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    "textoCompleto" => "<span class="elsevierStyleSections"><p id="par0005" class="elsevierStylePara elsevierViewall">We performed a systematic literature review and meta-analysis to assess the efficacy and safety of single-inhaler triple therapy &#40;SITT&#41; compared to monotherapy&#44; dual therapy&#44; and open TT &#40;OTT&#41;&#44; at 52 weeks&#44; in five predefined subgroups of moderate&#47;severe COPD patients &#40;see <a class="elsevierStyleCrossRef" href="#sec0055">supplementary material</a>&#41;&#46;</p><p id="par0010" class="elsevierStylePara elsevierViewall">We included nine articles from five randomized controlled trials of good quality&#46;<a class="elsevierStyleCrossRefs" href="#bib0100"><span class="elsevierStyleSup">1&#8211;9</span></a> The studies analyzed mortality&#44;<a class="elsevierStyleCrossRefs" href="#bib0110"><span class="elsevierStyleSup">3&#44;4</span></a> rate of moderate and severe exacerbations&#44;<a class="elsevierStyleCrossRefs" href="#bib0105"><span class="elsevierStyleSup">2&#44;5&#8211;10</span></a> changes in the FEV<span class="elsevierStyleInf">1</span>&#44;<a class="elsevierStyleCrossRefs" href="#bib0100"><span class="elsevierStyleSup">1&#44;6&#44;8&#44;9</span></a> dyspnea &#40;using the Transition Dyspnea Index &#91;TDI&#93;&#41;&#44;<a class="elsevierStyleCrossRef" href="#bib0125"><span class="elsevierStyleSup">6</span></a> and quality of life &#40;using the St&#46; George&#39;s Respiratory Questionnaire &#91;SGRQ&#93;&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0100"><span class="elsevierStyleSup">1&#44;6&#44;9</span></a></p><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0005">Previous Exacerbation History</span><p id="par0015" class="elsevierStylePara elsevierViewall">In the FULFIL trial&#44; SITT was associated with a lower rate of moderate-to-severe exacerbations than LABA&#47;ICS in patients with &#8805;<span class="elsevierStyleHsp" style=""></span>1 severe exacerbation &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#41;&#44; but there were no differences in patients with &#8805;<span class="elsevierStyleHsp" style=""></span>2 moderate exacerbations&#46; Besides&#44; SITT significantly improved trough FEV<span class="elsevierStyleInf">1</span> compared to LABA&#47;ICS in patients with &#8805;<span class="elsevierStyleHsp" style=""></span>2 moderate exacerbations &#40;difference&#58; 199<span class="elsevierStyleHsp" style=""></span>ml&#41; or &#8805;<span class="elsevierStyleHsp" style=""></span>1 severe exacerbation &#40;difference&#58; 166<span class="elsevierStyleHsp" style=""></span>ml&#41;&#44; but also in those with FEV<span class="elsevierStyleInf">1</span> &#8805;<span class="elsevierStyleHsp" style=""></span>50&#8211;&#60;<span class="elsevierStyleHsp" style=""></span>80&#37; and &#8805;<span class="elsevierStyleHsp" style=""></span>2 moderate exacerbations or &#8805;<span class="elsevierStyleHsp" style=""></span>1 severe exacerbation &#40;difference&#58; 179<span class="elsevierStyleHsp" style=""></span>ml&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">1</span></a> However&#44; improvements in SGRQ with SITT compared to LAMA&#47;ICS were only statistically significant &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;026&#41; in patients with &#8805;<span class="elsevierStyleHsp" style=""></span>2 moderate exacerbations&#46;<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">1</span></a></p><p id="par0020" class="elsevierStylePara elsevierViewall">The IMPACT trial found that SITT in patients with &#8805;<span class="elsevierStyleHsp" style=""></span>2 moderate&#47;severe exacerbations resulted in a reduction in the annual rate of exacerbations compared to LABA&#47;ICS &#40;difference&#58; 11&#37;&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;01&#41; and LAMA&#47;LABA &#40;difference&#58; 28&#37;&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;001&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">2</span></a> But in the TRIBUTE study&#44; there was no difference in the exacerbation rate between SITT and LAMA&#47;LABA in patients with &#62;<span class="elsevierStyleHsp" style=""></span>1 exacerbation&#46;<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">5</span></a></p><p id="par0025" class="elsevierStylePara elsevierViewall">The ETHOS trial compared SITT at two ICS dose levels with LABA&#47;ICS and LAMA&#47;LABA&#46;<a class="elsevierStyleCrossRef" href="#bib0130"><span class="elsevierStyleSup">7</span></a> Except for SITT at the low ICS dose level&#44; the rate of moderate or severe exacerbations was significantly lower with SITT than with LABA&#47;ICS and LAMA&#47;LABA in patients with &#8805;<span class="elsevierStyleHsp" style=""></span>2 exacerbations&#46;<a class="elsevierStyleCrossRef" href="#bib0130"><span class="elsevierStyleSup">7</span></a> Another analysis reported a significantly lower risk of death with SITT compared to LAMA&#47;LABA in patients with &#8805;<span class="elsevierStyleHsp" style=""></span>2 moderate or severe exacerbations&#58; HR<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;36 &#40;95&#37; CI 0&#46;19&#8211;0&#46;70&#41; and HR<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;55 &#40;95&#37; CI 0&#46;32&#8211;0&#46;97&#41; for SITT at high &#40;320<span class="elsevierStyleHsp" style=""></span>&#956;g&#41; and low &#40;160<span class="elsevierStyleHsp" style=""></span>&#956;g&#41; ICS dose levels&#46;<a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">4</span></a> No differences were observed compared to LABA&#47;ICS in patients with &#8805;<span class="elsevierStyleHsp" style=""></span>1 severe exacerbation&#46;<a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">4</span></a></p><p id="par0030" class="elsevierStylePara elsevierViewall">The TRINITY study&#44; which included patients with severe and very severe COPD&#44;<a class="elsevierStyleCrossRef" href="#bib0135"><span class="elsevierStyleSup">8</span></a> reported that SITT compared with LAMA and OTT significantly decreased the rate of moderate or severe exacerbations in patients with &#62;<span class="elsevierStyleHsp" style=""></span>1 exacerbation &#40;RR<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;72&#44; and RR<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;71&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0135"><span class="elsevierStyleSup">8</span></a></p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Lung Function and COPD Severity</span><p id="par0035" class="elsevierStylePara elsevierViewall">The FULFIL study showed that SITT significantly improved FEV<span class="elsevierStyleInf">1</span> at 52 weeks compared to LABA&#47;ICS in patients with FEV<span class="elsevierStyleInf">1</span> &#8804;<span class="elsevierStyleHsp" style=""></span>50&#37; and &#8805;<span class="elsevierStyleHsp" style=""></span>1 moderate or severe exacerbation &#40;difference&#58; 140<span class="elsevierStyleHsp" style=""></span>ml&#41;&#46; The difference was larger &#40;224<span class="elsevierStyleHsp" style=""></span>ml&#41; in patients without a history of exacerbations&#46;<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">1</span></a> No statistical differences in the SGRQ were observed between groups&#46;</p><p