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    "textoCompleto" => "<span class="elsevierStyleSections"><p id="par0005" class="elsevierStylePara elsevierViewall">Chronic obstructive pulmonary disease &#40;COPD&#41; is a major cause of death worldwide and although mortality from this disease is decreasing&#44; it continues to cause millions of deaths yearly&#46;<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">1</span></a> Knowledge about COPD is primarily derived from observations centered on cigarette smoking&#44; an important cause of the disease in all areas of the world&#46; This editorial reviews what do these patients die from&#44; the relevance of exacerbations or &#8220;chest attacks&#8221; on patient&#39;s outcomes and whether pharmacotherapy impacts on COPD mortality&#46;</p><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0005">Dying From or With COPD</span><p id="par0010" class="elsevierStylePara elsevierViewall">Divo and coworkers<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">2</span></a> have shown that COPD patients develop specific comorbidities that independently increase the risk of death&#44; particularly coronary artery disease and lung cancer&#44; which are the big mortality drivers in milder stages of COPD&#46; This should direct health care providers to search for these diseases and manage them appropriately&#46; The implementation of CT screening for lung cancer is one such measure that helps increase resectable tumor detection&#46;<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">3</span></a> As the severity of airflow limitation increases&#44; the causes of death shift toward more respiratory causes&#44; including pneumonia and respiratory insufficiency&#46; In these patients&#44; evaluation of lung function with lung volumes&#44; functional capacity with the 6<span class="elsevierStyleHsp" style=""></span>min walk distance&#44; oximetry and&#47;or arterial blood gases can help detect individuals who may benefit from pulmonary rehabilitation&#44; supplemental oxygen or non-invasive mechanical ventilation&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Exacerbation or the &#8220;Chest Attack&#8221;</span><p id="par0015" class="elsevierStylePara elsevierViewall">Exacerbations or &#8220;Chest Attacks&#8221; are crucial events in the natural course of COPD&#46; Although they can occur at any severity stage&#44; their impact increases as patients develop more severe airflow limitation&#46; Soler-Cataluna et al&#46;<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">4</span></a> first described the relationship between the presence and frequency of exacerbations with mortality&#46; We now know that the first event increases the tempo and severity of subsequent events that impact on patient&#39;s outcomes&#46; This was shown by Cote and co-workers<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">5</span></a> who followed 205 patients over 2 years and observed that the BODE index &#40;a surrogate marker of increased mortality risk&#41; in patients who exacerbated&#44; increased after the attacks and did not return to normal during the observation period&#46; This was confirmed by Kunisaki et al&#46; in a trial of over 16 thousand patients&#46;<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">6</span></a> The authors found that the hazard ratio &#40;HR&#41; for cardiovascular events was increased&#44; particularly in the first 30 days after the attack &#40;HR&#44; 3&#46;8&#59; 95&#37; CI&#44; 2&#46;7&#8211;5&#46;5&#41;&#46; The 30-day HR after a hospitalization for the episode was more than twofold greater &#40;HR&#44; 9&#46;9&#59; 95&#37; CI&#44; 6&#46;6&#8211;14&#46;9&#41;&#46; The numbers of cardiovascular events occurring after the exacerbations suggests some vascular dysfunction leading to myocardial infarction&#44; stroke and pulmonary embolism&#46; It is clear that prevention of exacerbations is an important goal of therapy&#44; if we are to decrease mortality in COPD&#46; It may not be wise to wait for exacerbations to occur in order to begin prevention&#46; In an analogy to coronary artery disease&#44; it makes no sense to wait for the first heart attack before starting therapy for the disease&#46; In this context&#44; every effort has to be made to help patients stop smoking&#44; institute appropriate vaccinations and maintain a healthy exercise program because all of these decrease exacerbations risk&#46;</p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Pharmacotherapy and Mortality</span><p id="par0020" class="elsevierStylePara elsevierViewall">The results of several large trials prove that pharmacotherapy reduces the risk of death in COPD&#46; Let us start with the TORCH study&#44; which randomized over 6000 patients for 3 years to four therapeutic arms&#59; the active arm combined twice daily fluticasone proprionate&#47;salmeterol &#40;an ICS&#47;LABA&#41; and compared it with placebo&#44; with two complementary arms corresponding to the individual components&#46;<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">7</span></a> There was a 17&#46;5&#37; relative risk reduction of mortality in the active arm compared with placebo&#44; but the adjusted <span class="elsevierStyleItalic">P</span> value &#40;due to an interim analysis that forced the statistical adjustment&#41; was &#46;052 and the study was unjustifiably seen as negative &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#46; The subsequent SUMMIT trial that included over 16 thousand patients with moderate COPD &#40;&#62;60&#37; predicted FEV1&#41; randomized them to either once daily fluticasone furoate&#47;vilanterol &#40;ICS&#47;LABA&#41; or placebo and two arms that included the individual components&#46;<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">8</span></a> In this study&#44; there