disease: a randomised controlled trial. Eur Respir J. 2006; 27:972-9. "
                  "contribucion" => array:1 [
                    0 => array:3 [
                      "titulo" => "Angiotensin II blockers in obstructive pulmonary disease&#58; a randomised controlled trial&#46;"
                      "idioma" => "en"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:7 [ …7]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:3 [
                        "tituloSerie" => "Eur Respir J. "
                        "fecha" => "2006"
                        "volumen" => "27:972-9."
                      ]
                    ]
                  ]
                ]
              ]
            ]
            89 => array:3 [
              "identificador" => "bib187"
              "etiqueta" => "90"
              "referencia" => array:1 [
                0 => array:3 [
                  "referenciaCompleta" => "Impact of cardioselective beta-blockers on mortality in patients with chronic obstructive pulmonary disease and atherosclerosis. Am J Respir Crit Care Med. 2008; 178:695-700. "
                  "contribucion" => array:1 [
                    0 => array:3 [
                      "titulo" => "Impact of cardioselective beta-blockers on mortality in patients with chronic obstructive pulmonary disease and atherosclerosis&#46;"
                      "idioma" => "en"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:7 [ …7]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:3 [
                        "tituloSerie" => "Am J Respir Crit Care Med. "
                        "fecha" => "2008"
                        "volumen" => "178:695-700."
                      ]
                    ]
                  ]
                ]
              ]
            ]
            90 => array:3 [
              "identificador" => "bib188"
              "etiqueta" => "91"
              "referencia" => array:1 [
                0 => array:3 [
                  "referenciaCompleta" => "Cardioselective beta blockers do not produce adverse respiratory effects in COPD. Evid Based Med. 2006; 11:84. "
                  "contribucion" => array:1 [
                    0 => array:3 [
                      "titulo" => "Cardioselective beta blockers do not produce adverse respiratory effects in COPD&#46;"
                      "idioma" => "en"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:1 [ …1]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:3 [
                        "tituloSerie" => "Evid Based Med. "
                        "fecha" => "2006"
                        "volumen" => "11:84."
                      ]
                    ]
                  ]
                ]
              ]
            ]
            91 => array:3 [
              "identificador" => "bib189"
              "etiqueta" => "92"
              "referencia" => array:1 [
                0 => array:3 [
                  "referenciaCompleta" => "Beta-blockers reduced the risk of mortality and exacerbation in patients with COPD: a meta-analysis of observational studies. PLOS ONE. 2014; 9:e113048. "
                  "contribucion" => array:1 [
                    0 => array:3 [
                      "titulo" => "Beta-blockers reduced the risk of mortality and exacerbation in patients with COPD&#58; a meta-analysis of observational studies&#46;"
                      "idioma" => "en"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:5 [ …5]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:3 [
                        "tituloSerie" => "PLOS ONE. "
                        "fecha" => "2014"
                        "volumen" => "9:e113048."
                      ]
                    ]
                  ]
                ]
              ]
            ]
            92 => array:3 [
              "identificador" => "bib190"
              "etiqueta" => "93"
              "referencia" => array:1 [
                0 => array:3 [
                  "referenciaCompleta" => "Use of beta blockers and the risk of death in hospitalised patients with acute exacerbations of COPD. Thorax. 2008; 63:301-5. "
                  "contribucion" => array:1 [
                    0 => array:3 [
                      "titulo" => "Use of beta blockers and the risk of death in hospitalised patients with acute exacerbations of COPD&#46;"
                      "idioma" => "en"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:5 [ …5]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:3 [
                        "tituloSerie" => "Thorax. "
                        "fecha" => "2008"
                        "volumen" => "63:301-5."
                      ]
                    ]
                  ]
                ]
              ]
            ]
            93 => array:3 [
              "identificador" => "bib191"
              "etiqueta" => "94"
              "referencia" => array:1 [
                0 => array:3 [
                  "referenciaCompleta" => "Impact of gastro-oesophageal reflux disease symptoms on COPD exacerbation. Thorax. 2008; 63:951-5. "
                  "contribucion" => array:1 [
                    0 => array:3 [
                      "titulo" => "Impact of gastro-oesophageal reflux disease symptoms on COPD exacerbation&#46;"
                      "idioma" => "en"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:7 [ …7]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:3 [
                        "tituloSerie" => "Thorax. "
                        "fecha" => "2008"
                        "volumen" => "63:951-5."
                      ]
                    ]
                  ]
                ]
              ]
            ]
            94 => array:3 [
              "identificador" => "bib192"
              "etiqueta" => "95"
              "referencia" => array:1 [
                0 => array:3 [
                  "referenciaCompleta" => "Association between chronic obstructive pulmonary disease and gastroesophageal reflux disease: a national cross-sectional cohort study. BMC Pulm Med. 2013; 13:51. "
                  "contribucion" => array:1 [
                    0 => array:3 [
                      "titulo" => "Association between chronic obstructive pulmonary disease and gastroesophageal reflux disease&#58; a national cross-sectional cohort study&#46;"
                      "idioma" => "en"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:7 [ …7]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:3 [
                        "tituloSerie" => "BMC Pulm Med. "
                        "fecha" => "2013"
                        "volumen" => "13:51."
                      ]
                    ]
                  ]
                ]
              ]
            ]
            95 => array:3 [
              "identificador" => "bib193"
              "etiqueta" => "96"
              "referencia" => array:1 [
                0 => array:3 [
                  "referenciaCompleta" => "Gastro-esophageal reflux disease and exacerbations in chronic obstructive pulmonary disease. Respirology. 2015; 20:101-7. "
                  "contribucion" => array:1 [
                    0 => array:3 [
                      "titulo" => "Gastro-esophageal reflux disease and exacerbations in chronic obstructive pulmonary disease&#46;"
                      "idioma" => "en"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:6 [ …6]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:3 [
                        "tituloSerie" => "Respirology. "
                        "fecha" => "2015"
                        "volumen" => "20:101-7."
                      ]
                    ]
                  ]
                ]
              ]
            ]
            96 => array:3 [
              "identificador" => "bib194"
              "etiqueta" => "97"
              "referencia" => array:1 [
                0 => array:3 [
                  "referenciaCompleta" => "A randomized, single-blind study of lansoprazole for the prevention of exacerbations of chronic obstructive pulmonary disease in older patients. J Am Geriatr Soc. 2009; 57:1453-7. "
                  "contribucion" => array:1 [
                    0 => array:3 [
                      "titulo" => "A randomized&#44; single-blind study of lansoprazole for the prevention of exacerbations of chronic obstructive pulmonary disease in older patients&#46;"
                      "idioma" => "en"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:7 [ …7]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:3 [
                        "tituloSerie" => "J Am Geriatr Soc. "
                        "fecha" => "2009"
                        "volumen" => "57:1453-7."
                      ]
                    ]
                  ]
                ]
              ]
            ]
          ]
        ]
      ]
    ]
  ]
  "idiomaDefecto" => "en"
  "url" => "/08732159/0000002200000001/v0_201604141139/X0873215916479478/v0_201604141140/en/main.assets"
  "Apartado" => array:4 [
    "identificador" => "50812"
    "tipo" => "SECCION"
    "es" => array:2 [
      "titulo" => "Thematic Series-COPD"
      "idiomaDefecto" => true
    ]
    "idiomaDefecto" => "es"
  ]
  "PDF" => "https://static.elsevier.es/multimedia/08732159/0000002200000001/v0_201604141139/X0873215916479478/v0_201604141140/en/320v22n01a90447947pdf001.pdf?idApp=UINPBA00004E&text.app=https://journalpulmonology.org/"
  "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/X0873215916479478?idApp=UINPBA00004E"
]