id="par0040" class="elsevierStylePara elsevierViewall">A sub analysis of the ETHOS trial revealed that mortality was significantly lower in patients with FEV<span class="elsevierStyleInf">1</span> &#60;<span class="elsevierStyleHsp" style=""></span>50&#37; on SITT at the high ICS dose level &#40;320<span class="elsevierStyleHsp" style=""></span>&#956;g&#41; compared to LAMA&#47;LABA&#46; However&#44; no differences were observed between SITT at both dose levels and LABA&#47;ICS and between SITT at the 160<span class="elsevierStyleHsp" style=""></span>&#956;g dose level and LAMA&#47;LABA&#46;<a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">4</span></a></p><p id="par0045" class="elsevierStylePara elsevierViewall">In the TRINITY study&#44;<a class="elsevierStyleCrossRef" href="#bib0135"><span class="elsevierStyleSup">8</span></a> SITT significantly reduced the rate of moderate or severe exacerbations &#40;HR<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;77&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;050&#41; compared to LAMA&#44; yet not in patients with very severe COPD&#46; Similar findings were reported for changes in FEV<span class="elsevierStyleInf">1</span>&#46; However&#44; there were no differences between SITT and OTT regarding the rate of exacerbations and changes in FEV<span class="elsevierStyleInf">1</span> in patients with severe or very severe COPD&#46;</p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Blood Eosinophil Concentration</span><p id="par0050" class="elsevierStylePara elsevierViewall">The IMPACT trial showed that in patients with eosinophil levels &#8805;<span class="elsevierStyleHsp" style=""></span>150<span class="elsevierStyleHsp" style=""></span>cells&#47;&#956;L&#44; the rate of moderate&#8211;severe exacerbations was significantly lower with SITT compared to LABA&#47;ICS and LAMA&#47;LABA&#44; amounting to 0&#46;95&#37;&#44; 1&#46;08&#37;&#44; and 1&#46;39&#37;&#44; respectively&#46;<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">2</span></a> Yet&#44; SITT was only statistically superior to LABA&#47;ICS and not to LAMA&#47;LABA in patients with &#60;<span class="elsevierStyleHsp" style=""></span>150<span class="elsevierStyleHsp" style=""></span>cells&#47;&#956;L&#46;<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">2</span></a></p><p id="par0055" class="elsevierStylePara elsevierViewall">In the ETHOS trial&#44;<a class="elsevierStyleCrossRef" href="#bib0130"><span class="elsevierStyleSup">7</span></a> the rate of moderate or severe exacerbations was significantly lower with SITT &#40;high and low ICS dose levels&#41; than with LABA&#47;ICS and LAMA&#47;LABA in patients with eosinophil counts &#8805;<span class="elsevierStyleHsp" style=""></span>150<span class="elsevierStyleHsp" style=""></span>cells&#47;&#956;L&#46; In patients with &#60;<span class="elsevierStyleHsp" style=""></span>150<span class="elsevierStyleHsp" style=""></span>cells&#47;&#956;L&#44; both SITT dose levels were significantly superior to LABA&#47;ICS&#44; but no differences were observed with LAMA&#47;LABA&#46;</p><p id="par0060" class="elsevierStylePara elsevierViewall">The IMPACT trial explored the rate of exacerbations and the changes in SGRQ&#44; FEV<span class="elsevierStyleInf">1</span>&#44; and TDI on SITT compared to LAMA&#47;LABA according to different eosinophil level cut-offs &#40;90&#44; &#8805;<span class="elsevierStyleHsp" style=""></span>90&#8211;&#60;<span class="elsevierStyleHsp" style=""></span>140&#44; &#8805;<span class="elsevierStyleHsp" style=""></span>140&#8211;&#60;<span class="elsevierStyleHsp" style=""></span>200&#44; &#8805;<span class="elsevierStyleHsp" style=""></span>200&#8211;&#60;<span class="elsevierStyleHsp" style=""></span>310&#44; and &#8805;<span class="elsevierStyleHsp" style=""></span>310<span class="elsevierStyleHsp" style=""></span>cells&#47;&#956;L&#41;&#46; In general&#44; the magnitude of the benefit on SITT increased proportionally to blood eosinophil count&#44; though the relationship with FEV<span class="elsevierStyleInf">1</span> was less marked&#46;<a class="elsevierStyleCrossRef" href="#bib0125"><span class="elsevierStyleSup">6</span></a></p><p id="par0065" class="elsevierStylePara elsevierViewall">In the TRIBUTE study&#44;<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">5</span></a> the annual rate of moderate&#47;severe exacerbations was significantly lower on SITT than on LAMA&#47;LABA in patients with eosinophil levels &#8805;<span class="elsevierStyleHsp" style=""></span>2&#37;&#44; while there were no differences between treatments for levels &#60;<span class="elsevierStyleHsp" style=""></span>2&#37;&#46;<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">5</span></a></p><p id="par0070" class="elsevierStylePara elsevierViewall">In the TRINITY trial&#44;<a class="elsevierStyleCrossRef" href="#bib0135"><span class="elsevierStyleSup">8</span></a> in which patients with eosinophil levels &#8805;<span class="elsevierStyleHsp" style=""></span>2&#37; had a lower risk of moderate or severe exacerbations with SITT than with LAMA &#40;RR<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;70&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;050&#41;&#44; there were no differences in patients with eosinophil levels &#60;<span class="elsevierStyleHsp" style=""></span>2&#37;&#46; On the other hand&#44; changes in FEV<span class="elsevierStyleInf">1</span> were significantly greater with SITT than with LAMA in both eosinophil level subgroups &#40;0&#46;07<span class="elsevierStyleHsp" style=""></span>L&#44; and 0&#46;04<span class="elsevierStyleHsp" style=""></span>L&#44; respectively&#41;&#46; However&#44; when comparing SITT with OTT&#44; there were no differences in the rate of exacerbations and FEV<span class="elsevierStyleInf">1</span> changes in any eosinophil level subgroups&#46;<a class="elsevierStyleCrossRef" href="#bib0135"><span class="elsevierStyleSup">8</span></a></p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Smoking Status</span><p id="par0075" class="elsevierStylePara elsevierViewall">In the IMPACT trial&#44; the reduction in the annual exacerbation rates was significantly more pronounced with SITT than with LABA&#47;ICS and LAMA&#47;LABA&#44; regardless of smoking status&#46;<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">2</span></a> In current smokers&#44; the reduction rates compared to dual therapies were 15&#37; &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;01&#41; and 14&#37; &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#41;&#44; respectively&#46; In former smokers 15&#37; &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;001&#41; and 30&#37; &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;001&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">2</span></a> Smoking status had also an impact on several variables&#44; including moderate or severe exacerbations&#44; TDI&#44; and FEV<span class="elsevierStyleInf">1</span>&#44; depending on blood eosinophil count&#46;<a class="elsevierStyleCrossRef" href="#bib0125"><span class="elsevierStyleSup">6</span></a></p><p id="par0080" class="elsevierStylePara elsevierViewall">In the TRIBUTE trial&#44; the reduction in the rate of moderate or severe exacerbations was significantly greater with SITT than with LAMA&#47;LABA in current smokers &#40;RR<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;77&#41;&#44; without differences in former smokers&#46;<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">5</span></a></p><p id="par0085" class="elsevierStylePara elsevierViewall">In the TRINITY study&#44; the risk of moderate or severe exacerbations was lower with SITT than with LAMA in current smokers &#40;RR<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;76&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;050&#41;&#44; with no differences in former smokers&#46;<a class="elsevierStyleCrossRef" href="#bib0135"><span class="elsevierStyleSup">8</span></a> On the other hand&#44; changes in FEV<span class="elsevierStyleInf">1</span> were significantly more marked with SITT than with LAMA in current smokers &#40;difference 0&#46;06<span class="elsevierStyleHsp" style=""></span>L&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;050&#41; and in former smokers &#40;difference 0&#46;06<span class="elsevierStyleHsp" style=""></span>L&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;050&#41;&#46;</p><p id="par0090" class="elsevierStylePara elsevierViewall">There were no differences between SITT and OTT in the rate of exacerbations and FEV<span class="elsevierStyleInf">1</span> changes in current and former smokers&#46;<a class="elsevierStyleCrossRef" href="#bib0135"><span class="elsevierStyleSup">8</span></a></p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Previous Medications &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;</span><p id="par0160" class="elsevierStylePara elsevierViewall"></p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0095" class="elsevierStylePara elsevierViewall">In the FULFIL trial&#44; SITT was statistically superior to LABA&#47;ICS in reducing exacerbations in patients previously on LABA&#47;ICS and OTT&#46;<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">1</span></a> Improvements in FEV<span class="elsevierStyleInf">1</span> were greater with SITT irrespective of previous medications&#44; but there were no differences when changes in quality of life were analyzed&#46;<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">1</span></a></p><p id="par0100" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Post hoc</span> data from the IMPACT study showed that in patients on ICS at screening&#44; mortality was significantly lower with SITT compared to LAMA&#47;LABA &#40;HR<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;63&#44; 95&#37; CI 0&#46;44&#8211;0&#46;89&#41;&#44; but no differences were found compared to ICS&#47;LABA&#46;<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">3</span></a> Besides&#44; the risk of death with SITT compared to LAMA&#47;LABA in patients on OTT at screening was HR<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;40 &#40;95&#37; CI 0&#46;19&#8211;0&#46;84&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">3</span></a> The reduction in moderate or severe exacerbations was also greater in the SITT group than in the LAMA&#47;LABA group in patients on ICS&#44; LABA&#47;ICS&#44; or OTT at screening&#44; yet with no statistically significant differences in patients with previous LAMA or LAMA&#47;LABA&#46;<a class="elsevierStyleCrossRef" href="#bib0140"><span class="elsevierStyleSup">9</span></a></p><p id="par0105" class="elsevierStylePara elsevierViewall">In the ETHOS trial&#44; there were no differences in mortality between SITT and LABA&#47;ICS in patients with prior ICS or OTT&#46;<a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">4</span></a> However&#44; this risk was significantly lower on SITT at the high ICS dose level &#40;budesonide 320<span class="elsevierStyleHsp" style=""></span>&#956;g&#41; than on LAMA&#47;LABA in patients with previous ICS or OTT&#46;<a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">4</span></a></p><p id="par0110" class="elsevierStylePara elsevierViewall">We did not identify any safety data specifically in the subgroups analyzed&#46;</p><p id="par0115" class="elsevierStylePara elsevierViewall">In the meta-analysis &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#41; we found that in patients with &#8805;<span class="elsevierStyleHsp" style=""></span>2 moderate and&#47;or &#8805;<span class="elsevierStyleHsp" style=""></span>1 severe exacerbations&#44; SITT resulted in greater reductions in the annual rate of exacerbations compared to LAMA&#47;LABA &#40;HR<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;73&#44; 95&#37; CI 0&#46;67&#8211;0&#46;79&#41;&#44; without relevant heterogeneity&#46;<a class="elsevierStyleCrossRefs" href="#bib0115"><span class="elsevierStyleSup">4&#44;5</span></a> Similar results were observed in patients with high eosinophil levels &#40;HR<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;70&#44; 95&#37; CI 0&#46;65&#8211;0&#46;76&#41;&#44; yet with a high and significant heterogeneity &#40;<span class="elsevierStyleItalic">I</span><span class="elsevierStyleSup">2</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>74&#46;3&#37;&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;020&#41;&#46; There was also a relevant heterogeneity &#40;<span class="elsevierStyleItalic">I</span><span class="elsevierStyleSup">2</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>83&#46;2&#37;&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;003&#41; in the rate of exacerbations in patients with high eosinophil levels when comparing SITT and LABA&#47;ICS &#40;HR<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;82&#44; 95&#37; CI 0&#46;76&#8211;0&#46;87&#41;&#46;</p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia><p id="par0120" class="elsevierStylePara elsevierViewall">In conclusion&#44; SITT results in more pronounced clinical benefits on exacerbations and lung function compared to other inhaled COPD medications in patients with moderate-to-severe COPD&#44; especially in those at high risk of exacerbations and with high blood eosinophil concentrations&#46; Further evidence &#40;in the long-term&#44; daily practice&#44; etc&#46;&#41; is needed to fully capture the characteristics of patient subgroups that may benefit most from SITT and to identify those with a substantial extra safety risk&#46;</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Ethical Approval</span><p id="par0125" class="elsevierStylePara elsevierViewall">This study was performed in line with the principles of the Declaration of Helsinki&#46;</p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Authors&#8217; Contributions</span><p id="par0130" class="elsevierStylePara elsevierViewall">The study was conceived by all authors&#44; all were involved in the study planning and design&#46; JAR was involved in study delivery&#44; prepared the data and carried out statistical analysis&#46; All authors provided expert opinion on development of the analysis and interpreting the data&#46; JAR and BC developed and wrote the manuscript&#44; with critical revisions and review of the final manuscript from all other authors&#46;</p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Funding</span><p id="par0135" class="elsevierStylePara elsevierViewall">The study was funded by an unrestricted educational grant from <span class="elsevierStyleGrantSponsor" id="gs1">Chiesi</span>&#46;</p></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Conflict of Interest</span><p id="par0140" class="elsevierStylePara elsevierViewall">The authors declare no conflicts of interest&#46;</p></span></span>"