was a 12&#37; relative reduction in mortality risk between the active arm and the placebo &#40;<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;137&#41; and the results were again considered negative&#46; There have been other studies with mortality included as a secondary outcome that further support the argument that pharmacotherapy decreases risk of death&#46; The first was the 4 year UPLIFT trial&#44; which recruited over 6000 patients randomized to receive the once daily LAMA tiotropium versus placebo&#46;<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">9</span></a> A statistical significance was observed at the end of the protocol-defined treatment period &#40;<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;034&#41; but not 30 days thereafter &#40;<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;086&#41;&#46; The hazard ratios for lower respiratory and cardiac mortality during treatment were 0&#46;86 &#40;95&#37; CI 0&#46;68&#8211;1&#46;09&#41; and 0&#46;86 &#40;95&#37; CI 0&#46;75&#8211;0&#46;99&#41; respectively&#46; Another smaller study&#44; the INSPIRE trial compared fluticasone Propionate&#47;Salmeterol with Tiotropium and reported a 53&#37; relative reduction in favor of the ICS&#47;LABA&#46;<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">10</span></a> More recently&#44; a stratified safety pooled analysis of all fatal events was performed comparing extrafine ICS-containing combinations versus ICS-free treatments in three 52-week studies &#40;Tribute&#44; Trinity and Trilogy&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">11</span></a> The comparisons included&#44; triple with beclomethasone&#47;formoterol&#47;glycopyrronium compared with tiotropium&#44; the same versus a combination of indacaterol&#47;glycopyrronium and another with beclomethasone&#47;formoterol&#46; The analysis showed a reduction in the risk of death with a HR of 0&#46;71 &#40;95&#37; CI 0&#46;50&#8211;1&#46;02&#59; <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;066&#41;&#46; Finally&#44; the results of the IMPACT trial further supported this benefit&#46;<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">12</span></a> This 10&#44;000 patients study compared triple therapy including fluticasone furoate&#47;vilanterol&#47;umeclidinium &#40;ICS&#47;LABA&#47;LAMA&#41; once daily&#44; to one arm containing the same ICS&#47;LABA and another the same LABA&#47;LAMA&#46; At study&#39;s end there was a relative risk reduction of death of 42&#37; between the triple therapy and the LABA&#47;LAMA combination and of 39&#37; between the ICS&#47;LABA and the LABA&#47;LAMA&#46; There was a non-significant relative reduction of 10&#46;3&#37; between triple and ICS&#47;LABA&#46; In the same studies&#44; there were improvements in lung function&#44; dyspnea&#44; health status and exacerbations&#44; including hospitalizations&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0025" class="elsevierStylePara elsevierViewall">With this evidence&#44; it is not justified to maintain a nihilistic attitude about the effectiveness of the pharmacological agents currently available to our patients&#46; Perhaps the decline in COPD deaths worldwide&#44; is not only the consequence of altered smoking habits&#44; but also of the judicious use of pharmacotherapy&#46;</p></span></span>"
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                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
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                  \t\t\t\t">UPLIFT&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="char" valign="\n
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                  \t\t\t\t">5993&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">TiotropiumversusPlacebo&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="char" valign="\n
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                  \t\t\t\t">0&#46;84 &#40;0&#46;73&#8211;0&#46;97&#41;&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">9&#46;4&#37;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">&#46;038&nbsp;\t\t\t\t\t\t\n
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                  \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">INSPIRE&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="char" valign="\n
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                  \t\t\t\t">1323&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">FP&#47;SversusTiotropium&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="char" valign="\n
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                  \t\t\t\t">0&#46;48 &#40;0&#46;27&#44;0&#46;85&#41;&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">52&#37;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
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                  \t\t\t\t">SUMMIT&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">16&#44;590&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">FFur&#47;VIversusPlacebo&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="char" valign="\n
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                  \t\t\t\t">0&#46;88 &#40;0&#46;73&#44;1&#46;04&#41;&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">12&#37;&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="char" valign="\n
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                  \t\t\t\t">&#46;134&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
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                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
