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        "titulo" => "Incorporando nuevas evidencias sobre medicamentos inhalados en la EPOC&#46; Asociaci&#243;n Latinoamericana de T&#243;rax &#40;ALAT&#41; 2019"
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          "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Inhaled treatment depending on the severity of COPD&#46; ALAT-2019&#46;</p>"
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    "textoCompleto" => "<span class="elsevierStyleSections"><p id="par0005" class="elsevierStylePara elsevierViewall">The different forms of obstructive pulmonary disease &#40;COPD&#41; require individualized treatment plans &#40;precision medicine&#41;&#46; Recent studies provide evidence of the benefits of different combinations of drugs that can impact on therapeutic regimens&#46;<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1&#8211;5</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">In 2014&#44; the Latin American Chest Association &#40;ALAT&#41; published a document on COPD using clinical questions in PICO format&#46;<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a> In this document&#44; we aim to update the information on inhaled medicines by analyzing the new evidence using the same methodology&#46; We have focused on inhaled medications because these drugs form the basis of the pharmacological treatment of COPD&#46; Major changes and controversies are emerging in this area&#44; regardless of the availability of controlled clinical studies&#46; This document is intended for clinicians&#44; particularly respiratory specialists and other professionals involved in the care and management of patients with COPD&#46;</p><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Methodology</span><p id="par0015" class="elsevierStylePara elsevierViewall">Medical specialists were invited by the COPD section of ALAT to participate in the development of this document&#46; The working group discussed controversies in inhaled medications in COPD in 3 in-person meetings and by teleconference&#46; New clinical questions were formulated on areas of controversy in inhaled medication&#44; and this evidence was incorporated in a proposal for the use of this therapy&#46; The 5 clinical questions discussed in this document were selected by consensus&#46;</p><p id="par0020" class="elsevierStylePara elsevierViewall">A more extensive description of the methodology&#44; covering the formulation of clinical questions in PICO format&#44; search strategy&#44; eligibility criteria&#44; critical analysis&#44; and formulation of recommendations&#44; can be found in <a class="elsevierStyleCrossRef" href="#sec0170">Appendix B</a> supplementary material of this document and in a prior publication&#46;<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a><a class="elsevierStyleCrossRefs" href="#tbl0005">Tables 1 and 2</a> describe the search strategies &#40;Trip Database and MeSH terms&#41;&#44; and number and type of selected studies&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><elsevierMultimedia ident="tbl0010"></elsevierMultimedia><p id="par0025" class="elsevierStylePara elsevierViewall">Using a cutoff date of September 2018&#44; we rated publications in Spanish&#44; Portuguese&#44; and English according to the ACCP grading system&#44; and classified the recommendation as strong or weak&#44; according to risk&#44; benefit&#44; and burden ratios&#44; and occasionally&#44; cost&#46; The quality of evidence was classed as high&#44; moderate&#44; or low&#44; depending on the design of the study&#44; consistency of results&#44; and clarity of the evidence to answer the clinical question&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Bronchodilator monotherapy</span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Question&#58; are long-acting bronchodilators &#40;LABA or LAMA&#41; more effective than short-acting bronchodilators &#40;SABA or SAMA&#41; in patients with mild chronic obstructive pulmonary disease&#63;</span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Rationale</span><p id="par0030" class="elsevierStylePara elsevierViewall">Around 70 &#37; of patients with COPD have mild-moderate airflow obstruction &#40;FEV<span class="elsevierStyleInf">1</span> &#8805; 50 &#37;&#41;&#44; with few respiratory symptoms&#46;<a class="elsevierStyleCrossRefs" href="#bib0035"><span class="elsevierStyleSup">7&#8211;10</span></a> Information on inhaled medication in the initial stages or in mild disease is limited&#46; Only 2 randomized controlled trials &#40;RCT&#41; in patients with mild-moderate obstruction have assessed the benefits of treatment with long-acting bronchodilators &#40;BD&#41; vs&#46; placebo&#58; one with tiotropium<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">11</span></a> and another with the combination of long-acting &#174;<span class="elsevierStyleInf">2</span>-agonists<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>inhaled corticosteroids &#40;LABA&#47;ICS&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">12</span></a> Tiotropium showed improvement in forced expiratory volume in 1<span class="elsevierStyleHsp" style=""></span>s &#40;FEV<span class="elsevierStyleInf">1</span>&#41;&#44; quality of life&#44; frequency of exacerbations&#44; and lung function decline&#46;<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">11</span></a> In mild COPD&#44; the use of any BD is usually recommended&#44; so it would be interesting to analyze whether a long-acting BD instead of a short-acting BD is justified in these patients&#46;</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Search outcome</span><p id="par0035" class="elsevierStylePara elsevierViewall">A total of 485 references &#40;MeSH&#58; 465&#59; Trip Database&#58; 20&#41; were retrieved&#44; and 2 systematic reviews were selected to answer the question&#46;<a class="elsevierStyleCrossRefs" href="#bib0065"><span class="elsevierStyleSup">13&#44;14</span></a></p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Quality of evidence</span><p id="par0040" class="elsevierStylePara elsevierViewall">In terms of efficacy&#44; a systematic review comparing tiotropium vs&#46; ipratropium &#40;SAMA&#41; in patients with moderate-severe obstruction shows greater benefit for tiotropium in lung function &#40;increased FEV<span class="elsevierStyleInf">1</span>&#58; 109<span class="elsevierStyleHsp" style=""></span>ml&#59; 95 &#37; CI&#58; 80&#8722;137<span class="elsevierStyleHsp" style=""></span>ml&#41;&#44; quality of life &#40;St&#46; George&#39;s Respiratory Questionnaire &#91;SGRQ&#93; difference&#58; &#8722;3&#46;3&#59; 95 &#37; CI&#58; 0&#46;97&#8211;5&#46;63&#41;&#44; fewer hospitalizations &#40;OR&#58; 0&#46;34&#59; 95 &#37; CI&#58; 0&#46;15-0&#46;76&#41; and exacerbations &#40;OR&#58; 0&#46;71&#59; 95 &#37; CI&#58; 0&#46;52&#8211;0&#46;95&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">13</span></a> Another systematic review comparing ipratropium and LABAs<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">14</span></a> in patients with moderate-severe obstruction showed greater benefits for salmeterol in FEV<span class="elsevierStyleInf">1</span> &#40;60<span class="elsevierStyleHsp" style=""></span>ml&#59; 95 &#37; CI&#58; 110&#8722;0<span class="elsevierStyleHsp" style=""></span>ml&#41; and morning peak flow &#40;&#8722;10&#46;96 lit&#47;min&#59; 95 &#37; CI&#58; &#8722;16&#46;09 to &#8722;5&#46;83&#41;&#44; with no difference in quality of life&#44; exacerbations&#44; rescue medication&#44; exercise