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          "leyenda" => "<p id="spar0010" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleItalic">Abbreviations</span>&#58; SITT&#58; single-inhaler triple therapy&#59; FEV<span class="elsevierStyleInf">1</span>&#58; forced expiratory volume in 1 second&#59; &#956;L&#58; microliter&#59; LAMA&#58; long-acting muscarinic antagonists&#59; LABA&#58; long-acting &#946;2-agonists&#59; ICS&#58; inhaled corticosteroids&#59; HR&#58; hazard ratio&#59; CI&#58; confidence interval&#46;</p><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">1&#46; Vestbo J&#44; Papi A&#44; Corradi M&#44; Blazhko V&#44; Montagna I&#44; Francisco C&#44; et al&#46; Single inhaler extrafine triple therapy <span class="elsevierStyleItalic">versus</span> long-acting muscarinic antagonist therapy for chronic obstructive pulmonary disease &#40;TRINITY&#41;&#58; a double-blind&#44; parallel group&#44; randomized controlled trial&#46; Lancet&#46; 2017&#59;389&#40;10082&#41;&#58;1919&#8211;29&#46;</p><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">2&#46; Martinez FJ&#44; Rabe KF&#44; Ferguson GT&#44; Wedzicha JA&#44; Singh D&#44; Wang C&#44; et al&#46; Reduced all-cause mortality in the ETHOS trial of budesonide&#47;glycopyrrolate&#47;formoterol for COPD&#58; a randomized&#44; double-blind&#44; multi-center parallel-group study&#46; Am J Respir Crit Care Med&#46; 2020&#46;</p><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">3&#46; Papi A&#44; Vestbo J&#44; Fabbri L&#44; Corradi M&#44; Prunier H&#44; Cohuet G&#44; et al&#46; Extrafine inhaled triple therapy <span class="elsevierStyleItalic">versus</span> dual bronchodilator therapy in chronic obstructive pulmonary disease &#40;TRIBUTE&#41;&#58; a double-blind&#44; parallel group&#44; randomized controlled trial&#46; Lancet&#46; 2018&#59;391&#40;10125&#41;&#58;1076&#8211;84&#46;</p><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">4&#46; Lipson DA&#44; Barnhart F&#44; Brealey N&#44; Brooks J&#44; Criner GJ&#44; Day NC&#44; et al&#46; Once-daily single-inhaler triple <span class="elsevierStyleItalic">versus</span> dual therapy in patients with COPD&#46; N Engl J Med&#46; 2018&#59;378&#40;18&#41;&#58;1671&#8211;80&#46;</p><p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">5&#46; Rabe KF&#44; Martinez FJ&#44; Ferguson GT&#44; Wang C&#44; Singh D&#44; Wedzicha JA&#44; et al&#46; Triple inhaled therapy at two glucocorticoid doses in moderate-to-very-severe COPD&#46; N Engl J Med&#46; 2020&#59;383&#40;1&#41;&#58;35&#8211;48&#46;</p><p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">6&#46; Pascoe S&#44; Barnes N&#44; Brusselle G&#44; Compton C&#44; Criner GJ&#44; Dransfield MT&#44; et al&#46; Blood eosinophils and treatment response with triple and dual combination therapy in chronic obstructive pulmonary disease&#58; analysis of the IMPACT trial&#46; Lancet Respir Med&#46; 2019&#59;7&#40;9&#41;&#58;745&#8211;56&#46;</p><p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">7&#46; Axson EL&#44; Lewis A&#44; Potts J&#44; Pang M&#44; Dickinson S&#44; Vioix H&#44; et al&#46; Inhaled therapies for chronic obstructive pulmonary disease&#58; a systematic review and meta-analysis&#46; BMJ Open&#46; 2020&#59;10&#40;9&#41;&#58;e036455&#46;</p><p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">8&#46; Halpin DMG&#44; Birk R&#44; Brealey N&#44; Criner GJ&#44; Dransfield MT&#44; Hilton E&#44; et al&#46; Single-inhaler triple therapy in symptomatic COPD patients&#58; FULFIL subgroup analyses&#46; ERJ Open Res&#46; 2018&#59;4&#40;2&#41;&#46;</p>"
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          "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Summary of the Main Results of the Meta-analysis at 52 Weeks&#46; Green Color Represents Comparisons With Higher Level of Evidence in Favor of Single-inhaler Triple Therapy &#40;Meta-analysis or Clear Effect From Randomized Clinical Trials&#41;&#46; Yellow Color Depicts Contradictory Results or an Absence of Difference Between Treatment Groups Across Several Comparisons&#46; Light Blue Color Indicates Lacking Data&#46; For Each Result the Study References are Provided&#46;</p>"
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          "leyenda" => "<p id="spar0060" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleItalic">Abbreviations</span>&#58; COPD&#58; chronic obstructive pulmonary disease&#59; LAMA&#58; long-acting muscarinic antagonists&#59; LABA&#58; long-acting &#946;2-agonists&#59; ICS&#58; inhaled corticosteroids&#59; SITT&#58; single-inhaler triple therapy&#59; BF&#58; budesonide&#47;formoterol&#59; FEV<span class="elsevierStyleInf">1</span>&#58; forced expiratory volume in 1 second&#59; ml&#58; milliliter&#59; SGRQ&#58; St&#46; George&#39;s Respiratory Questionnaire&#59; Dif&#46;&#58; difference&#59; HR&#58; hazard ratio&#59; CI&#58; confidence interval&#46;</p><p id="spar0065" class="elsevierStyleSimplePara elsevierViewall">1&#46; Halpin DMG&#44; Birk R&#44; Brealey N&#44; Criner GJ&#44; Dransfield MT&#44; Hilton E&#44; et al&#46; Single-inhaler triple therapy in symptomatic COPD patients&#58; FULFIL subgroup analyses&#46; ERJ Open Res&#46; 2018&#59;4&#40;2&#41;&#46;</p><p id="spar0070" class="elsevierStyleSimplePara elsevierViewall">2&#46; Han MK&#44; Criner GJ&#44; Dransfield MT&#44; Halpin DMG&#44; Jones CE&#44; Kilbride S&#44; et al&#46; The effect of inhaled corticosteroid withdrawal and baseline inhaled treatment on exacerbations in the IMPACT study&#46; A randomized&#44; double-blind&#44; multicenter clinical trial&#46; Am J Respir Crit Care Med&#46; 2020&#59;202&#40;9&#41;&#58;1237&#8211;43&#46;</p><p id="spar0075" class="elsevierStyleSimplePara elsevierViewall">3&#46; Rabe KF&#44; Martinez FJ&#44; Ferguson GT&#44; Wang C&#44; Singh D&#44; Wedzicha JA&#44; et al&#46; Triple inhaled therapy at two glucocorticoid doses in moderate-to-very-severe COPD&#46; N Engl J Med&#46; 2020&#59;383&#40;1&#41;&#58;35&#8211;48&#46;</p><p id="spar0080" class="elsevierStyleSimplePara elsevierViewall">4&#46; Lipson DA&#44; Crim C&#44; Criner GJ&#44; Day NC&#44; Dransfield MT&#44; Halpin DMG&#44; et al&#46; Reduction in all-cause mortality with fluticasone furoate&#47;umeclidinium&#47;vilanterol in patients with chronic obstructive pulmonary disease&#46; Am J Respir Crit Care Med&#46; 2020&#59;201&#40;12&#41;&#58;1508&#8211;16&#46;</p><p id="spar0085" class="elsevierStyleSimplePara elsevierViewall">5&#46; Martinez FJ&#44; Rabe KF&#44; Ferguson GT&#44; Wedzicha JA&#44; Singh D&#44; Wang C&#44; et al&#46; Reduced all-cause mortality in the ETHOS trial of budesonide&#47;glycopyrrolate&#47;formoterol for COPD&#58; a randomized&#44; double-blind&#44; multi-center parallel-group study&#46; Am J Respir Crit Care Med&#46; 2020&#46;</p>"
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Scientific Letter
Efficacy and Safety of Single-inhaler Triple Therapy Containing Dual Bronchodilator With Corticosteroids Compared to Monotherapy, Dual Therapy, or Open Triple Therapy in Moderate/Severe COPD: A Systematic Literature Review
Juan Antonio Riesco Mirandaa,
Corresponding author
jantonio.riesco@gmail.com

Corresponding author.