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                  \t\t\t\t">TRINITY&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="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">5589&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">BDP&#47;FF&#47;G&#44; BDP&#47;FF&#44; BDP&#47;FF<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>TIO&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="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;71 &#40;0&#46;50&#44;1&#46;02&#41;&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">NA&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="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#46;066&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">TRIBUTE&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="" valign="\n
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                  \t\t\t\t">&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">versus&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="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&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="" valign="\n
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                  \t\t\t\t">&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="" valign="\n
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                  \t\t\t\t">&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">TRILOGY&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="" valign="\n
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                  \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">TIO&#44; IND&#47;GB&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="" valign="\n
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                  \t\t\t\t">&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="" valign="\n
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                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="" valign="\n
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                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&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="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">4372&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">BDP&#47;FF&#47;GversusTIO&#44; IND&#47;GB&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="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;72 &#40;0&#46;49&#44;1&#46;06&#41;&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">NA&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="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#46;096&nbsp;\t\t\t\t\t\t\n
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                  \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">IMPACT&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="char" valign="\n
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                  \t\t\t\t">10&#44;355&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
                  \t\t\t\t\ttop\n
                  \t\t\t\t">FFur&#47;VI&#47;UMEversusVI&#47;UME&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="char" valign="\n
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                  \t\t\t\t">0&#46;71 &#40;0&#46;51&#44;0&#46;99&#41;&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">28&#46;6&#37;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t">&#46;043&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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        "descripcion" => array:1 [
          "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Summary of Results of Randomized Trials of Different Inhaled Therapies Where All-cause Mortality Was Either the Primary or a Secondary Outcome&#46; Only the Primary Comparisons Are Shown for Those Studies Where There Were More Than 2 Arms&#46;</p>"
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        0 => array:2 [
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                    0 => array:2 [
                      "titulo" => "Global&#44; regional&#44; and national age-sex-specific mortality for 282 causes of death in 195 countries and territories&#44; 1980&#8211;2017&#58; a systematic analysis for the global burden of disease study 2017"
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                        "tituloSerie" => "Lancet"
                        "fecha" => "2018"
                        "volumen" => "392"
                        "paginaInicial" => "1736"
                        "paginaFinal" => "1788"
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                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/30496103"
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                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Comorbidities and risk of mortality in patients with chronic obstructive pulmonary disease"
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                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "M&#46; Divo"
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                            2 => "J&#46;P&#46; de Torres"
                            3 => "C&#46; Casanova"
                            4 => "J&#46;M&#46; Marin"
                            5 => "V&#46; Pinto-Plata"
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                      ]
                    ]
                  ]
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                    0 => array:2 [
                      "doi" => "10.1164/rccm.201201-0034OC"
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                        "tituloSerie" => "Am J Respir Crit Care Med"
                        "fecha" => "2012"
                        "volumen" => "186"
                        "paginaInicial" => "155"
                        "paginaFinal" => "161"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/22561964"
                            "web" => "Medline"
