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mortality&#44; exacerbations&#44; cardiac adverse event&#44; and serious adverse event &#40;SAE&#41; outcomes of patients from Latin American geographical region versus RoW in the TIOSPIR<span class="elsevierStyleSup">&#174;</span> trial&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Methods</span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Study design</span><p id="par0020" class="elsevierStylePara elsevierViewall">TIOSPIR<span class="elsevierStyleSup">&#174;</span> &#40;<a id="intr0005" class="elsevierStyleInterRef" href="https://clinicaltrials.gov/NCT01126437">NCT01126437</a>&#41; was a large &#40;<span class="elsevierStyleItalic">N</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>17<span class="elsevierStyleHsp" style=""></span>135&#41;&#44; long-term &#40;2&#8211;3-year&#41;&#44; randomized&#44; double-blind&#44; parallel-group&#44; double-dummy&#44; event-driven trial in patients with COPD comparing the safety and efficacy of once-daily tiotropium &#40;SPIRIVA<span class="elsevierStyleSup">&#174;</span> &#91;Boehringer Ingelheim&#44; Ingelheim am Rhein&#44; Germany&#93;&#41; via Respimat<span class="elsevierStyleSup">&#174;</span> 5<span class="elsevierStyleHsp" style=""></span>&#956;g &#40;2 inhalations of 2&#46;5<span class="elsevierStyleHsp" style=""></span>&#956;g&#41;&#44; and 2&#46;5<span class="elsevierStyleHsp" style=""></span>&#956;g &#40;2 inhalations of 1&#46;25<span class="elsevierStyleHsp" style=""></span>&#956;g&#41;&#44; or via HandiHaler<span class="elsevierStyleSup">&#174;</span> 18<span class="elsevierStyleHsp" style=""></span>&#956;g&#59; 17<span class="elsevierStyleHsp" style=""></span>116 patients constituted the as-treated population and were included in this analysis&#46; The study design&#44; detailed methods&#44; and primary results were published previously&#46;<a class="elsevierStyleCrossRefs" href="#bib0200"><span class="elsevierStyleSup">12&#44;14</span></a></p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Study population</span><p id="par0025" class="elsevierStylePara elsevierViewall">All participants had a confirmed diagnosis of COPD &#40;forced expiratory volume in 1 second &#91;FEV<span class="elsevierStyleInf">1</span>&#93; &#8804;70&#37; predicted and FEV<span class="elsevierStyleInf">1</span>&#47;forced vital capacity &#8804;0&#46;70&#41;&#44; were aged &#8805;40 years&#44; and had &#8805;10 pack-years of smoking history&#46;<a class="elsevierStyleCrossRef" href="#bib0210"><span class="elsevierStyleSup">14</span></a> Patients with concomitant cardiac diseases were included in the study&#44; except those with recent &#40;&#8804;6 months&#41; myocardial infarction &#40;MI&#41;&#44; severe arrhythmia&#44; or a change in drug therapy within the previous year&#59; or hospitalization for cardiac failure within the previous year&#46;<a class="elsevierStyleCrossRef" href="#bib0210"><span class="elsevierStyleSup">14</span></a> All usual background treatments for COPD&#44; except other inhaled anticholinergics&#44; were allowed&#46;<a class="elsevierStyleCrossRef" href="#bib0210"><span class="elsevierStyleSup">14</span></a></p><p id="par0030" class="elsevierStylePara elsevierViewall">The geographical region of Latin America enrolled patients in Argentina&#44; Brazil&#44; Colombia&#44; Guatemala&#44; Mexico&#44; Panama&#44; and Peru&#46;</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Outcome measures</span><p id="par0035" class="elsevierStylePara elsevierViewall">Outcomes of interest in this analysis were time to all-cause death&#44; time to first moderate-to-severe or severe exacerbation&#44; time to major adverse cardiovascular events &#40;MACE&#41; and fatal MACE&#44; and SAEs for patients in Latin America versus RoW&#46;</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Assessments</span><p id="par0040" class="elsevierStylePara elsevierViewall">An independent mortality adjudication committee&#44; blinded to treatment assignments attributed the cause of each death&#46;<a class="elsevierStyleCrossRef" href="#bib0210"><span