, Myriam Calle Rubiob, David Díaz Pérezc, Jose Luis López-Camposd, Juan Antonio Trigueros Carreroe, Bartolomé Cellif
a Servicio de Neumología, Hospital San Pedro de Alcántara, Ciberes, Cáceres, Spain
b Servicio de Neumología, Hospital Universitario Clínico San Carlos, Madrid, Spain
c Servicio de Neumología y Cirugía Torácica, Hospital Universitario Nuestra Señora de la Candelaria, Santa Cruz de Tenerife, Spain
d Unidad Médico-Quirúrgica de Enfermedades Respiratorias, Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocío/Universidad de Sevilla, Sevilla, Spain
e Centro de salud Menasalbas, Menasalbas, Toledo, Spain
f Pulmonary and Critical Care Division, Brigham and Women's Hospital, Harvard University Medical School, Boston, MA, USA
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    "titulo" => "Efficacy and Safety of Single-inhaler Triple Therapy Containing Dual Bronchodilator With Corticosteroids Compared to Monotherapy&#44; Dual Therapy&#44; or Open Triple Therapy in Moderate&#47;Severe COPD&#58; A Systematic Literature Review"
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    "textoCompleto" => "<span class="elsevierStyleSections"><p id="par0005" class="elsevierStylePara elsevierViewall">We performed a systematic literature review and meta-analysis to assess the efficacy and safety of single-inhaler triple therapy &#40;SITT&#41; compared to monotherapy&#44; dual therapy&#44; and open TT &#40;OTT&#41;&#44; at 52 weeks&#44; in five predefined subgroups of moderate&#47;severe COPD patients &#40;see <a class="elsevierStyleCrossRef" href="#sec0055">supplementary material</a>&#41;&#46;</p><p id="par0010" class="elsevierStylePara elsevierViewall">We included nine articles from five randomized controlled trials of good quality&#46;<a class="elsevierStyleCrossRefs" href="#bib0100"><span class="elsevierStyleSup">1&#8211;9</span></a> The studies analyzed mortality&#44;<a class="elsevierStyleCrossRefs" href="#bib0110"><span class="elsevierStyleSup">3&#44;4</span></a> rate of moderate and severe exacerbations&#44;<a class="elsevierStyleCrossRefs" href="#bib0105"><span class="elsevierStyleSup">2&#44;5&#8211;10</span></a> changes in the FEV<span class="elsevierStyleInf">1</span>&#44;<a class="elsevierStyleCrossRefs" href="#bib0100"><span class="elsevierStyleSup">1&#44;6&#44;8&#44;9</span></a> dyspnea &#40;using the Transition Dyspnea Index &#91;TDI&#93;&#41;&#44;<a class="elsevierStyleCrossRef" href="#bib0125"><span class="elsevierStyleSup">6</span></a> and quality of life &#40;using the St&#46; George&#39;s Respiratory Questionnaire &#91;SGRQ&#93;&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0100"><span class="elsevierStyleSup">1&#44;6&#44;9</span></a></p><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0005">Previous Exacerbation History</span><p id="par0015" class="elsevierStylePara elsevierViewall">In the FULFIL trial&#44; SITT was associated with a lower rate of moderate-to-severe exacerbations than LABA&#47;ICS in patients with &#8805;<span class="elsevierStyleHsp" style=""></span>1 severe exacerbation &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#41;&#44; but there were no differences in patients with &#8805;<span class="elsevierStyleHsp" style=""></span>2 moderate exacerbations&#46; Besides&#44; SITT significantly improved trough FEV<span class="elsevierStyleInf">1</span> compared to LABA&#47;ICS in patients with &#8805;<span class="elsevierStyleHsp" style=""></span>2 moderate exacerbations &#40;difference&#58; 199<span class="elsevierStyleHsp" style=""></span>ml&#41; or &#8805;<span class="elsevierStyleHsp" style=""></span>1 severe exacerbation &#40;difference&#58; 166<span class="elsevierStyleHsp" style=""></span>ml&#41;&#44; but also in those with FEV<span class="elsevierStyleInf">1</span> &#8805;<span class="elsevierStyleHsp" style=""></span>50&#8211;&#60;<span class="elsevierStyleHsp" style=""></span>80&#37; and &#8805;<span class="elsevierStyleHsp" style=""></span>2 moderate exacerbations or &#8805;<span class="elsevierStyleHsp" style=""></span>1 severe exacerbation &#40;difference&#58; 179<span class="elsevierStyleHsp" style=""></span>ml&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">1</span></a> However&#44; improvements in SGRQ with SITT compared to LAMA&#47;ICS were only statistically significant &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;026&#41; in patients with &#8805;<span class="elsevierStyleHsp" style=""></span>2 moderate exacerbations&#46;<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">1</span></a></p><p id="par0020" class="elsevierStylePara elsevierViewall">The IMPACT trial found that SITT in patients with &#8805;<span class="elsevierStyleHsp" style=""></span>2 moderate&#47;severe exacerbations resulted in a reduction in the annual rate of exacerbations compared to LABA&#47;ICS &#40;difference&#58; 11&#37;&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;01&#41; and LAMA&#47;LABA &#40;difference&#58; 28&#37;&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;001&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">2</span></a> But in the TRIBUTE study&#44; there was no difference in the exacerbation rate between SITT and LAMA&#47;LABA in patients with &#62;<span class="elsevierStyleHsp" style=""></span>1 exacerbation&#46;<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">5</span></a></p><p id="par0025" class="elsevierStylePara elsevierViewall">The ETHOS trial compared SITT at two ICS dose levels with LABA&#47;ICS and LAMA&#47;LABA&#46;<a class="elsevierStyleCrossRef" href="#bib0130"><span class="elsevierStyleSup">7</span></a> Except for SITT at the low ICS dose level&#44; the rate of moderate or severe exacerbations was significantly lower with SITT than with LABA&#47;ICS and LAMA&#47;LABA in patients with &#8805;<span class="elsevierStyleHsp" style=""></span>2 exacerbations&#46;<a class="elsevierStyleCrossRef" href="#bib0130"><span class="elsevierStyleSup">7</span></a> Another analysis reported a significantly lower risk of death with SITT compared to LAMA&#47;LABA in patients with &#8805;<span class="elsevierStyleHsp" style=""></span>2 moderate or severe exacerbations&#58; HR<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;36 &#40;95&#37; CI 0&#46;19&#8211;0&#46;70&#41; and HR<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;55 &#40;95&#37; CI 0&#46;32&#8211;0&#46;97&#41; for SITT at high &#40;320<span class="elsevierStyleHsp" style=""></span>&#956;g&#41; and low &#40;160<span class="elsevierStyleHsp" style=""></span>&#956;g&#41; ICS dose levels&#46;<a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">4</span></a> No differences were observed compared to LABA&#47;ICS in patients with &#8805;<span class="elsevierStyleHsp" style=""></span>1 severe exacerbation&#46;<a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">4</span></a></p><p id="par0030" class="elsevierStylePara elsevierViewall">The TRINITY study&#44; which included patients with severe and very severe COPD&#44;<a class="elsevierStyleCrossRef" href="#bib0135"><span class="elsevierStyleSup">8</span></a> reported that SITT compared with LAMA and OTT significantly decreased the rate of moderate or severe exacerbations in patients with &#62;<span class="elsevierStyleHsp" style=""></span>1 exacerbation &#40;RR<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;72&#44; and RR<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;71&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0135"><span class="elsevierStyleSup">8</span></a></p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Lung Function and COPD Severity</span><p id="par0035" class="elsevierStylePara elsevierViewall">The