Article information

ISSN: 08732159
Original language: English

DOI:10.1016/j.rppnen.2015.10.009

The statistics are updated each day

Year/Month	Html	Pdf	Total

2024 November	8	4	12
2024 October	44	24	68
2024 September	78	34	112
2024 August	90	44	134
2024 July	63	32	95
2024 June	56	31	87
2024 May	49	29	78
2024 April	41	28	69
2024 March	52	21	73
2024 February	129	25	154
2024 January	68	27	95
2023 December	19	26	45
2023 November	25	41	66
2023 October	31	39	70
2023 September	20	39	59
2023 August	10	11	21
2023 July	15	24	39
2023 June	16	21	37
2023 May	42	35	77
2017 December	1	0	1
2017 September	1	0	1
2017 August	4	0	4
2017 July	3	0	3
2017 June	2	0	2
2017 May	2	0	2
2017 April	2	0	2
2017 February	5	0	5
2017 January	2	1	3
2016 November	2	0	2
2016 October	1	0	1
2016 September	6	0	6
2016 August	6	1	7
2016 July	2	4	6
2016 May	2	0	2
2016 April	95	12	107
2016 March	179	90	269
2016 February	153	173	326

Show all

Indexed in:

Follow us:

Statistics

Indexed in:

Follow us:

Statistics

Subscribe to our newsletter