class="elsevierStyleSup">14</span></a> Non-fatal stroke and MI &#40;included in MACE&#41; were reported by study investigators and verified for classification accuracy by central reviewers who were blinded to treatment assignment&#46;</p><p id="par0045" class="elsevierStylePara elsevierViewall">Exacerbations were defined as the worsening of &#8805;2 major respiratory symptoms &#40;dyspnoea&#44; cough&#44; sputum&#44; chest tightness&#44; or wheezing&#41; for &#8805;3 days and requiring specified treatment changes&#46; Moderate-to-severe exacerbations required a prescription for antibiotics&#44; systemic corticosteroids&#44; or both &#40;with no hospitalization&#41;&#59; severe exacerbations required hospitalization&#46; The onset of exacerbation was defined as the onset of the first recorded symptom&#59; the end of exacerbation was decided by the investigator&#44; based on clinical judgment&#46;</p><p id="par0050" class="elsevierStylePara elsevierViewall">A composite endpoint of MACE was included in the analyses&#44; comprising stroke&#44; transient ischaemic attack &#40;TIA&#41;&#44; MI&#44; sudden death&#44; cardiac death&#44; sudden cardiac death&#44; or fatal event in the system organ classes &#40;SOCs&#41; for cardiac and vascular disorders&#46; SOCs were defined according to the Medical Dictionary for Regulatory Activities standardizing attributions of AEs globally&#46;</p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Statistical analysis</span><p id="par0055" class="elsevierStylePara elsevierViewall">Based on similar efficacy and safety results among the tiotropium treatment arms in the primary analysis&#44;<a class="elsevierStyleCrossRef" href="#bib0200"><span class="elsevierStyleSup">12</span></a> data were pooled for this post-hoc exploratory analysis&#46;</p><p id="par0060" class="elsevierStylePara elsevierViewall">Baseline characteristics discriminating between patients in Latin America and RoW were identified and compared descriptively&#46;</p><p id="par0065" class="elsevierStylePara elsevierViewall">Hazard ratios &#40;HRs&#41; and 95&#37; confidence intervals &#40;CIs&#41; for time to events by region were calculated using a Cox proportional hazards regression model without covariate adjustment&#44; and displayed via Kaplan&#8211;Meier plots&#46; A negative binomial regression model was used to estimate the number of exacerbations&#46; HRs for time to death and time to moderate-to-severe exacerbation analyses&#44; by region and baseline characteristics&#44; are shown as forest plots&#46; Additional analyses of time to death and moderate-to-severe exacerbation&#44; severe exacerbations&#44; and MACE were adjusted for covariates including age&#44; post-bronchodilator FEV<span class="elsevierStyleInf">1</span>&#37; predicted&#44; gender&#44; exacerbation history&#44; smoking history &#40;pack-years&#41;&#44; body mass index &#40;BMI&#41;&#44; and history of cardiac disorders&#44; MI&#44; coronary artery disease&#47;ischaemic heart disease &#40;CAD&#47;IHD&#41;&#44; cardiac arrhythmia&#44; heart failure &#40;class I&#8211;IV&#41;&#44; and stroke&#47;TIA&#46;</p><p id="par0070" class="elsevierStylePara elsevierViewall">Incidence rates&#44; incidence rate ratios &#40;IRRs&#41;&#44; and 95&#37; CIs for causes of death were calculated&#46; SAEs are provided in the Supplementary Material&#46;</p><p id="par0075" class="elsevierStylePara elsevierViewall">For the mortality analysis &#40;vital status&#41;&#44; data were included if death occurred up until the study end date&#44; irrespective of treatment discontinuation&#46; For the exacerbation analysis &#40;on-treatment&#41;&#44; events were counted from randomization to drug stop date<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>1 day&#44; and for MACE to drug stop date<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>30 days&#46;</p></span></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Results</span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">Study population</span><p id="par0080" class="elsevierStylePara elsevierViewall">Of the TIOSPIR<span class="elsevierStyleSup">&#174;</span> population&#44; 