capacity&#44; or symptoms&#46; The use of formoterol compared with ipratropium seems to show improvement in morning peak flow with no difference in FEV<span class="elsevierStyleInf">1</span>&#44; quality of life&#44; dyspnea&#44; or exercise capacity&#46;</p><p id="par0045" class="elsevierStylePara elsevierViewall">In terms of safety&#44; the study that compared ipratropium vs&#46; tiotropium reported fewer serious adverse events &#40;OR&#58; 0&#46;50&#59; 95 &#37; CI&#58; 0&#46;34&#8211;0&#46;73&#41; and disease events with tiotropium &#40;OR&#58; 0&#46;59&#59; 95 &#37; CI&#58; 0&#46;41&#8211;0&#46;85&#41;&#44; and no differences in mortality&#46;<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">13</span></a> No comparative studies of long-acting BD monotherapy vs&#46; short-acting &#174;<span class="elsevierStyleInf">2</span>-agonists &#40;SABA&#41;&#44; or comparative studies between short-acting vs&#46; long-acting BD in patients with mild obstruction were retrieved&#46;</p></span></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Conclusions and recommendations</span><p id="par0050" class="elsevierStylePara elsevierViewall">There is no available evidence that compares the use of short and long-acting BDs in COPD patients with mild obstruction&#46; The comparative studies retrieved in the search and the evidence selected involves patients with moderate-severe obstruction&#46; These show that&#44; in terms of efficacy&#44; tiotropium bromide<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>LABA compared with ipratropium has greater benefits in lung function&#46; Tiotropium also showed greater benefits in dyspnea&#44; exacerbations&#44; and quality of life&#44; and a better safety profile&#46;</p><p id="par0055" class="elsevierStylePara elsevierViewall">The only recommendation that can be drawn from these findings is that LABA or tiotropium should be used in preference to ipratropium in COPD patients with moderate-severe obstruction in terms of dyspnea&#44; quality of life&#44; and lung function&#44; and tiotropium bromide in preference to ipratropium in terms of improved exacerbation and hospitalization rates&#46;</p></span></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Combined therapies &#40;LABA&#47;ICS&#44; LABA&#47;LAMA and LABA&#47;LAMA&#47;ICS&#41;</span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Question&#58; does the combination of LABA<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>ICS provide greater benefits than monotherapy with LAMA or dual bronchodilator therapy with LABA<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>LAMA&#63;</span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Rationale</span><p id="par0060" class="elsevierStylePara elsevierViewall">LAMA monotherapy offers benefits in dyspnea&#44; quality of life&#44; and frequency of exacerbations and hospitalizations&#46;<a class="elsevierStyleCrossRefs" href="#bib0075"><span class="elsevierStyleSup">15&#8211;18</span></a> A reduction in exacerbations and improved quality of life and lung function have also been reported for LABA&#47;ICS<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">19</span></a> and LABA&#47;LAMA&#46;<a class="elsevierStyleCrossRefs" href="#bib0090"><span class="elsevierStyleSup">18&#44;20&#8211;29</span></a> The question arises as to whether there are differences between these treatments&#46;</p></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Search outcome</span><p id="par0065" class="elsevierStylePara elsevierViewall">A total of 238 references &#40;MeSH&#58; 230&#59; Trip Database&#58; 8&#41; were retrieved&#44; and 4 systematic reviews were selected to answer the question&#46;<a class="elsevierStyleCrossRefs" href="#bib0150"><span class="elsevierStyleSup">30&#44;32&#8211;34</span></a></p></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Quality of evidence</span><p id="par0070" class="elsevierStylePara elsevierViewall">In terms of efficacy&#44; a systematic review comparing fluticasone&#47;salmeterol vs&#46; tiotropium in patients with moderate-severe obstruction shows similar results in exacerbation and hospitalization rates and quality of life&#46;<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">30</span></a> However&#44; the number of drop-outs in one of the studies was high&#44; the groups were poorly matched&#44; and patients were not followed up after drop-out&#44; which limits the applicability of its results&#46;<a class="elsevierStyleCrossRef" href="#bib0155"><span class="elsevierStyleSup">31</span></a></p><p id="par0075" class="elsevierStylePara elsevierViewall">Another systematic review in patients with moderate-severe obstruction showed modest improvement &#40;without clinical relevance&#41; with LABA&#47;ICS &#40;fluticasone&#47;salmeterol&#41; compared with tiotropium in pre-BD FEV<span class="elsevierStyleInf">1</span> &#40;60<span class="elsevierStyleHsp" style=""></span>ml&#41;&#44; rescue medication&#44; and quality of life &#40;SGRQ&#44; &#8722;2&#46;07 units&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">32</span></a></p><p id="par0080" class="elsevierStylePara elsevierViewall">A systematic review compared the effectiveness of LABA&#47;LAMA with LABA&#47;ICS &#40;fluticasone&#47;salmeterol&#41; in patients with mostly moderate-severe COPD&#46;<a class="elsevierStyleCrossRef" href="#bib0165"><span class="elsevierStyleSup">33</span></a> LABA&#47;LAMA showed greater benefits in lung function &#40;trough FEV<span class="elsevierStyleInf">1</span> &#91;MD 80<span class="elsevierStyleHsp" style=""></span>ml&#93;&#41; and risk of exacerbations &#40;OR&#58; 0&#46;82&#41;&#46; There was no difference in quality of life &#40;SGRQ total score&#41;&#59; however&#44; the minimum clinical difference of 4 points was achieved more frequently with LABA&#47;LAMA than with fluticasone&#47;salmeterol &#40;OR&#58; 1&#46;25&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0165"><span class="elsevierStyleSup">33</span></a></p><p id="par0085" class="elsevierStylePara elsevierViewall">Another systematic review and meta-analysis in patients with moderate-very severe COPD showed greater benefits from LABA&#47;LAMA in lung function &#40;trough FEV<span class="elsevierStyleInf">1</span> &#91;MD 80<span class="elsevierStyleHsp" style=""></span>ml&#93;&#41;&#44; risk of moderate-severe exacerbations &#40;RR&#58; 0&#46;82&#41;&#44; and use of rescue medication &#40;-0&#46;18 puffs&#47;day&#41; compared with LABA&#47;ICS &#40;fluticasone&#47;salmeterol&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">34</span></a> There was no difference between the therapies in quality of life or severity of dyspnea&#46;</p><p id="par0090" class="elsevierStylePara elsevierViewall">With regard to safety&#44; systematic reviews show an increased risk of pneumonia and serious adverse effects with fluticasone&#47;salmeterol vs&#46; tiotropium or LABA&#47;LAMA&#46;<a class="elsevierStyleCrossRef" href="#bib0165"><span class="elsevierStyleSup">33</span></a></p></span></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Conclusions and recommendations</span><p id="par0095" class="elsevierStylePara elsevierViewall">The efficacy of tiotropium and fluticasone&#47;salmeterol in patients with moderate-severe COPD is similar&#46; LABA&#47;LAMA has greater benefits in lung function and risk of exacerbations compared with fluticasone&#47;salmeterol&#46; With regard to safety&#44; there is evidence of an increased risk of pneumonia with fluticasone&#47;salmeterol vs&#46; tiotropium bromide<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>LABA&#47;LAMA&#46;</p><p