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              "etiqueta" => "3"
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Reduced lung-cancer mortality with low-dose computed tomographic screening"
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                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "D&#46;R&#46; Aberle"
                            1 => "A&#46;M&#46; Adams"
                            2 => "C&#46;D&#46; Berg"
                            3 => "W&#46;C&#46; Black"
                            4 => "J&#46;D&#46; Clapp"
                            5 => "R&#46;M&#46; Fagerstrom"
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                        ]
                      ]
                    ]
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                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1056/NEJMoa1102873"
                      "Revista" => array:6 [
                        "tituloSerie" => "N Engl J Med"
                        "fecha" => "2011"
                        "volumen" => "365"
                        "paginaInicial" => "395"
                        "paginaFinal" => "409"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/21714641"
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                0 => array:2 [
                  "contribucion" => array:1 [
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                      "titulo" => "Severe acute exacerbations and mortality in patients with chronic obstructive pulmonary disease"
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                        0 => array:2 [
                          "etal" => false
                          "autores" => array:6 [
                            0 => "J&#46;J&#46; Soler-Cataluna"
                            1 => "M&#46;A&#46; Martinez-Garcia"
                            2 => "P&#46; Roman Sanchez"
                            3 => "E&#46; Salcedo"
                            4 => "M&#46; Navarro"
                            5 => "R&#46; Ochando"
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                    ]
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                    0 => array:2 [
                      "doi" => "10.1136/thx.2005.040527"
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                        "tituloSerie" => "Thorax"
                        "fecha" => "2005"
                        "volumen" => "60"
                        "paginaInicial" => "925"
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                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/16055622"
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                  "contribucion" => array:1 [
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                      "titulo" => "Impact of copd exacerbations on patient-centered outcomes"
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                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [
                            0 => "C&#46;G&#46; Cote"
                            1 => "L&#46;J&#46; Dordelly"
                            2 => "B&#46;R&#46; Celli"
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                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1378/chest.06-1610"
                      "Revista" => array:6 [
                        "tituloSerie" => "Chest"
                        "fecha" => "2007"
                        "volumen" => "131"
                        "paginaInicial" => "696"
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                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/17356082"
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Editorial
Pharmacotherapy Impacts on COPD Mortality
La farmacoterapia tiene impacto en la mortalidad de la EPOC
Bartolome Cellia,
Corresponding author
bcelli@copdnet.org

Corresponding author.
, Miguel Divoa, Victor Pinto Platab
a Brigham and Women's Hospital, Harvard Medical School, Boston, USA
b Bay State Medical Center, University of Massachusetts Medical School, Springfield, USA
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particularly coronary artery disease and lung cancer&#44; which are the big mortality drivers in milder stages of COPD&#46; This should direct health care providers to search for these diseases and manage them appropriately&#46; The implementation of CT screening for lung cancer is one such measure that helps increase resectable tumor detection&#46;<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">3</span></a> As the severity of airflow limitation increases&#44; the causes of death shift toward more respiratory causes&#44; including pneumonia and respiratory insufficiency&#46; In these patients&#44; evaluation of lung function with lung volumes&#44; functional capacity with the 6<span class="elsevierStyleHsp" style=""></span>min walk distance&#44; oximetry and&#47;or arterial blood gases can help detect individuals who may benefit from pulmonary rehabilitation&#44; supplemental oxygen or non-invasive mechanical ventilation&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Exacerbation or the &#8220;Chest Attack&#8221;</span><p id="par0015" class="elsevierStylePara elsevierViewall">Exacerbations or &#8220;Chest Attacks&#8221; are crucial events in the natural course of COPD&#46; Although they can occur at any severity stage&#44; their impact increases as patients develop more severe airflow limitation&#46; Soler-Cataluna et al&#46;<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">4</span></a> first described the relationship between the presence and frequency of exacerbations with mortality&#46; We now know that the first event increases the tempo and severity of subsequent events that impact on patient&#39;s outcomes&#46; This was shown by Cote and