1000 patients from Latin America and 16<span class="elsevierStyleHsp" style=""></span>116 patients from RoW were included &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#46; Total exposure to tiotropium was 1855 and 32<span class="elsevierStyleHsp" style=""></span>229 patient-years for Latin America and RoW&#44; respectively&#46; A total of 228 &#40;22&#46;8&#37;&#41; patients from Latin America and 3689 &#40;22&#46;9&#37;&#41; patients from RoW discontinued prematurely from trial medication&#46; Reasons for premature discontinuation were similar&#44; and mainly due to AEs&#44; with respiratory disorders &#40;including COPD&#41; being the most common AEs&#44; followed by neoplasms&#44; and infections and infestations&#46;<a class="elsevierStyleCrossRef" href="#bib0200"><span class="elsevierStyleSup">12</span></a> Vital status follow-up was complete for 99&#46;1&#37; and 99&#46;8&#37; of patients from Latin America and RoW&#44; respectively&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0110">Baseline characteristics</span><p id="par0085" class="elsevierStylePara elsevierViewall">At baseline&#44; patients enrolled in Latin America were comparatively older &#40;higher proportion of patients aged &#8805;70 years&#41;&#44; and had higher mean pack-years of smoking history than those in RoW&#44; although a lower percentage were current smokers &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#46; A higher proportion of patients in Latin America had COPD exacerbation in the year prior to the trial than those in RoW&#46; Latin American patients were more likely to have very severe COPD &#40;Global Initiative for Chronic Obstructive Lung Disease &#91;GOLD&#93; Stage IV&#41; versus RoW &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#46; Fewer Latin American patients had a history of cardiac disorders&#44; or were receiving cardiovascular medication at baseline versus RoW &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#46; The proportions of patients receiving long-acting muscarinic antagonist &#40;LAMA&#41; or long-acting &#946;<span class="elsevierStyleInf">2</span>-agonist &#40;LABA&#41; at baseline were lower in Latin America than in RoW&#59; however&#44; they were more likely to receive inhaled corticosteroids &#40;ICS&#41; &#40;with or without LABA&#41; &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#46;</p></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0115">Mortality</span><p id="par0090" class="elsevierStylePara elsevierViewall">During the study&#44; a greater proportion of patients died in the Latin American population &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>100 &#91;10&#46;0&#37;&#93;&#41; versus RoW &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>1200 &#91;7&#46;4&#37;&#93;&#41; &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>A&#41;&#46; Analysis of time to death confirmed that patients in Latin America had a higher risk of death than those in RoW &#40;HR &#91;95&#37; CI&#93;&#58; 1&#46;52 &#91;1&#46;24&#8211;1&#46;86&#93;&#41; &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>A&#59; <a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41;&#46; This was also true when the analysis of time to death was adjusted for age&#44; gender&#44; FEV<span class="elsevierStyleInf">1</span>&#37; predicted&#44; exacerbation history&#44; smoking history &#40;pack-years&#41;&#44; BMI&#44; history of cardiac disorders&#44; MI&#44; CAD&#47;IHD&#44; cardiac arrhythmia&#44; heart failure &#40;class I&#8211;IV&#41;&#44; and stroke&#47;TIA &#40;HR &#91;95&#37; CI&#93;&#58; 1&#46;37 &#91;1&#46;11&#8211;1&#46;69&#93;&#41; &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>A&#41;&#46;</p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0095" class="elsevierStylePara elsevierViewall">While the overall risk of death was increased in patients from Latin America versus RoW&#44; regression analysis according to baseline characteristics showed that the risk of death was similar for Latin America and RoW in patients with BMI &#8805;30<span class="elsevierStyleHsp" style=""></span>kg&#47;m<span