id="par0100" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">HIGH evidence</span> for the use of tiotropium or LABA&#47;ICS &#40;fluticasone&#47;salmeterol&#41; in terms of dyspnea&#44; pulmonary function&#44; quality of life&#44; and frequency of exacerbations and hospitalizations in patients with moderate-severe COPD&#46;</p><p id="par0105" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">STRONG recommendation</span> to prefer tiotropium over fluticasone&#47;salmeterol&#44; due to an increased risk of pneumonia with the latter&#46;</p><p id="par0110" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">HIGH evidence and STRONG recommendation</span> for the use of LABA&#47;LAMA in preference to LABA&#47;ICS &#40;fluticasone&#47;salmeterol&#41; to improve lung function and frequency of exacerbations&#44; with less risk of pneumonia in patients with moderate-very severe COPD&#46;</p></span><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Question&#58; does the combination of LABA<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>LAMA<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>ICS &#40;triple therapy&#41; provide greater benefits compared with LAMA monotherapy&#44; combination therapy &#40;LABA&#47;ICS&#41; or dual bronchodilator therapy &#40;LABA&#47;LAMA&#41; in patients with COPD&#63;</span><span id="sec0075" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Rationale</span><p id="par0115" class="elsevierStylePara elsevierViewall">The combination of LABA&#47;LAMA&#47;ICS may decrease the risk of exacerbations&#44; hospitalizations&#44; and healthcare costs in COPD patients with moderate-very severe obstruction&#46;<a class="elsevierStyleCrossRefs" href="#bib0175"><span class="elsevierStyleSup">35&#44;36</span></a> Controversy persists on the efficacy and safety of fixed-dose combination triple therapy or combining different devices &#40;LABA&#47;ICS<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>tiotropium or LABA&#47;ICS<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>glycopyrronium&#41;&#44; compared with LAMA&#44; LAMA&#47;ICS or LABA&#47;LAMA&#46;</p></span><span id="sec0080" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Search outcome</span><p id="par0120" class="elsevierStylePara elsevierViewall">A total of 193 references &#40;MeSH&#58; 181&#59; Trip Database&#58; 12&#41;&#44; and 2 systematic reviews<a class="elsevierStyleCrossRefs" href="#bib0185"><span class="elsevierStyleSup">37&#44;38</span></a> and 5 RCTs<a class="elsevierStyleCrossRefs" href="#bib0015"><span class="elsevierStyleSup">3&#44;4&#44;39&#8211;41</span></a> were selected to answer the question&#46;</p></span><span id="sec0085" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">Quality of evidence</span><p id="par0125" class="elsevierStylePara elsevierViewall">One systematic review showed greater benefits with triple therapy &#40;LABA&#47;ICS<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>tiotropium&#41; in hospitalizations for all causes &#40;reduction of risk&#58; 39 &#37;&#59; OR&#58; 0&#46;61&#59; 95 &#37; CI&#58; 0&#46;40&#8211;0&#46;92&#41;&#44; quality of life &#40;SGRQ difference&#58; &#8722;3&#46;46&#59; 95 &#37; CI&#58; &#8722;5&#46;05 to &#8722;1&#46;87&#41;&#44; and lung function &#40;pre-BD FEV<span class="elsevierStyleInf">1</span>&#58; 60<span class="elsevierStyleHsp" style=""></span>ml&#59; 95 &#37; CI&#58; 40&#8722;80<span class="elsevierStyleHsp" style=""></span>ml at 3&#8211;6 months&#41; compared with tiotropium in patients with moderate-severe COPD&#44; with no differences in mortality or frequency of exacerbations&#46;<a class="elsevierStyleCrossRef" href="#bib0185"><span class="elsevierStyleSup">37</span></a> Similar results were reported by another systematic review and meta-analysis&#46;<a class="elsevierStyleCrossRef" href="#bib0190"><span class="elsevierStyleSup">38</span></a> Three RCTs in patients with FEV<span class="elsevierStyleInf">1</span> &#60; 50 &#37; and a history of exacerbations evaluated the efficacy and safety of a fixed-dose combination &#40;beclomethasone dipropionate<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>formoterol fumarate<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>glycopyrronium &#91;BDP&#47;FF&#47;GLY&#93;&#41; compared with tiotropium<a class="elsevierStyleCrossRef" href="#bib0195"><span class="elsevierStyleSup">39</span></a>&#59; with BDP&#47;FF<a class="elsevierStyleCrossRef" href="#bib0205"><span class="elsevierStyleSup">41</span></a>&#59; and with indacaterol<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>glycopyrronium&#46;<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a> BDP&#47;FF&#47;GLY compared with tiotropium showed greater benefits in the frequency of moderate-severe exacerbations &#40;RR&#58; 0&#46;80&#59; 95 &#37; CI&#58; 0&#46;69 to &#8722;0&#46;92&#41;&#44; lung function &#40;pre-BD FEV<span class="elsevierStyleInf">1</span> difference&#58; 61<span class="elsevierStyleHsp" style=""></span>ml&#59; 95 &#37; CI&#58; 37&#8722;86<span class="elsevierStyleHsp" style=""></span>ml&#41;&#44; quality of life &#40;SGRQ responders&#58; 1&#46;33&#59; 95 &#37; CI&#58; 1&#46;10&#8211;1&#46;59&#41;&#44; and reduced use of rescue medication&#46;<a class="elsevierStyleCrossRef" href="#bib0195"><span class="elsevierStyleSup">39</span></a> The combination showed greater benefits compared with BDP&#47;FF in lung function at 26 weeks &#40;FEV<span class="elsevierStyleInf">1</span> pre-dose difference&#58; 81<span class="elsevierStyleHsp" style=""></span>ml&#59; 95 &#37; CI&#58; 52&#8722;109<span class="elsevierStyleHsp" style=""></span>ml&#41;&#44; a 23 &#37; reduction in moderate-severe exacerbations &#40;RR&#58; 0&#46;77&#59; 95 &#37; CI&#58; 0&#46;65-0&#46;92&#41;&#44; quality of life &#40;responders&#41; at 52 weeks &#40;SGRQ&#44; OR&#58; 1&#46;33&#59; 95 &#37; CI&#58; 1&#46;06&#8211;1&#46;66&#41;&#44; with no differences in dyspnea severity&#46;<a class="elsevierStyleCrossRef" href="#bib0205"><span class="elsevierStyleSup">41</span></a> BDP&#47;FF&#47;GLY compared to indacaterol&#47;glycopyrronium showed greater benefits in the frequency of moderate-severe exacerbations &#40;RR&#58; 0&#46;85&#59; 95 &#37; C&#58; 0&#46;72-0&#46;99&#41;&#59; there were no differences in lung function or quality of life&#46;<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a></p><p id="par0130" class="elsevierStylePara elsevierViewall">Two RCTS compared a fixed-dose combination of fluticasone furoate&#47;umeclidinium&#47;vilanterol &#40;FFL&#47;UMEC&#47;VI&#41; with budesonide&#47;formoterol &#40;BUD&#47;FF&#41;&#44;<a class="elsevierStyleCrossRef" href="#bib0200"><span class="elsevierStyleSup">40</span></a> FFL&#47;VI and UMEC&#47;VI<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a> in symptomatic patients with moderate-severe obstruction and history of exacerbations&#46; Compared to BUD&#47;FF&#44; the triple therapy showed greater benefits in lung function &#40;trough FEV<span class="elsevierStyleInf">1</span>&#58; difference 171<span class="elsevierStyleHsp" style=""></span>ml&#59; 95 &#37; CI&#58; 148&#8211;194&#44; in favor of FFL&#47;UMEC&#47;VI&#41;&#44; quality of life &#40;SGRQ difference&#58; &#8722;2&#46;2&#59; 95 &#37; CI&#58; &#8722;3&#46;5 to &#8722;1&#44; in favor of FFL&#47;UMEC&#47;VI&#41;&#44; and the frequency of moderate-severe exacerbations &#40;35 &#37; reduction&#59; 95 &#37; CI&#58; 14 &#37;&#8211;51 &#37;&#41;&#46; A subanalysis<a class="elsevierStyleCrossRef" href="#bib0200"><span class="elsevierStyleSup">40</span></a> shows