co-workers<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">5</span></a> who followed 205 patients over 2 years and observed that the BODE index &#40;a surrogate marker of increased mortality risk&#41; in patients who exacerbated&#44; increased after the attacks and did not return to normal during the observation period&#46; This was confirmed by Kunisaki et al&#46; in a trial of over 16 thousand patients&#46;<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">6</span></a> The authors found that the hazard ratio &#40;HR&#41; for cardiovascular events was increased&#44; particularly in the first 30 days after the attack &#40;HR&#44; 3&#46;8&#59; 95&#37; CI&#44; 2&#46;7&#8211;5&#46;5&#41;&#46; The 30-day HR after a hospitalization for the episode was more than twofold greater &#40;HR&#44; 9&#46;9&#59; 95&#37; CI&#44; 6&#46;6&#8211;14&#46;9&#41;&#46; The numbers of cardiovascular events occurring after the exacerbations suggests some vascular dysfunction leading to myocardial infarction&#44; stroke and pulmonary embolism&#46; It is clear that prevention of exacerbations is an important goal of therapy&#44; if we are to decrease mortality in COPD&#46; It may not be wise to wait for exacerbations to occur in order to begin prevention&#46; In an analogy to coronary artery disease&#44; it makes no sense to wait for the first heart attack before starting therapy for the disease&#46; In this context&#44; every effort has to be made to help patients stop smoking&#44; institute appropriate vaccinations and maintain a healthy exercise program because all of these decrease exacerbations risk&#46;</p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Pharmacotherapy and Mortality</span><p id="par0020" class="elsevierStylePara elsevierViewall">The results of several large trials prove that pharmacotherapy reduces the risk of death in COPD&#46; Let us start with the TORCH study&#44; which randomized over 6000 patients for 3 years to four therapeutic arms&#59; the active arm combined twice daily fluticasone proprionate&#47;salmeterol &#40;an ICS&#47;LABA&#41; and compared it with placebo&#44; with two complementary arms corresponding to the individual components&#46;<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">7</span></a> There was a 17&#46;5&#37; relative risk reduction of mortality in the active arm compared with placebo&#44; but the adjusted <span class="elsevierStyleItalic">P</span> value &#40;due to an interim analysis that forced the statistical adjustment&#41; was &#46;052 and the study was unjustifiably seen as negative &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#46; The subsequent SUMMIT trial that included over 16 thousand patients with moderate COPD &#40;&#62;60&#37; predicted FEV1&#41; randomized them to either once daily fluticasone furoate&#47;vilanterol &#40;ICS&#47;LABA&#41; or placebo and two arms that included the individual components&#46;<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">8</span></a> In this study&#44; there was a 12&#37; relative reduction in mortality risk between the active arm and the placebo &#40;<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;137&#41; and the results were again considered negative&#46; There have been other studies with mortality included as a secondary outcome that further support the argument that pharmacotherapy decreases risk of death&#46; The first was the 4 year UPLIFT trial&#44; which recruited over 6000 patients randomized to receive the once daily LAMA tiotropium versus placebo&#46;<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">9</span></a> A statistical significance was observed at the end of the protocol-defined treatment period &#40;<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;034&#41; but not 30 days thereafter &#40;<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;086&#41;&#46; The hazard ratios for lower respiratory and cardiac mortality during treatment were 0&#46;86 &#40;95&#37; CI 0&#46;68&#8211;1&#46;09&#41; and 0&#46;86 &#40;95&#37; CI 0&#46;75&#8211;0&#46;99&#41; respectively&#46; Another smaller study&#44; the INSPIRE trial compared fluticasone Propionate&#47;Salmeterol with Tiotropium and reported a 53&#37; relative reduction in favor of the ICS&#47;LABA&#46;<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">10</span></a> More recently&#44; a stratified safety pooled analysis of all fatal events was performed comparing extrafine ICS-containing combinations versus ICS-free treatments in three 52-week studies &#40;Tribute&#44; Trinity and Trilogy&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">11</span></a> The comparisons included&#44; triple with beclomethasone&#47;formoterol&#47;glycopyrronium compared with tiotropium&#44; the same versus a combination of indacaterol&#47;glycopyrronium and another with beclomethasone&#47;formoterol&#46; The analysis showed a reduction in the risk of death with a HR of 0&#46;71 &#40;95&#37; CI 0&#46;50&#8211;1&#46;02&#59; <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;066&#41;&#46; Finally&#44; the results of the IMPACT trial further supported this benefit&#46;<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">12</span></a> This 10&#44;000 patients study compared triple therapy including fluticasone furoate&#47;vilanterol&#47;umeclidinium &#40;ICS&#47;LABA&#47;LAMA&#41; once daily&#44; to one arm containing the same ICS&#47;LABA and another the same LABA&#47;LAMA&#46; At study&#39;s end there was a relative risk reduction of death of 42&#37; between the triple therapy and the LABA&#47;LAMA combination and of 39&#37; between the ICS&#47;LABA and the LABA&#47;LAMA&#46; There was a non-significant relative reduction of 10&#46;3&#37; between triple and ICS&#47;LABA&#46; In the same studies&#44; there were improvements in lung function&#44; dyspnea&#44; health status and exacerbations&#44; including hospitalizations&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0025" class="elsevierStylePara elsevierViewall">With this evidence&#44; it is not justified to maintain a nihilistic attitude about the effectiveness of the pharmacological agents currently available to our patients&#46; Perhaps the decline in COPD deaths worldwide&#44; is not only the consequence of altered smoking habits&#44; but also of the judicious use of pharmacotherapy&#46;</p></span></span>"