class="elsevierStyleSup">2</span> &#40;HR &#91;95&#37; CI&#93;&#58; 1&#46;07 &#91;0&#46;58&#8211;1&#46;96&#93;&#41;&#44; and patients with cardiac arrhythmia &#40;HR &#91;95&#37; CI&#93;&#58; 1&#46;06 &#91;0&#46;62&#8211;1&#46;82&#93;&#41; &#40;<a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>&#41;&#46; The largest HRs were observed in patients with GOLD Stage IV &#40;HR &#91;95&#37; CI&#93;&#58; 1&#46;87 &#91;1&#46;26&#8211;2&#46;77&#93;&#41; and in those who received LABA &#40;but no ICS&#41; &#40;HR &#91;95&#37; CI&#93;&#58; 1&#46;94 &#91;1&#46;05&#8211;3&#46;60&#93;&#41; &#40;<a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>&#41;&#44; however the LABA &#40;no ICS&#41; result is based on small patient number&#46; Causes of death were mainly similar between the regions&#44; except for respiratory&#44; thoracic&#44; and mediastinal disorders&#44; including COPD&#44; gastrointestinal disorders&#44; general disorders including death due to unknown reason &#40;sudden cardiac death and death&#41;&#44; and infections and infestations&#44; where the incidence rate was higher in the Latin American region versus RoW&#46; General disorders&#44; neoplasms&#44; and respiratory disorders&#44; including COPD&#44; contributed the majority of deaths &#40;<a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>&#41;&#46;</p><elsevierMultimedia ident="fig0010"></elsevierMultimedia><elsevierMultimedia ident="tbl0015"></elsevierMultimedia></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0120">COPD exacerbations</span><p id="par0100" class="elsevierStylePara elsevierViewall">Similar to the mortality analysis&#44; the risk of moderate-to-severe exacerbation &#40;time to first moderate-to-severe exacerbation&#41; was higher in patients in Latin America versus RoW &#40;HR &#91;95&#37; CI&#93;&#58; 1&#46;29 &#91;1&#46;18&#8211;1&#46;41&#93;&#41; &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>B&#59; <a class="elsevierStyleCrossRef" href="#fig0015">Fig&#46; 3</a>&#41;&#46; Additional analysis adjusting for relevant covariates confirmed a higher risk of moderate-to-severe exacerbations in Latin American patients versus RoW &#40;HR &#91;95&#37; CI&#93;&#58; 1&#46;13 &#91;1&#46;03&#8211;1&#46;23&#93;&#41; &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>B&#41;&#46; Accordingly&#44; the annual rate of moderate-to-severe exacerbations was higher in Latin America &#40;RR &#91;95&#37; CI&#93;&#58; 1&#46;25 &#91;1&#46;13&#8211;1&#46;38&#93;&#41; even when adjusted for covariates &#40;RR &#91;95&#37; CI&#93;&#58; 1&#46;07 &#91;0&#46;97&#8211;1&#46;18&#93;&#41; &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>B&#41;&#46; Time to first moderate-to-severe exacerbation according to baseline characteristics confirmed the increased risk in Latin America versus RoW&#44; except for patients receiving LABA &#40;but no ICS&#41; at baseline &#40;HR &#91;95&#37; CI&#93;&#58; 1&#46;06 &#91;0&#46;77&#8211;1&#46;47&#93;&#41;&#44; where the risk was similar between both regions &#40;<a class="elsevierStyleCrossRef" href="#fig0020">Fig&#46; 4</a>&#41;&#46; In contrast&#44; patients in Latin America had a lower risk of severe COPD exacerbation &#40;longer time to first severe exacerbation leading to hospitalization&#41; &#40;HR &#91;95&#37; CI&#93;&#58; 0&#46;82 &#91;0&#46;68&#8211;0&#46;98&#93;&#41; &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>C&#59; <a class="elsevierStyleCrossRef" href="#fig0025">Fig&#46; 5</a>&#41;&#44; including when adjusted for covariates &#40;HR &#91;95&#37; CI&#93;&#58; 0&#46;67 &#91;0&#46;55&#8211;0&#46;81&#93;&#41; &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>C&#41;&#46; Severe exacerbations also occurred less frequently versus RoW &#40;RR &#91;95&#37; CI&#93;&#58; 0&#46;76 &#91;0&#46;61&#8211;0&#46;94&#93;&#41; &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>C&#41;&#44; and similar results were obtained when adjusted for covariates &#40;RR &#91;95&#37; CI&#93;&#58; 0&#46;62 &#91;0&#46;50&#8211;0&#46;77&#93;&#41; &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>C&#41;&#46; Time to first severe exacerbation