similar benefits with FFL&#47;UMEC&#47;VI over BUD&#47;FF in symptomatic patients&#44; regardless of the severity of COPD or prior treatment&#46; One of the studies<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a> showed greater benefits with FFL&#47;UMEC&#47;VI in the frequency of moderate-severe exacerbations&#44; compared with FFL&#47;VI &#40;RR&#58; 0&#46;85&#59; 95 &#37; CI&#58; 0&#46;80 &#37;&#8211;0&#46;90 &#37;&#44; 15 &#37; difference&#41; and UMEC&#47;VI &#40;RR&#58; 0&#46;75&#59; 95 &#37; CI&#58; 0&#46;70&#8211;0&#46;81&#44; 25 &#37; difference&#41;&#44; regardless of the eosinophil count in blood&#44; although there was a greater reduction of risk in patients with eosinophils &#62; 150 cells&#47;&#956;l&#46; This combination also showed greater benefits in lung function &#40;FFL&#47;UMEC&#47;VI vs&#46; FFL&#47;VI<span class="elsevierStyleSmallCaps">&#44;</span> trough FEV<span class="elsevierStyleInf">1</span> difference&#58; 97<span class="elsevierStyleHsp" style=""></span>ml&#59; 95 &#37; CI&#58; 85&#8722;109<span class="elsevierStyleHsp" style=""></span>ml&#44; and FFL&#47;UMEC&#47;VI vs&#46; UMEC&#47;VI<span class="elsevierStyleSmallCaps">&#44;</span> trough FEV<span class="elsevierStyleInf">1</span> difference&#58; 54<span class="elsevierStyleHsp" style=""></span>ml&#59; 95 &#37; CI&#58; 39&#8722;69<span class="elsevierStyleHsp" style=""></span>ml&#41; and quality of life &#40;SGRQ&#44; FFL&#47;UMEC&#47;VI vs&#46; FFL&#47;VI difference &#8722;1&#46;8&#59; 95 &#37; CI&#58; &#8722;2&#46;4 to &#8722;1&#46;1&#44; and FFL&#47;UMEC&#47;VI vs&#46; UMEC&#47;VI &#8722;1&#46;8&#59; 95 &#37; CI&#58; &#8722;2&#46;6 to &#8722;1&#46;0&#41;&#46; With regard to safety&#44; triple therapy in different devices compared to tiotropium showed no differences in the appearance of adverse effects&#46;<a class="elsevierStyleCrossRefs" href="#bib0185"><span class="elsevierStyleSup">37&#44;38</span></a> BDP&#47;FF&#47;GLY showed an incidence of pneumonia in a small group of patients &#40;BDP&#47;FF&#47;GLY 2 &#37; vs&#46; tiotropium 1 &#37;&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0200"><span class="elsevierStyleSup">40</span></a> There were no differences in the incidence of pneumonia between BDP&#47;FF&#47;GLY and BDP&#47;FF<a class="elsevierStyleCrossRef" href="#bib0205"><span class="elsevierStyleSup">41</span></a> or indacaterol&#47;glycopyrronium<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a>&#59; however&#44; the risk of a medical diagnosis of pneumonia with FFL&#47;UMEC&#47;VI was higher than with UMEC&#47;VI &#40;HR&#58; 1&#46;52&#59; 95 &#37; CI&#58; 1&#46;22&#8211;1&#46;92&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a></p></span></span><span id="sec0090" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0110">Conclusions and recommendations</span><p id="par0135" class="elsevierStylePara elsevierViewall">In symptomatic COPD patients with severe-very severe obstruction and a history of exacerbations&#44; triple therapy offers greater benefits in terms of efficacy&#44; lung function&#44; quality of life&#44; and risk of exacerbations than tiotropium or LABA&#47;ICS&#46; Triple therapy compared with LABA&#47;LAMA shows greater benefits in the risk of moderate-severe exacerbations&#46; In comparison with FFL&#47;VI or UMEC&#47;VI&#44; the FFL&#47;UMEC&#47;VI combination shows greater benefits in the frequency of moderate-severe exacerbations&#44; regardless of eosinophil blood counts&#59; although the benefit is greater in patients with &#62; 150 cells&#47;&#956;l&#46; The risk of pneumonia is greater in treatments containing ICS&#46;</p><p id="par0140" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">HIGH evidence and STRONG recommendation</span> for the use of triple therapy in symptomatic COPD patients with severe-very severe obstruction and risk of exacerbations to improve lung function and quality of life and decrease the risk of exacerbations&#46;</p></span><span id="sec0095" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0115">Question&#58; which COPD patients benefit from the use of ICS in the reduction of exacerbations&#63;</span><span id="sec0100" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0120">Rationale</span><p id="par0145" class="elsevierStylePara elsevierViewall">The use of ICS alone or in combination with LABA has shown benefits in COPD patients&#44; including lower exacerbation rates and health status decline&#46;<a class="elsevierStyleCrossRefs" href="#bib0210"><span class="elsevierStyleSup">42&#44;43</span></a></p><p id="par0150" class="elsevierStylePara elsevierViewall">These outcomes should be analyzed in terms of the risk&#47;benefit ratio&#44; in particular the risk of pneumonia associated with ICS&#46;</p><p id="par0155" class="elsevierStylePara elsevierViewall">A need is emerging to define the subgroup of patients with COPD who benefit most from ICS&#44; focused on reducing the risk of exacerbation&#46;</p></span><span id="sec0105" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0125">Search outcome</span><p id="par0160" class="elsevierStylePara elsevierViewall">A total of 338 references &#40;MeSH&#58; 246&#59; Trip Database&#58; 92&#41;&#44; and 3 systematic reviews<a class="elsevierStyleCrossRefs" href="#bib0165"><span class="elsevierStyleSup">33&#44;44&#44;45</span></a> and 2 RCTs<a class="elsevierStyleCrossRefs" href="#bib0015"><span class="elsevierStyleSup">3&#44;46</span></a> were selected to answer the question&#46;</p></span><span id="sec0110" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0130">Quality of evidence</span><p id="par0165" class="elsevierStylePara elsevierViewall">A systematic review comparing the efficacy of any dose or type of ICS with placebo in patients with moderate-severe COPD showed that ICS reduced the rate of exacerbations &#40;-0&#46;26 exacerbations per patient&#47;year&#44; 95 &#37; CI&#58; &#8722;0&#46;37 to &#8722;0&#46;14&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0220"><span class="elsevierStyleSup">44</span></a> Another systematic review comparing the effectiveness of LABA&#47;ICS &#40;mainly fluticasone&#47;salmeterol&#41; with ICS monotherapy in patients with mild-severe COPD showed a reduction in the frequency of exacerbation with LABA&#47;ICS &#40;RR&#58; 0&#46;91&#59; 95 &#37; CI&#58; 0&#46;85&#8211;0&#46;97&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0225"><span class="elsevierStyleSup">45</span></a> Two RCTs with fluticasone&#47;salmeterol included in this review showed that exacerbations requiring oral steroids were reduced with fluticasone&#47;salmeterol&#44; and another found no difference in the rate of hospitalization&#46;<a class="elsevierStyleCrossRef" href="#bib0225"><span class="elsevierStyleSup">45</span></a> A systematic review comparing the effectiveness of LABA&#47;LAMA with LABA&#47;ICS &#40;fluticasone&#47;salmeterol&#41; in patients with mostly moderate-severe COPD showed greater benefits with LABA&#47;LAMA in the risk of exacerbations &#40;OR&#58; 0&#46;82&#59; 95 &#37; CI&#58; 0&#46;70&#8211;0&#46;96&#41;&#46; The studies included in the analysis were heterogeneous&#44; and included an observation period of less than 1<span class="elsevierStyleHsp" style=""></span>year&#46; Most included patients with moderate-severe COPD&#44; with no recent exacerbations&#46;<a class="elsevierStyleCrossRef" href="#bib0165"><span class="elsevierStyleSup">33</span></a></p><p id="par0170" class="elsevierStylePara elsevierViewall">An RCT that compared FFL&#47;UMEC&#47;VI with FFL&#47;VI and UMEC&#47;VI<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a> in