FULFIL study showed that SITT significantly improved FEV<span class="elsevierStyleInf">1</span> at 52 weeks compared to LABA&#47;ICS in patients with FEV<span class="elsevierStyleInf">1</span> &#8804;<span class="elsevierStyleHsp" style=""></span>50&#37; and &#8805;<span class="elsevierStyleHsp" style=""></span>1 moderate or severe exacerbation &#40;difference&#58; 140<span class="elsevierStyleHsp" style=""></span>ml&#41;&#46; The difference was larger &#40;224<span class="elsevierStyleHsp" style=""></span>ml&#41; in patients without a history of exacerbations&#46;<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">1</span></a> No statistical differences in the SGRQ were observed between groups&#46;</p><p id="par0040" class="elsevierStylePara elsevierViewall">A sub analysis of the ETHOS trial revealed that mortality was significantly lower in patients with FEV<span class="elsevierStyleInf">1</span> &#60;<span class="elsevierStyleHsp" style=""></span>50&#37; on SITT at the high ICS dose level &#40;320<span class="elsevierStyleHsp" style=""></span>&#956;g&#41; compared to LAMA&#47;LABA&#46; However&#44; no differences were observed between SITT at both dose levels and LABA&#47;ICS and between SITT at the 160<span class="elsevierStyleHsp" style=""></span>&#956;g dose level and LAMA&#47;LABA&#46;<a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">4</span></a></p><p id="par0045" class="elsevierStylePara elsevierViewall">In the TRINITY study&#44;<a class="elsevierStyleCrossRef" href="#bib0135"><span class="elsevierStyleSup">8</span></a> SITT significantly reduced the rate of moderate or severe exacerbations &#40;HR<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;77&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;050&#41; compared to LAMA&#44; yet not in patients with very severe COPD&#46; Similar findings were reported for changes in FEV<span class="elsevierStyleInf">1</span>&#46; However&#44; there were no differences between SITT and OTT regarding the rate of exacerbations and changes in FEV<span class="elsevierStyleInf">1</span> in patients with severe or very severe COPD&#46;</p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Blood Eosinophil Concentration</span><p id="par0050" class="elsevierStylePara elsevierViewall">The IMPACT trial showed that in patients with eosinophil levels &#8805;<span class="elsevierStyleHsp" style=""></span>150<span class="elsevierStyleHsp" style=""></span>cells&#47;&#956;L&#44; the rate of moderate&#8211;severe exacerbations was significantly lower with SITT compared to LABA&#47;ICS and LAMA&#47;LABA&#44; amounting to 0&#46;95&#37;&#44; 1&#46;08&#37;&#44; and 1&#46;39&#37;&#44; respectively&#46;<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">2</span></a> Yet&#44; SITT was only statistically superior to LABA&#47;ICS and not to LAMA&#47;LABA in patients with &#60;<span class="elsevierStyleHsp" style=""></span>150<span class="elsevierStyleHsp" style=""></span>cells&#47;&#956;L&#46;<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">2</span></a></p><p id="par0055" class="elsevierStylePara elsevierViewall">In the ETHOS trial&#44;<a class="elsevierStyleCrossRef" href="#bib0130"><span class="elsevierStyleSup">7</span></a> the rate of moderate or severe exacerbations was significantly lower with SITT &#40;high and low ICS dose levels&#41; than with LABA&#47;ICS and LAMA&#47;LABA in patients with eosinophil counts &#8805;<span class="elsevierStyleHsp" style=""></span>150<span class="elsevierStyleHsp" style=""></span>cells&#47;&#956;L&#46; In patients with &#60;<span class="elsevierStyleHsp" style=""></span>150<span class="elsevierStyleHsp" style=""></span>cells&#47;&#956;L&#44; both SITT dose levels were significantly superior to LABA&#47;ICS&#44; but no differences were observed with LAMA&#47;LABA&#46;</p><p id="par0060" class="elsevierStylePara elsevierViewall">The IMPACT trial explored the rate of exacerbations and the changes in SGRQ&#44; FEV<span class="elsevierStyleInf">1</span>&#44; and TDI on SITT compared to LAMA&#47;LABA according to different eosinophil level cut-offs &#40;90&#44; &#8805;<span class="elsevierStyleHsp" style=""></span>90&#8211;&#60;<span class="elsevierStyleHsp" style=""></span>140&#44; &#8805;<span class="elsevierStyleHsp" style=""></span>140&#8211;&#60;<span class="elsevierStyleHsp" style=""></span>200&#44; &#8805;<span class="elsevierStyleHsp" style=""></span>200&#8211;&#60;<span class="elsevierStyleHsp" style=""></span>310&#44; and &#8805;<span class="elsevierStyleHsp" style=""></span>310<span class="elsevierStyleHsp" style=""></span>cells&#47;&#956;L&#41;&#46; In general&#44; the magnitude of the benefit on SITT increased proportionally to blood eosinophil count&#44; though the relationship with FEV<span class="elsevierStyleInf">1</span> was less marked&#46;<a class="elsevierStyleCrossRef" href="#bib0125"><span class="elsevierStyleSup">6</span></a></p><p id="par0065" class="elsevierStylePara elsevierViewall">In the TRIBUTE study&#44;<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">5</span></a> the annual rate of moderate&#47;severe exacerbations was significantly lower on SITT than on LAMA&#47;LABA in patients with eosinophil levels &#8805;<span class="elsevierStyleHsp" style=""></span>2&#37;&#44; while there were no differences between treatments for levels &#60;<span class="elsevierStyleHsp" style=""></span>2&#37;&#46;<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">5</span></a></p><p id="par0070" class="elsevierStylePara elsevierViewall">In the TRINITY trial&#44;<a class="elsevierStyleCrossRef" href="#bib0135"><span class="elsevierStyleSup">8</span></a> in which patients with eosinophil levels &#8805;<span class="elsevierStyleHsp" style=""></span>2&#37; had a lower risk of moderate or severe exacerbations with SITT than with LAMA &#40;RR<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;70&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;050&#41;&#44; there were no differences in patients with eosinophil levels &#60;<span class="elsevierStyleHsp" style=""></span>2&#37;&#46; On the other hand&#44; changes in FEV<span class="elsevierStyleInf">1</span> were significantly greater with SITT than with LAMA in both eosinophil level subgroups &#40;0&#46;07<span class="elsevierStyleHsp" style=""></span>L&#44; and 0&#46;04<span class="elsevierStyleHsp" style=""></span>L&#44; respectively&#41;&#46; However&#44; when comparing SITT with OTT&#44; there were no differences in the rate of exacerbations and FEV<span class="elsevierStyleInf">1</span> changes in any eosinophil level subgroups&#46;<a class="elsevierStyleCrossRef" href="#bib0135"><span class="elsevierStyleSup">8</span></a></p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Smoking Status</span><p id="par0075" class="elsevierStylePara elsevierViewall">In the IMPACT trial&#44; the reduction in the annual exacerbation rates was significantly more pronounced with SITT than with LABA&#47;ICS and LAMA&#47;LABA&#44; regardless of smoking status&#46;<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">2</span></a> In current smokers&#44; the reduction rates compared to dual therapies were 15&#37; &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;01&#41; and 14&#37; &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#41;&#44; respectively&#46; In former smokers 15&#37; &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;001&#41; and 30&#37; &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;001&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">2</span></a> Smoking status had also an impact on several variables&#44; including moderate or severe