according to baseline characteristics adjusted for covariates supported the lower risk of severe exacerbation in Latin American patients versus RoW&#44; except for patients receiving ICS &#40;but no LABA&#41; at baseline &#40;HR &#91;95&#37; CI&#93;&#58; 1&#46;01 &#91;0&#46;63&#8211;1&#46;63&#93;&#41; and patients with cardiac arrhythmia &#40;HR &#91;95&#37;CI&#93;&#58; 1&#46;07 &#91;0&#46;68&#8211;1&#46;66&#93;&#41;&#46; However&#44; an increased risk of severe exacerbations was observed in underweight &#40;BMI<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>18&#46;5&#41; patients in Latin America versus RoW &#40;HR &#91;95&#37;CI&#93;&#58; 1&#46;30 &#91;0&#46;79&#8211;2&#46;12&#93;&#41; &#40;<a class="elsevierStyleCrossRef" href="#fig0030">Fig&#46; 6</a>&#41;&#46;</p><elsevierMultimedia ident="fig0015"></elsevierMultimedia><elsevierMultimedia ident="fig0020"></elsevierMultimedia><elsevierMultimedia ident="fig0025"></elsevierMultimedia><elsevierMultimedia ident="fig0030"></elsevierMultimedia></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0125">Time to first MACE and SAEs</span><p id="par0105" class="elsevierStylePara elsevierViewall">The risk of MACE &#40;HR &#91;95&#37; CI&#93;&#58; 0&#46;99 &#91;0&#46;71&#8211;1&#46;40&#93;&#41; was similar between Latin America and RoW &#40;<a class="elsevierStyleCrossRef" href="#fig0035">Fig&#46; 7</a>&#41; even when adjusted for covariates &#40;HR &#91;95&#37; CI&#93;&#58; 1&#46;01 &#91;0&#46;71&#8211;1&#46;42&#93;&#41; &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>D&#41;&#46; However&#44; the risk of fatal MACE &#40;HR &#91;95&#37; CI&#93;&#58; 1&#46;41 &#91;0&#46;93&#8211;2&#46;13&#93;&#41; &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>D&#41; was numerically higher in Latin America versus RoW&#44; although only a small proportion of patients had fatal MACE &#40;2&#46;4&#37; in Latin America vs 1&#46;9&#37; in RoW&#59; <a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>D&#41;&#46;</p><elsevierMultimedia ident="fig0035"></elsevierMultimedia><p id="par0110" class="elsevierStylePara elsevierViewall">Incidence rates of SAEs were lower in Latin America than in the RoW&#44; including cardiac disorders&#44; cancer&#44; nervous system disorders&#44; and overall respiratory disorders including COPD &#40;Table S1&#41;&#46;</p></span></span><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0130">Discussion and conclusions</span><p id="par0115" class="elsevierStylePara elsevierViewall">Latin America is undergoing demographic changes characterized by increased ageing of the population&#44; and the higher proportion of patients aged &#8805;60 years in Latin American countries is a reflection of this statistic&#46;<a class="elsevierStyleCrossRefs" href="#bib0175"><span class="elsevierStyleSup">7&#44;15</span></a> As expected&#44; Latin American patients also had higher pack-years of smoking history versus RoW&#44; although current smokers were less frequent in Latin America&#44; indicating that more patients had stopped smoking prior to study start&#46;</p><p id="par0120" class="elsevierStylePara elsevierViewall">Compared with RoW&#44; more patients in Latin America had very severe COPD &#40;GOLD Stage IV&#41; at baseline&#44; possibly indicating that these patients remained undiagnosed during the early stages of COPD&#44; and reflecting suboptimal disease management in this region&#46;<a class="elsevierStyleCrossRefs" href="#bib0215"><span class="elsevierStyleSup">15&#44;16</span></a> The PLATINO study&#44; identified underdiagnosis as an issue across Latin America&#44;<a class="elsevierStyleCrossRef" href="#bib0225"><span class="elsevierStyleSup">17</span></a> while more than half of patients included in the PUMA study were not using bronchodilators&#46;<a class="elsevierStyleCrossRef" href="#bib0230"><span class="elsevierStyleSup">18</span></a> Our findings support this earlier research&#44; with few patients using bronchodilators at baseline&#44; suggesting a significant gap between guideline recommendations and prescribing patterns in this region&#46;<a class="elsevierStyleCrossRef" href="#bib0230"><span