patients with moderate-very severe obstruction and a history of exacerbations showed greater benefits with FFL&#47;UMEC&#47;VI in frequency of moderate-severe exacerbations&#44; compared with FFL&#47;VI &#40;RR&#58; 0&#46;85&#59; 95 &#37; CI&#58; 0&#46;80 &#37;&#8211;0&#46;90 &#37;&#44; 15 &#37; difference&#41; and UMEC&#47;VI &#40;RR&#58; 0&#46;75&#59; 95 &#37; CI&#58; 0&#46;70&#8211;0&#46;81&#44; 25 &#37; difference&#41;&#44; regardless of the eosinophil count in blood&#44; although there was a greater reduction of risk in patients with a eosinophil count &#62; 150 cells&#47;&#956;l&#46;</p><p id="par0175" class="elsevierStylePara elsevierViewall">Another RCT evaluated the effect of intensifying LABA&#47;ICS therapy &#40;budesonide&#47;formoterol&#41; on the exacerbation rate in moderate-severe patients at the onset of upper respiratory tract infection&#46;<a class="elsevierStyleCrossRef" href="#bib0230"><span class="elsevierStyleSup">46</span></a> The incidence of exacerbations in the budesonide&#47;formoterol and placebo groups was similar &#40;14&#46;6 vs&#46; 16&#46;2 &#37;&#59; HR&#58; 0&#46;77&#59; 95 &#37; CI&#58; 0&#44;46&#8211;1&#44;33&#41;&#44; although the risk of severe exacerbations was reduced by 72 &#37; &#40;HR&#58; 0&#46;28&#59; 95 &#37; CI&#58; 0&#44;11&#8211;0&#44;74&#41; with intensified therapy&#46; A significantly reduced risk of exacerbation was observed in the subgroup of patients with more severe disease&#46;</p><p id="par0180" class="elsevierStylePara elsevierViewall">In terms of safety&#44; evidence suggests that treatments that include ICS are associated with more frequent serious adverse effects&#44; in particular&#44; an increased risk of pneumonia&#46;<a class="elsevierStyleCrossRefs" href="#bib0015"><span class="elsevierStyleSup">3&#44;33&#44;44</span></a></p></span></span><span id="sec0115" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0135">Conclusions and recommendations</span><p id="par0185" class="elsevierStylePara elsevierViewall">In terms of efficacy&#44; the use of long-term ICS shows a benefit in the risk of exacerbations in patients with moderate-severe COPD&#44; which is greater in individuals with elevated eosinophils in blood&#46; This benefit must be weighed up against the increased risk of pneumonia&#46;</p><p id="par0190" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Moderate evidence and strong recommendation</span> for the use of ICS in patients with moderate-severe COPD with a history of exacerbation and elevated eosinophils in blood&#44; in terms of a reduced risk of exacerbations&#46;</p></span><span id="sec0120" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0140">Question&#58; in which patients can ICS be safely withdrawn&#63;</span><span id="sec0125" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0145">Rationale</span><p id="par0195" class="elsevierStylePara elsevierViewall">Overuse of ICS in COPD is a common practice&#44;<a class="elsevierStyleCrossRefs" href="#bib0235"><span class="elsevierStyleSup">47&#8211;49</span></a> even though these medications are usually reserved for patients at high risk of exacerbations &#40;one third of the total population&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0250"><span class="elsevierStyleSup">50&#44;51</span></a> The long-term use of ICS is associated with an increased risk of adverse events&#44; particularly pneumonia&#46;<a class="elsevierStyleCrossRefs" href="#bib0210"><span class="elsevierStyleSup">42&#44;52</span></a> Patients who are unlikely to benefit and in whom discontinuation is safe must be identified&#46;</p></span><span id="sec0130" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0150">Search outcome</span><p id="par0200" class="elsevierStylePara elsevierViewall">A total of 588 references &#40;MeSH&#58; 247&#59; Trip Database&#58; 341&#41; were retrieved&#44; and 1 meta-analysis<a class="elsevierStyleCrossRef" href="#bib0265"><span class="elsevierStyleSup">53</span></a> and 2 RCTs<a class="elsevierStyleCrossRefs" href="#bib0270"><span class="elsevierStyleSup">54&#44;55</span></a> were selected to answer the question&#46;</p></span><span id="sec0135" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0155">Quality of evidence</span><p id="par0205" class="elsevierStylePara elsevierViewall">A meta-analysis that includes RCTs and real-world observational studies in patients with moderate-severe obstruction showed no increase in the overall risk of exacerbations after ICS withdrawal &#40;OR&#58; 1&#46;03&#59; 95 &#37; CI&#58; 0&#46;95&#8211;1&#46;12&#59; p<span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#41;&#46; However&#44; the risk of moderate-severe exacerbation increased &#40;2&#46;4 &#37; and 33&#46;6 &#37;&#44; respectively&#41;&#44; and the time to first exacerbation was shorter &#40;p<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#41; in patients who discontinued ICS&#46; ICS withdrawal was also associated with lung function decline &#40;FEV<span class="elsevierStyleInf">1</span>&#58; &#8722;30<span class="elsevierStyleHsp" style=""></span>ml&#41; and reduced quality of life &#40;&#43;1&#44;24 SGRQ units&#41;&#44; without reaching a minimally significant clinical difference&#46;<a class="elsevierStyleCrossRef" href="#bib0265"><span class="elsevierStyleSup">53</span></a></p><p id="par0210" class="elsevierStylePara elsevierViewall">An RCT evaluated the efficacy and safety of abrupt withdrawal of ICS from long-term triple therapy in COPD patients who were frequent exacerbators with FEV<span class="elsevierStyleInf">1</span> between 40 &#37;&#8211;80 &#37;&#46;<a class="elsevierStyleCrossRef" href="#bib0270"><span class="elsevierStyleSup">54</span></a> Patients were randomized to continue fluticasone&#47;salmeterol<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>tiotropium or to switch to indacaterol&#47;glycopyrronium&#46; No differences were observed between groups in the frequency of moderate-severe exacerbations &#40;0&#46;52 vs&#46; 0&#46;48&#41; &#40;RR&#58; 1&#46;08&#59; 95 &#37; CI&#58; 0&#46;83&#8211;1&#46;40&#41; or the time to the first moderate-severe exacerbation &#40;HR&#58; 1&#46;11&#59; 95 &#37; CI&#58; 0&#46;85&#8211;1&#46;46&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0270"><span class="elsevierStyleSup">54</span></a> The withdrawal of ICS was associated with a slight reduction in trough FEV<span class="elsevierStyleInf">1</span>&#58; &#8722;26<span class="elsevierStyleHsp" style=""></span>ml &#40;95 &#37; CI&#58; &#8722;53 to 1<span class="elsevierStyleHsp" style=""></span>ml&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0270"><span class="elsevierStyleSup">54</span></a> Patients with a blood eosinophil count &#8805; 300 cells&#47;&#956;l presented greater deterioration in lung function and an increased risk of exacerbation &#40;RR&#58; 1&#46;86&#59; 95 &#37; CI&#58; 1&#46;06&#8211;3&#46;29&#41; Adverse events were similar between the groups&#46;<a class="elsevierStyleCrossRef" href="#bib0270"><span class="elsevierStyleSup">54</span></a> Another RCT assessed changes in airway inflammation after fluticasone was withdrawn in patients with moderate-severe COPD who received this medication long term&#46;<a class="elsevierStyleCrossRef" href="#bib0275"><span class="elsevierStyleSup">55</span></a> The interruption of fluticasone induced an increase in bronchial T cells&#44; mast cells&#44; and several types of cells in sputum &#40;relapse in the production of inflammatory cells&#41;&#44; which was accompanied by further lung function decline&#46;<a