exacerbations&#44; TDI&#44; and FEV<span class="elsevierStyleInf">1</span>&#44; depending on blood eosinophil count&#46;<a class="elsevierStyleCrossRef" href="#bib0125"><span class="elsevierStyleSup">6</span></a></p><p id="par0080" class="elsevierStylePara elsevierViewall">In the TRIBUTE trial&#44; the reduction in the rate of moderate or severe exacerbations was significantly greater with SITT than with LAMA&#47;LABA in current smokers &#40;RR<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;77&#41;&#44; without differences in former smokers&#46;<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">5</span></a></p><p id="par0085" class="elsevierStylePara elsevierViewall">In the TRINITY study&#44; the risk of moderate or severe exacerbations was lower with SITT than with LAMA in current smokers &#40;RR<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;76&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;050&#41;&#44; with no differences in former smokers&#46;<a class="elsevierStyleCrossRef" href="#bib0135"><span class="elsevierStyleSup">8</span></a> On the other hand&#44; changes in FEV<span class="elsevierStyleInf">1</span> were significantly more marked with SITT than with LAMA in current smokers &#40;difference 0&#46;06<span class="elsevierStyleHsp" style=""></span>L&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;050&#41; and in former smokers &#40;difference 0&#46;06<span class="elsevierStyleHsp" style=""></span>L&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;050&#41;&#46;</p><p id="par0090" class="elsevierStylePara elsevierViewall">There were no differences between SITT and OTT in the rate of exacerbations and FEV<span class="elsevierStyleInf">1</span> changes in current and former smokers&#46;<a class="elsevierStyleCrossRef" href="#bib0135"><span class="elsevierStyleSup">8</span></a></p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Previous Medications &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;</span><p id="par0160" class="elsevierStylePara elsevierViewall"></p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0095" class="elsevierStylePara elsevierViewall">In the FULFIL trial&#44; SITT was statistically superior to LABA&#47;ICS in reducing exacerbations in patients previously on LABA&#47;ICS and OTT&#46;<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">1</span></a> Improvements in FEV<span class="elsevierStyleInf">1</span> were greater with SITT irrespective of previous medications&#44; but there were no differences when changes in quality of life were analyzed&#46;<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">1</span></a></p><p id="par0100" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Post hoc</span> data from the IMPACT study showed that in patients on ICS at screening&#44; mortality was significantly lower with SITT compared to LAMA&#47;LABA &#40;HR<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;63&#44; 95&#37; CI 0&#46;44&#8211;0&#46;89&#41;&#44; but no differences were found compared to ICS&#47;LABA&#46;<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">3</span></a> Besides&#44; the risk of death with SITT compared to LAMA&#47;LABA in patients on OTT at screening was HR<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;40 &#40;95&#37; CI 0&#46;19&#8211;0&#46;84&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">3</span></a> The reduction in moderate or severe exacerbations was also greater in the SITT group than in the LAMA&#47;LABA group in patients on ICS&#44; LABA&#47;ICS&#44; or OTT at screening&#44; yet with no statistically significant differences in patients with previous LAMA or LAMA&#47;LABA&#46;<a class="elsevierStyleCrossRef" href="#bib0140"><span class="elsevierStyleSup">9</span></a></p><p id="par0105" class="elsevierStylePara elsevierViewall">In the ETHOS trial&#44; there were no differences in mortality between SITT and LABA&#47;ICS in patients with prior ICS or OTT&#46;<a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">4</span></a> However&#44; this risk was significantly lower on SITT at the high ICS dose level &#40;budesonide 320<span class="elsevierStyleHsp" style=""></span>&#956;g&#41; than on LAMA&#47;LABA in patients with previous ICS or OTT&#46;<a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">4</span></a></p><p id="par0110" class="elsevierStylePara elsevierViewall">We did not identify any safety data specifically in the subgroups analyzed&#46;</p><p id="par0115" class="elsevierStylePara elsevierViewall">In the meta-analysis &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#41; we found that in patients with &#8805;<span class="elsevierStyleHsp" style=""></span>2 moderate and&#47;or &#8805;<span class="elsevierStyleHsp" style=""></span>1 severe exacerbations&#44; SITT resulted in greater reductions in the annual rate of exacerbations compared to LAMA&#47;LABA &#40;HR<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;73&#44; 95&#37; CI 0&#46;67&#8211;0&#46;79&#41;&#44; without relevant heterogeneity&#46;<a class="elsevierStyleCrossRefs" href="#bib0115"><span class="elsevierStyleSup">4&#44;5</span></a> Similar results were observed in patients with high eosinophil levels &#40;HR<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;70&#44; 95&#37; CI 0&#46;65&#8211;0&#46;76&#41;&#44; yet with a high and significant heterogeneity &#40;<span class="elsevierStyleItalic">I</span><span class="elsevierStyleSup">2</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>74&#46;3&#37;&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;020&#41;&#46; There was also a relevant heterogeneity &#40;<span class="elsevierStyleItalic">I</span><span class="elsevierStyleSup">2</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>83&#46;2&#37;&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;003&#41; in the rate of exacerbations in patients with high eosinophil levels when comparing SITT and LABA&#47;ICS &#40;HR<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;82&#44; 95&#37; CI 0&#46;76&#8211;0&#46;87&#41;&#46;</p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia><p id="par0120" class="elsevierStylePara elsevierViewall">In conclusion&#44; SITT results in more pronounced clinical benefits on exacerbations and lung function compared to other inhaled COPD medications in patients with moderate-to-severe COPD&#44; especially in those at high risk of exacerbations and with high blood eosinophil concentrations&#46; Further evidence &#40;in the long-term&#44; daily practice&#44; etc&#46;&#41; is needed to fully capture the characteristics of patient subgroups that may benefit most from SITT and to identify those with a substantial extra safety risk&#46;</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Ethical Approval</span><p id="par0125" class="elsevierStylePara elsevierViewall">This study was performed in line with the principles of the Declaration of Helsinki&#46;</p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Authors&#8217; Contributions</span><p id="par0130" class="elsevierStylePara elsevierViewall">The study was conceived by all authors&#44; all were involved in the study planning and design&#46; JAR was involved in study delivery&#44; prepared the data and carried out statistical analysis&#46; All authors provided expert opinion on development of the analysis and interpreting the data&#46; JAR and BC developed and wrote the manuscript&#44; with critical revisions and review of the final manuscript from all other authors&#46;</p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Funding</span><p id="par0135" class="elsevierStylePara elsevierViewall">The study was funded by an unrestricted educational grant from <span class="elsevierStyleGrantSponsor" id="gs1">Chiesi</span>&#46;</p></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Conflict of Interest</span><p id="par0140" class="elsevierStylePara elsevierViewall">The authors declare no conflicts of interest&#46;</p></span></span>"