class="elsevierStyleSup">18</span></a> A scarcity of respiratory specialists and training programmes in many Latin American countries<a class="elsevierStyleCrossRef" href="#bib0175"><span class="elsevierStyleSup">7</span></a> is likely to increase the risk of poor clinical outcomes&#46;<a class="elsevierStyleCrossRef" href="#bib0190"><span class="elsevierStyleSup">10</span></a> These factors could also have contributed to the observed higher proportion of patients with exacerbations in the year prior to our study&#46; Thorough assessment&#44; accurate diagnosis&#44; and prompt initiation of management strategies &#40;such as smoking cessation and maintenance respiratory therapy&#41; in COPD are known to be essential for mitigating future risks&#46;<a class="elsevierStyleCrossRefs" href="#bib0175"><span class="elsevierStyleSup">7&#44;10&#44;15</span></a> Evidence-based literature recommends smoking cessation at early stages of COPD&#46;<a class="elsevierStyleCrossRef" href="#bib0235"><span class="elsevierStyleSup">19</span></a></p><p id="par0125" class="elsevierStylePara elsevierViewall">Latin American patients had increased risk of death compared with RoW&#44; even when adjusted for age&#44; gender&#44; FEV<span class="elsevierStyleInf">1</span>&#37; predicted&#44; exacerbation history&#44; smoking history &#40;pack-years&#41;&#44; BMI&#44; and history of cardiac disorders&#44; MI&#44; CAD&#47;IHD&#44; cardiac arrhythmia&#44; heart failure &#40;class I&#8211;IV&#41;&#44; and stroke&#47;TIA&#46; These factors are proposed drivers of mortality and morbidity in COPD<a class="elsevierStyleCrossRefs" href="#bib0190"><span class="elsevierStyleSup">10&#44;20&#44;21</span></a> and are likely to be relevant regardless of geographical location&#46; Findings from the PLATINO study also support an association between COPD and increased mortality when adjusted by age&#44; smoking status&#44; pack-years smoking&#44; quality of life&#44; BMI&#44; and comorbidities&#46;<a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">4</span></a> Comparable with previous findings&#44;<a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">4</span></a> the incidence rate of death due to respiratory&#44; thoracic&#44; and mediastinal disorders&#44; including COPD&#44; was higher in Latin America versus RoW in our study&#46;</p><p id="par0130" class="elsevierStylePara elsevierViewall">Latin American patients also had a higher risk of moderate-to-severe exacerbation than patients in RoW&#46; The risk was consistently higher in most subgroups&#44; except for patients receiving LABA &#40;but not ICS&#41; at baseline&#46; Nevertheless&#44; although Latin American patients presented with more severe disease at baseline&#44; and higher mortality or moderate-to-severe exacerbation risks&#44; our analysis demonstrated that they were less likely to have severe exacerbation than RoW&#46; This was true even when the analysis was adjusted for covariates&#44; except for patients receiving ICS at baseline and patients with cardiac arrhythmia&#59; underweight patients had an increased risk in Latin America versus RoW&#46; Fewer severe exacerbations were recorded as a result of the scarcity of admission beds<a class="elsevierStyleCrossRef" href="#bib0250"><span class="elsevierStyleSup">22</span></a> in Latin American hospitals&#44; or related healthcare challenges such as inadequate facilities for critical care units&#46;<a class="elsevierStyleCrossRef" href="#bib0175"><span class="elsevierStyleSup">7</span></a> Our findings were contrary to those of several Latin American epidemiology studies&#44; which found that hospitalization due to exacerbation was commonplace&#44; reflecting undertreatment&#46;<a class="elsevierStyleCrossRefs" href="#bib0215"><span class="elsevierStyleSup">15&#44;16&#44;18</span></a> In the PUMA study&#44; frequent overtreatment with corticosteroids was observed in patients without an exacerbation in the past year&#44; while a lower hospitalization rate was not deemed to support the extensive use of corticosteroids&#46;<a class="elsevierStyleCrossRef" href="#bib0220"><span