class="elsevierStyleCrossRef" href="#bib0275"><span class="elsevierStyleSup">55</span></a> The results suggest that airway inflammation is suppressed during treatment with fluticasone&#44; but the nonsteroidal anti-inflammatory effects are not maintained after withdrawal&#46;<a class="elsevierStyleCrossRef" href="#bib0275"><span class="elsevierStyleSup">55</span></a></p></span></span><span id="sec0140" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0160">Conclusions and recommendations</span><p id="par0215" class="elsevierStylePara elsevierViewall">ICS can be withdrawn abruptly in COPD patients with a low risk of exacerbation&#44; moderate-severe obstruction&#44; and blood eosinophil count &#60; 300 cells&#47;&#956;l without increasing the risk of exacerbation or affecting lung function&#46; ICS should not be withdrawn in patients at high risk of exacerbation and moderate-severe obstruction&#44; due to an increased risk of exacerbation and lung function decline&#46;</p><p id="par0220" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Moderate evidence and strong recommendation</span> for withdrawal of ICS in COPD patients with a low risk of exacerbations&#44; moderate-severe obstruction&#44; and eosinophil blood count &#60; 300 cells&#47;&#956;l&#46;</p></span><span id="sec0145" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0165">Incorporation of new evidence</span><p id="par0225" class="elsevierStylePara elsevierViewall">The treatment of COPD should be individualized according to disease severity and drug availability&#46; General measures and prevention &#40;education&#44; smoking cessation&#44; vaccination&#44; and physical activity&#44; among others&#41;&#44; and pharmacological and non-pharmacological treatments should be taken into account&#46;</p><p id="par0230" class="elsevierStylePara elsevierViewall">In view of all the evidence analyzed&#44; we propose a scheme with progressive inhaled medication according to COPD severity &#40;dyspnea&#44; obstruction&#44; or exacerbations&#41; that can be modified according to clinical response &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41;&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0235" class="elsevierStylePara elsevierViewall">BD monotherapy is recommended in patients with mild disease &#40;all criteria&#58; dyspnea mMRC grade 1&#44; FEV<span class="elsevierStyleInf">1</span> &#8805; 80 &#37; post-BD&#41;&#46;</p><p id="par0240" class="elsevierStylePara elsevierViewall">The efficacy and safety of LAMA vs&#46; LABA monotherapy were analyzed in an earlier study&#46;<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a> The evidence shows that in terms of efficacy&#44; tiotropium and LABAs have similar benefits in dyspnea&#44; lung function&#44; and quality of life&#44; but tiotropium is more effective in reducing the frequency of exacerbations&#46; On the basis of the evidence analyzed&#44; patients with moderate disease &#40;with at least 1 parameter of severity&#58; dyspnea mMRC grade 2&#44; FEV<span class="elsevierStyleInf">1</span> 79 &#37;&#8722;50 &#37;&#44; an exacerbation without hospitalization in the preceding year&#41; should start bronchodilator monotherapy with LAMA or LABA&#44; instead of LABA&#47;ICS in view of the increased risk of pneumonia associated with ICS&#46; LAMA&#47;LABA can be escalated&#44; according to response&#46; The LABA&#47;ICS combination is recommended in patients with asthma or a medical diagnosis of asthma before the age of 40 years &#40;asthma&#8722;COPD overlap&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0280"><span class="elsevierStyleSup">56</span></a></p><p id="par0245" class="elsevierStylePara elsevierViewall">Patients with severe disease &#40;at least 1 severity parameter&#58; mMRC dyspnea grade 3&#8211;4&#44; FEV<span class="elsevierStyleInf">1</span> &#60;50 &#37;&#44; &#8805; 2 exacerbations in the last year&#44; or &#8805; 1 hospitalization for exacerbation&#41; should start treatment with LAMA&#47;LABA&#44; except individuals with an eosinophil blood count &#8805; 300 cells&#47;&#956;l&#44; who should receive LABA&#47;LAMA&#47;ICS&#44; given the benefits of triple therapy in the risk of exacerbations and lung function decline&#46;<a class="elsevierStyleCrossRef" href="#bib0270"><span class="elsevierStyleSup">54</span></a> Escalation to LABA&#47;LAMA&#47;ICS is indicated in patients who started LAMA&#47;LABA&#44; but who persist with exacerbations regardless of their eosinophil count&#46;<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a> ICS withdrawal must be considered in certain circumstances&#58; when the initial indication was incorrect or no response is elicited&#59; in patients with side effects such as pneumonia&#59; and in patients with a low risk of exacerbation and a serum eosinophil count of &#60;300 cells&#47;&#956;l&#46;<a class="elsevierStyleCrossRef" href="#bib0270"><span class="elsevierStyleSup">54</span></a> The prophylactic use of azithromycin or roflumilast can be useful as additional therapy in reducing the number of exacerbations in severe patients&#46;<a class="elsevierStyleCrossRefs" href="#bib0285"><span class="elsevierStyleSup">57&#44;58</span></a></p></span></span><span id="sec0150" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0170">Conclusions</span><p id="par0250" class="elsevierStylePara elsevierViewall">This ALAT 2019 statement provides an overview of treatment with inhaled medication in chronic obstructive pulmonary disease &#40;COPD&#41;&#44; incorporating the evidence analyzed using PICO methodology&#44; according to severity of the obstruction&#44; symptoms&#44; and risk of exacerbations&#46;</p></span><span id="sec0155" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0175">Conflict of interests</span><p id="par0255" class="elsevierStylePara elsevierViewall">August&#237;n Acu&#241;a and Ephraim Sanchez declare that they have received professional honoraria for the development and implementation of methodological aspects of this paper from ITSalud&#47;Medsolid&#46; All other authors declare no real or perceived conflict of interest&#46;</p></span><span id="sec0160" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0180">Funding</span><p id="par0260" class="elsevierStylePara elsevierViewall">This study was funded by <span class="elsevierStyleGrantSponsor" id="gs0005">AstraZeneca</span>&#44; <span class="elsevierStyleGrantSponsor" id="gs0010">Boehringer Ingelheim</span>&#44; and <span class="elsevierStyleGrantSponsor" id="gs0015">GlaxoSmithKline</span>&#46; The sponsors did not play any part in the study and did not participate at any stage of the development of these guidelines&#46; None of the authors was paid for their participation in the preparation of this update&#46;</p></span></span>"
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        "titulo" => "Abstract"