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            "apendice" => "<p id="par0155" class="elsevierStylePara elsevierViewall">The following are the supplementary data to this article&#58;<elsevierMultimedia ident="upi0005"></elsevierMultimedia></p>"
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          "leyenda" => "<p id="spar0010" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleItalic">Abbreviations</span>&#58; SITT&#58; single-inhaler triple therapy&#59; FEV<span class="elsevierStyleInf">1</span>&#58; forced expiratory volume in 1 second&#59; &#956;L&#58; microliter&#59; LAMA&#58; long-acting muscarinic antagonists&#59; LABA&#58; long-acting &#946;2-agonists&#59; ICS&#58; inhaled corticosteroids&#59; HR&#58; hazard ratio&#59; CI&#58; confidence interval&#46;</p><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">1&#46; Vestbo J&#44; Papi A&#44; Corradi M&#44; Blazhko V&#44; Montagna I&#44; Francisco C&#44; et al&#46; Single inhaler extrafine triple therapy <span class="elsevierStyleItalic">versus</span> long-acting muscarinic antagonist therapy for chronic obstructive pulmonary disease &#40;TRINITY&#41;&#58; a double-blind&#44; parallel group&#44; randomized controlled trial&#46; Lancet&#46; 2017&#59;389&#40;10082&#41;&#58;1919&#8211;29&#46;</p><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">2&#46; Martinez FJ&#44; Rabe KF&#44; Ferguson GT&#44; Wedzicha JA&#44; Singh D&#44; Wang C&#44; et al&#46; Reduced all-cause mortality in the ETHOS trial of budesonide&#47;glycopyrrolate&#47;formoterol for COPD&#58; a randomized&#44; double-blind&#44; multi-center parallel-group study&#46; Am J Respir Crit Care Med&#46; 2020&#46;</p><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">3&#46; Papi A&#44; Vestbo J&#44; Fabbri L&#44; Corradi M&#44; Prunier H&#44; Cohuet G&#44; et al&#46; Extrafine inhaled triple therapy <span class="elsevierStyleItalic">versus</span> dual bronchodilator therapy in chronic obstructive pulmonary disease &#40;TRIBUTE&#41;&#58; a double-blind&#44; parallel group&#44; randomized controlled trial&#46; Lancet&#46; 2018&#59;391&#40;10125&#41;&#58;1076&#8211;84&#46;</p><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">4&#46; Lipson DA&#44; Barnhart F&#44; Brealey N&#44; Brooks J&#44; Criner GJ&#44; Day NC&#44; et al&#46; Once-daily single-inhaler triple <span class="elsevierStyleItalic">versus</span> dual therapy in patients with COPD&#46; N Engl J Med&#46; 2018&#59;378&#40;18&#41;&#58;1671&#8211;80&#46;</p><p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">5&#46; Rabe KF&#44; Martinez FJ&#44; Ferguson GT&#44; Wang C&#44; Singh D&#44; Wedzicha JA&#44; et al&#46; Triple inhaled therapy at two glucocorticoid doses in moderate-to-very-severe COPD&#46; N Engl J Med&#46; 2020&#59;383&#40;1&#41;&#58;35&#8211;48&#46;</p><p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">6&#46; Pascoe S&#44; Barnes N&#44; Brusselle G&#44; Compton C&#44; Criner GJ&#44; Dransfield MT&#44; et al&#46; Blood eosinophils and treatment response with triple and dual combination therapy in chronic obstructive pulmonary disease&#58; analysis of the IMPACT trial&#46; Lancet Respir Med&#46; 2019&#59;7&#40;9&#41;&#58;745&#8211;56&#46;</p><p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">7&#46; Axson EL&#44; Lewis A&#44; Potts J&#44; Pang M&#44; Dickinson S&#44; Vioix H&#44; et al&#46; Inhaled therapies for chronic obstructive pulmonary disease&#58; a systematic review and meta-analysis&#46; BMJ Open&#46; 2020&#59;10&#40;9&#41;&#58;e036455&#46;</p><p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">8&#46; Halpin DMG&#44; Birk R&#44; Brealey N&#44; Criner GJ&#44; Dransfield MT&#44; Hilton E&#44; et al&#46; Single-inhaler triple therapy in symptomatic COPD patients&#58; FULFIL subgroup analyses&#46; ERJ Open Res&#46; 2018&#59;4&#40;2&#41;&#46;</p>"
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          "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Summary of the Main Results of the Meta-analysis at 52 Weeks&#46; Green Color Represents Comparisons With Higher Level of Evidence in Favor of Single-inhaler Triple Therapy &#40;Meta-analysis or Clear Effect From Randomized Clinical Trials&#41;&#46; Yellow Color Depicts Contradictory Results or an Absence of Difference Between Treatment Groups Across Several Comparisons&#46; Light Blue Color Indicates Lacking Data&#46; For Each Result the Study References are Provided&#46;</p>"
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          "leyenda" => "<p id="spar0060" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleItalic">Abbreviations</span>&#58; COPD&#58; chronic obstructive pulmonary disease&#59; LAMA&#58; long-acting muscarinic antagonists&#59; LABA&#58; long-acting &#946;2-agonists&#59; ICS&#58; inhaled corticosteroids&#59; SITT&#58; single-inhaler triple therapy&#59; BF&#58; budesonide&#47;formoterol&#59; FEV<span class="elsevierStyleInf">1</span>&#58; forced expiratory volume in 1 second&#59; ml&#58; milliliter&#59; SGRQ&#58; St&#46; George&#39;s Respiratory Questionnaire&#59; Dif&#46;&#58; difference&#59; HR&#58; hazard ratio&#59; CI&#58; confidence interval&#46;</p><p id="spar0065" class="elsevierStyleSimplePara elsevierViewall">1&#46; Halpin DMG&#44; Birk R&#44; Brealey N&#44; Criner GJ&#44; Dransfield MT&#44; Hilton E&#44; et al&#46; Single-inhaler triple therapy in symptomatic COPD patients&#58; FULFIL subgroup analyses&#46; ERJ Open Res&#46; 2018&#59;4&#40;2&#41;&#46;</p><p id="spar0070" class="elsevierStyleSimplePara elsevierViewall">2&#46; Han MK&#44; Criner GJ&#44; Dransfield MT&#44; Halpin DMG&#44; Jones CE&#44; Kilbride S&#44; et al&#46; The effect of inhaled corticosteroid withdrawal and baseline inhaled treatment on exacerbations in the IMPACT study&#46; A randomized&#44; double-blind&#44; multicenter clinical trial&#46; Am J Respir Crit Care Med&#46; 2020&#59;202&#40;9&#41;&#58;1237&#8211;43&#46;</p><p id="spar0075" class="elsevierStyleSimplePara elsevierViewall">3&#46; Rabe KF&#44; Martinez FJ&#44; Ferguson GT&#44; Wang C&#44; Singh D&#44; Wedzicha JA&#44; et al&#46; Triple inhaled therapy at two glucocorticoid doses in moderate-to-very-severe COPD&#46; N Engl J Med&#46; 2020&#59;383&#40;1&#41;&#58;35&#8211;48&#46;</p><p id="spar0080" class="elsevierStyleSimplePara elsevierViewall">4&#46; Lipson DA&#44; Crim C&#44; Criner GJ&#44; Day NC&#44; Dransfield MT&#44; Halpin DMG&#44; et al&#46; Reduction in all-cause mortality with fluticasone furoate&#47;umeclidinium&#47;vilanterol in patients with chronic obstructive pulmonary disease&#46; Am J Respir Crit Care Med&#46; 2020&#59;201&#40;12&#41;&#58;1508&#8211;16&#46;</p><p id="spar0085" class="elsevierStyleSimplePara elsevierViewall">5&#46; Martinez FJ&#44; Rabe KF&#44; Ferguson GT&#44; Wedzicha JA&#44; Singh D&#44; Wang C&#44; et al&#46; Reduced all-cause mortality in the ETHOS trial of budesonide&#47;glycopyrrolate&#47;formoterol for COPD&#58; a randomized&#44; double-blind&#44; multi-center parallel-group study&#46; Am J Respir Crit Care Med&#46; 2020&#46;</p>"
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                      "titulo" => "Single-inhaler triple therapy in symptomatic COPD patients&#58; FULFIL subgroup analyses"
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ISSN: 03002896
Original language: English
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