class="elsevierStyleSup">16</span></a> Our results showed that corticosteroid overuse was prevalent in Latin America&#44; as more patients were likely to receive ICS at baseline versus RoW&#46;</p><p id="par0135" class="elsevierStylePara elsevierViewall">Unlike the regional differences we identified for Latin American patients&#44; the TIOSPIR<span class="elsevierStyleSup">&#174;</span> subanalysis of an Asian cohort observed similar mortality rates in Asian patients versus RoW patients&#46;<a class="elsevierStyleCrossRef" href="#bib0205"><span class="elsevierStyleSup">13</span></a> Further&#44; Asian patients reported fewer exacerbations than those in RoW&#44; whereas the proportion with a severe exacerbation was higher&#46;<a class="elsevierStyleCrossRef" href="#bib0205"><span class="elsevierStyleSup">13</span></a> This may be attributed to differences in the healthcare system in different regions&#59; for example&#44; in Asia&#44; patients are frequently hospitalized for an exacerbation due to non-availability of corticosteroids or antibiotics in a primary healthcare unit&#46;<a class="elsevierStyleCrossRef" href="#bib0205"><span class="elsevierStyleSup">13</span></a> The observed discrepancies between the results for the Asian and the Latin American cohort illustrate how racial and&#47;or geographical differences can impact hospitalization rates and treatment outcomes in COPD trials&#46;</p><p id="par0140" class="elsevierStylePara elsevierViewall">Patients enrolled in TIOSPIR<span class="elsevierStyleSup">&#174;</span> in Latin America were less likely to have a history of cardiac disorders or to be receiving cardiovascular medications at baseline compared with RoW&#46; Assuming that their initial cardiovascular comorbidity was indeed lower&#44; it is therefore rational that Latin American patients were less likely to experience a cardiac disorder SAE than those in RoW during the trial&#46; The composite outcome of MACE was actually similar for both regions&#44; though the risk of fatal MACE was numerically increased in Latin American patients&#46; Further research is needed to clarify relative cardiac risks in this cohort&#44; and the predisposing factors&#46;</p><p id="par0145" class="elsevierStylePara elsevierViewall">It was beyond the scope of our analysis to assess differences in baseline characteristics and outcomes between individual countries in the Latin American region&#44; as the sample sizes may be too small to enable meaningful assessment&#46; Environmental factors not assessed here also influence COPD-related risks&#44; such as access to healthcare and alternative disease management strategies&#44;<a class="elsevierStyleCrossRefs" href="#bib0175"><span class="elsevierStyleSup">7&#44;23&#8211;25</span></a> the extent of solid fuel use&#44;<a class="elsevierStyleCrossRef" href="#bib0190"><span class="elsevierStyleSup">10</span></a> or living at high altitude&#46; Hypoxia can have unwanted extra pulmonary systemic effects in patients with COPD&#44; and might be associated with high altitude and mortality from COPD&#46;<a class="elsevierStyleCrossRef" href="#bib0270"><span class="elsevierStyleSup">26</span></a> Temperature inversions can also result in a buildup of air pollution that is detrimental to those with respiratory conditions&#46;<a class="elsevierStyleCrossRef" href="#bib0275"><span class="elsevierStyleSup">27</span></a> In addition&#44; patients with COPD in tropical countries &#40;such as Brazil&#44; Columbia&#44; and Peru&#41; may be particularly prone to exacerbations&#44; as infections are more prevalent throughout the year&#44; and not just in the winter months &#40;owing to the high humidity and lack of seasonal variation in temperature&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0280"><span class="elsevierStyleSup">28</span></a></p><p id="par0150" class="elsevierStylePara elsevierViewall">The large population size and 2- to 3-year duration of the TIOSPIR<span class="elsevierStyleSup">&#174;</span> trial&#44; along with the wide range of nationalities included &#40;50 countries across different regions of the world<a