        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">This document on COPD from the Latin American Chest Association &#40;ALAT-2019&#41; uses PICO methodology to analyze new evidence on inhaled medication and answer clinical questions&#46; The following key points emerged from this analysis&#58; 1&#41; evidence is lacking on the comparison of short-acting vs&#46; long-acting bronchodilators in patients with mild COPD&#59; patients with moderate-to-severe COPD obtain greater benefit from long-acting bronchodilators&#59; 2&#41; the benefits of monotherapy with long-acting antimuscarinic agents &#40;LAMA&#41; and combined therapy with long-acting &#946;<span class="elsevierStyleInf">2</span>-agonists and inhaled corticosteroids &#40;LABA&#47;ICS&#41; are similar&#44; although the latter is associated with a greater risk of pneumonia&#59; 3&#41; LABA&#47;LAMA offer greater benefits in terms of lung function and risk of exacerbation than LABA&#47;ICS &#40;the latter involve an increased risk of pneumonia&#41;&#44; 4&#41; LAMA&#47;LABA&#47;ICS have greater therapeutic benefits than LABA&#47;LAMA on the risk of moderate-severe exacerbations&#46; With regard to the role of eosinophils in guiding the use of ICS&#44; ICS withdrawal must be considered when the initial indication was wrong or no response is elicited&#44; in patients with side effects such as pneumonia&#44; and in patients with a low risk of exacerbation and an eosinophil blood count of &#60; 300 cells&#47;&#956;l&#46; All this evidence&#44; categorized according to the severity of the obstruction&#44; symptoms&#44; and risk of exacerbations&#44; has been used to generate an algorithm for the use of inhaled medication in COPD&#46;</p></span>"
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        "resumen" => "<span id="abst0010" class="elsevierStyleSection elsevierViewall"><p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Este documento sobre EPOC de la Asociaci&#243;n Latinoamericana de T&#243;rax &#40;ALAT&#41;-2019 analiza las nuevas evidencias de medicaci&#243;n inhalada utilizando la metodolog&#237;a de preguntas cl&#237;nicas en formato PICO&#46; Surgen de este an&#225;lisis los siguientes puntos claves&#58; 1&#41; No hay evidencia que compare el uso de broncodilatadores de acci&#243;n corta vs&#46; larga en pacientes con EPOC leve&#59; en aquellos con EPOC moderada-grave existe mayor beneficio de los broncodilatadores de acci&#243;n larga&#44; 2&#41; beneficios similares de la monoterapia con antimuscar&#237;nicos de acci&#243;n prolongada &#40;LAMA&#41; y la terapia combinada &#946;<span class="elsevierStyleInf">2</span>-agonistas de acci&#243;n larga&#47;corticosteroides inhalados &#40;LABA&#47;CIS&#41;&#44; asociada esta &#250;ltima a mayor riesgo de neumon&#237;a 3&#41; mayores beneficios del LABA&#47;LAMA en funci&#243;n pulmonar y riesgo de exacerbaci&#243;n vs&#46; LABA&#47;CIS &#40;esta &#250;ltima con mayor riesgo de neumon&#237;a&#41;&#44; 4&#41; mayores beneficios de la terapia LAMA&#47;LABA&#47;CIS comparada con LABA&#47;LAMA sobre el riesgo de exacerbaciones moderadas-severas&#46; En relaci&#243;n al rol de los eosin&#243;filos para guiar el uso de CIS&#58; debe considerarse su retiro cuando la indicaci&#243;n inicial fue errada o sin respuesta&#44; en pacientes con efectos secundarios&#44; como neumon&#237;a y en aquellos con bajo riesgo de exacerbaci&#243;n con recuento de eosin&#243;filos en sangre &#60;300cels&#47;&#956;l&#46; Incorporando estas evidencias seg&#250;n la gravedad de la obstrucci&#243;n&#44; s&#237;ntomas y riesgo de exacerbaciones&#44; se genera un algoritmo para el uso de medicaci&#243;n inhalada en la EPOC&#46;</p></span>"
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        "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as&#58; Montes de Oca M et al&#46; Incorporando nuevas evidencias sobre medicamentos inhalados en la EPOC&#46; Asociaci&#243;n Latinoamericana de T&#243;rax &#40;ALAT&#41; 2019&#46; Arch Bronconeumol&#46; 2020&#59;56&#58;106&#8211;113&#46;</p>"
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            "etiqueta" => "Appendix A"
            "titulo" => "Supplementary data"
            "identificador" => "sec0170"
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          "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Inhaled treatment depending on the severity of COPD&#46; ALAT-2019&#46;</p>"
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          "leyenda" => "<p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">COPD&#58; chronic obstructive pulmonary disease&#59; ICS&#58; inhaled corticosteroid&#59; LABA&#58; long-acting &#946;2-agonists&#59; LAMA&#58; long-acting antimuscarinic agents&#59; RCT&#58; randomized controlled trials&#59; SABA&#58; short-acting &#946;-agonist&#59; SAMA&#58; short-acting muscarinic antagonist&#46;</p>"
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                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Clinical question&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">PICO question&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Search strategy with MeSH terms&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
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                  \t\t\t\t">Are long-acting bronchodilators &#40;LABA or LAMA&#41; more effective than short-acting bronchodilators &#40;SABA or SAMA&#41; in patients with mild COPD&#63;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">P<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>COPD or Chronic Obstructive Pulmonary DiseaseI &#61; LABA or LAMAC<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>SABA or SAMAO &#61; &#216;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">a&#41; &#40;&#40;&#40;&#40;&#40;&#96;&#96;pulmonary disease&#44; chronic obstructive&#8221;&#91;MeSH Terms&#93; OR copd OR chronic obstructive pulmonary disease OR coad OR chronic obstructive airway disease OR chronic obstructive lung disease OR airflow obstruction&#44; chronic OR airflow obstructions&#44; chronic OR chronic airflow obstructions OR chronic airflow obstruction&#41;&#41;&#41;&#41;&#41; AND &#40;&#96;&#96;Albuterol&#8221;&#91;MeSH&#93; OR salbutamol OR 2-t-Butylamino-1- AND &#40;4-hydroxy-3-hydroxy-3-hydroxymethyl&#41; AND phenylethanol OR ventolin OR sultanov OR albuterol sulfate OR prove it&#41;b&#41; &#40;&#40;&#40;&#40;&#40;&#96;&#96;pulmonary disease&#44; chronic obstructive&#8221;&#91;MeSH Terms&#93; OR COPD OR Chronic Obstructive Pulmonary Disease OR COAD OR Chronic Obstructive Airway Disease OR Chronic Obstructive Lung Disease OR Airflow Obstruction&#44; Chronic OR Airflow Obstructions&#44; Chronic OR Chronic Airflow Obstructions OR Chronic Airflow Obstruction&#41;&#41;&#41;&#41;&#41; AND &#40;&#96;&#96;Ipratropium&#8221;&#91;MeSH&#93; OR atrovent OR ALovent&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
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                  \t\t\t\t">Does the combination of LABA<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>ICS provide greater benefits than monotherapy with LAMA or dual bronchodilator therapy with LABA<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>LAMA&#63;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">P<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>COPD or Chronic Obstructive Pulmonary DiseaseI &#61; LABA<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>ICSC<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>LAMA or LAMA<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>LABAO &#61; &#216;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">&#40;&#40;&#40;&#40;&#40;&#40;&#96;&#96;pulmonary disease&#44; chronic obstructive&#8221;&#91;MeSH Terms&#93; OR COPD OR Chronic Obstructive Pulmonary Disease OR COAD OR Chronic Obstructive Airway Disease OR Chronic Obstructive Lung Disease OR Airflow Obstruction&#44; Chronic OR Airflow Obstructions&#44; Chronic OR Chronic Airflow Obstructions OR Chronic Airflow Obstruction&#41;&#41;&#41;&#41;&#41; AND &#96;&#96;Bronchodilator Agents&#8221;&#91;MeSH&#93;&#41; AND Inhale&#42; corticosteroids&#42;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Does the combination of LABA<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>LAMA<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>ICS &#40;triple therapy&#41; provide greater benefits compared with LAMA monotherapy&#44; combination therapy &#40;LABA&#47;ICS&#41; or dual bronchodilator therapy &#40;LABA&#47;LAMA&#41; in patients with COPD&#63;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">P<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>COPD or Chronic Obstructive Pulmonary DiseaseI &#61; LABA<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>LAMA<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>ICSC<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>LAMA or LABA<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>ICs or LAMA<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>LABAO &#61; &#216;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">&#40;&#40;&#40;&#40;&#40;&#96;&#96;pulmonary disease&#44; chronic obstructive&#8221;&#91;MeSH Terms&#93; OR COPD OR Chronic Obstructive Pulmonary Disease OR COAD OR Chronic Obstructive Airway Disease OR Chronic Obstructive Lung Disease OR Airflow Obstruction&#44; Chronic OR Airflow Obstructions&#44; Chronic OR Chronic Airflow Obstructions OR Chronic Airflow Obstruction&#41;&#41;&#41;&#41;&#41; AND Triple Therapy&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t\ttop\n
                  \t\t\t\t">Which COPD patients benefit from the use of ICS in the reduction of exacerbations&#63;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">P<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>COPD or Chronic Obstructive Pulmonary DiseaseI &#61; inhaled corticosteroidsC &#61; &#216;O<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>exacerbation&#42; OR mortality&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#40;&#40;&#40;&#40;&#40;&#40;&#96;&#96;pulmonary disease&#44; chronic obstructive&#8221;&#91;MeSH Terms&#93; OR COPD OR Chronic Obstructive Pulmonary Disease OR COAD OR Chronic Obstructive Airway Disease OR Chronic Obstructive Lung Disease OR Airflow Obstruction&#44; Chronic OR Airflow Obstructions&#44; Chronic OR Chronic Airflow Obstructions OR Chronic Airflow Obstruction&#41;&#41;&#41;&#41; AND Inhale&#42; corticosteroid&#42;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">In which patients can ICS be safely withdrawn&#63;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">P<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>COPD or Chronic Obstructive Pulmonary DiseaseI &#61; &#40;&#40;withdrawal of ICS&#41; OR &#40;withdrawal of corticoid&#42;&#41;&#41;C &#61; &#216;O &#61; &#216;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#40;&#40;&#40;&#40;&#96;&#96;pulmonary disease&#44; chronic obstructive&#8221;&#91;MeSH Terms&#93; OR COPD OR Chronic Obstructive Pulmonary Disease OR COAD OR Chronic Obstructive Airway Disease OR Chronic Obstructive Lung Disease OR Airflow Obstruction&#44; Chronic OR Airflow Obstructions&#44; Chronic OR Chronic Airflow Obstructions OR Chronic Airflow Obstruction&#41;&#41;&#41;&#41; AND Withdra&#42; AND Inhale&#42; AND corticosteroid&#42;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
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          "leyenda" => "<p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">COPD&#58; chronic obstructive pulmonary disease&#59; ICS&#58; inhaled corticosteroid&#59; LABA&#58; long-acting &#946;2-agonists&#59; LAMA&#58; long-acting antimuscarinic agents&#59; RCT&#58; randomized controlled trials&#59; SABA&#58; short-acting &#946;-agonist&#59; SAMA&#58; short-acting muscarinic antagonist&#46;</p>"
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                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Clinical question&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Total references selected&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Total references retrieved from the Trip Database&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Total references retrieved from MeSH&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Total references selected to answer the question&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Type of studies selected&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Are long-acting bronchodilators &#40;LABA or LAMA&#41; more effective than short-acting bronchodilators &#40;SABA or SAMA&#41; in patients with mild COPD&#63;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">485&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">20&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">465&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2 systematic reviews<a class="elsevierStyleCrossRefs" href="#bib0060"><span class="elsevierStyleSup">12&#44;13</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Does the combination of LABA plus ICS provide greater benefits than monotherapy with LAMA or dual bronchodilator therapy with LABA<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>LAMA&#63;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">238&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">8&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">230&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">5 systematic reviews<a class="elsevierStyleCrossRefs" href="#bib0115"><span class="elsevierStyleSup">23&#8211;27</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Does the combination of LABA<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>LAMA<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>CIS &#40;triple therapy&#41; provide greater benefits compared with LAMA monotherapy&#44; combination therapy &#40;LABA&#47;ICS&#41; or dual bronchodilator therapy &#40;LABA&#47;LAMA&#41; in patients with COPD&#63;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">193&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">12&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">181&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">7&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2 systematic reviews<a class="elsevierStyleCrossRefs" href="#bib0150"><span class="elsevierStyleSup">30&#44;31</span></a>5 RCTs<a class="elsevierStyleCrossRefs" href="#bib0015"><span class="elsevierStyleSup">3&#44;4&#44;32&#8211;34</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Which COPD patients benefit from the use of ICS in the reduction of exacerbations&#63;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">338&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">92&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">246&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">3 systematic reviews<a class="elsevierStyleCrossRefs" href="#bib0130"><span class="elsevierStyleSup">26&#44;36&#44;37</span></a>2 RCTs<a class="elsevierStyleCrossRefs" href="#bib0015"><span class="elsevierStyleSup">3&#44;38</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">In which patients can ICS be safely withdrawn&#63;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">588&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">341&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">247&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1 meta-analysis<a class="elsevierStyleCrossRef" href="#bib0225"><span class="elsevierStyleSup">45</span></a>2 RCTs<a class="elsevierStyleCrossRefs" href="#bib0230"><span class="elsevierStyleSup">46&#44;47</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
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                      "titulo" => "Blood eosinophils and inhaled corticosteroid&#47;long-acting &#946;-2 agonist efficacy in COPD"
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