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          "leyenda" => "<p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">FP&#58; fluticasone propionate&#59; S&#58; salmeterol&#46; BDP&#58; beclometasone dipropionate&#59; FF&#58; formoterol fumarate&#59; G&#58; glycopyrronium&#59; TIO&#58; tiotropium&#59; IND&#58; indacaterol&#59; GB&#58; glycopyrronium bromide&#59; FFur&#58; fluticasone furoate&#59; VI&#58; vilanterol UME&#58; umeclidinium&#46;</p><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">TORCH&#44; Toward a Revolution in COPD Health&#46;</p><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">UPLIFT&#44; Understanding Potential Long-Term Impacts on Function with Tiotropium&#46;</p><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">INSPIRE&#44; Investigating New Standards for Prophylaxis in Reducing Exacerbations&#46;</p><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">SUMMIT&#44; Study to Understand Mortality and Morbidity in COPD&#46;</p><p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">IMPACT&#44; Informing the Pathway of COPD Treatment&#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">Study&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">Number of Patients&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">Comparators&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">HR and 95&#37; CIActive Versus Reference&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">Relative Risk Reduction&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"><span class="elsevierStyleItalic">P</span> Value&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">TORCH&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="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">6112&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">FP&#47;SversusPlacebo&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="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;83 &#40;0&#46;68&#44;1&#46;02&#41;&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">17&#46;5&#37;&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="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#46;052&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">UPLIFT&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="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">5993&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">TiotropiumversusPlacebo&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="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;84 &#40;0&#46;73&#8211;0&#46;97&#41;&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">9&#46;4&#37;&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="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#46;038&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">INSPIRE&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="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1323&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">FP&#47;SversusTiotropium&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="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;48 &#40;0&#46;27&#44;0&#46;85&#41;&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">52&#37;&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="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#46;012&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">SUMMIT&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="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">16&#44;590&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">FFur&#47;VIversusPlacebo&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="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;88 &#40;0&#46;73&#44;1&#46;04&#41;&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&#37;&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="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#46;134&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">TRINITY&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="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">5589&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">BDP&#47;FF&#47;G&#44; BDP&#47;FF&#44; BDP&#47;FF<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>TIO&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="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;71 &#40;0&#46;50&#44;1&#46;02&#41;&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">NA&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="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#46;066&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">TRIBUTE&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="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&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">versus&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="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&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="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&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="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&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
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Article information
ISSN: 03002896
Original language: English
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