class="elsevierStyleCrossRef" href="#bib0210"><span class="elsevierStyleSup">14</span></a>&#41;&#44; constitute strengths of this analysis&#46; Patients in TIOSPIR<span class="elsevierStyleSup">&#174;</span> constituted a convenience sample from 7 Latin American countries &#40;rather than a sample representative of the whole population&#41; and should therefore be interpreted with caution if generalized to Latin America overall&#46; However&#44; the patient characteristics are representative of the patients seen in specialist practice globally&#44; and the continuation of regular maintenance respiratory medication and inclusion of patients with cardiac disease ensured that the population reflects real-world patients&#46;<a class="elsevierStyleCrossRefs" href="#bib0200"><span class="elsevierStyleSup">12&#44;14</span></a> Thus&#44; we feel that the results are likely to be valid in a clinical setting&#46; However&#44; as this was a post-hoc rather than a predefined subgroup analysis&#44; it is not possible to confirm the reasons why outcome risks differed between Latin America and RoW&#46;</p><p id="par0155" class="elsevierStylePara elsevierViewall">Latin American patients with COPD in TIOSPIR<span class="elsevierStyleSup">&#174;</span> had a higher risk of death and COPD exacerbations versus RoW patients&#44; but were less likely to be hospitalized for an exacerbation&#46; The prevalence of tobacco smoking&#44; exposure to environmental contaminants&#44; or healthcare challenges might impact treatment outcomes and lead to different results for patients enrolled from various regions in international trials of COPD&#46; This should be considered when designing trials and evaluating the global clinical relevance of the results&#46; Further studies should explore factors influencing the increased risk of mortality in Latin America compared with RoW&#46;</p></span><span id="sec0075" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0135">Funding</span><p id="par0160" class="elsevierStylePara elsevierViewall">The TIOSPIR<span class="elsevierStyleSup">&#174;</span> trial and this post-hoc study were funded by Boehringer Ingelheim&#46;</p></span><span id="sec0080" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0140">Authorship</span><p id="par0165" class="elsevierStylePara elsevierViewall">All authors confirm involvement in the conception&#44; hypotheses delineation&#44; and design of the study&#59; acquisition&#44; analysis&#44; or interpretation of the data&#59; writing or substantial involvement in the article&#39;s revision prior to submission&#46;</p></span><span id="sec0085" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0145">Conflict of interest</span><p id="par0170" class="elsevierStylePara elsevierViewall">AA reports receiving consulting fees&#44; lecture fees&#44; or travel support from AstraZeneca&#44; Boehringer Ingelheim&#44; Forest Laboratories&#44; GlaxoSmithKline&#44; and Novartis&#46; PMAC has received research grants from GlaxoSmithKline and Takeda&#59; personal fees from AstraZeneca&#44; Boehringer Ingelheim&#44; GlaxoSmithKline&#44; Novartis&#44; and Takeda&#59; and non-financial support from Boehringer Ingelheim&#46; AM&#44; NM&#44; and MH are employees of Boehringer Ingelheim&#46; JRJ reports receiving consulting fees&#44; lecture fees&#44; or travel support from AstraZeneca&#44; Boehringer Ingelheim&#44; Novartis&#44; Grifols&#44; CSL&#44; Zambon&#44; EMS&#44; and Chiesi in the past 12 months&#46; EP reports receiving consulting fees&#44; lecture fees&#44; or travel support from Ache&#44; AstraZeneca&#44; Boehringer Ingelheim&#44; GlaxoSmithKline&#44; Novartis&#44; and Chiesi in the past 12 months&#59; EP is currently a Global Medical Expert for GlaxoSmithKline&#46; HG is an advisory member of Boehringer Ingelheim&#44; Novartis&#44; GSK&#44; AstraZeneca&#44; and Mundipharma&#59; and has received lecture fees from Novartis&#44; and travel support from MSD and AstraZeneca&#46; ARV reports travel support from AstraZeneca and Novartis in the past 12 months&#46; ERG reports receiving travel support&#44; consulting fees and lecture fees from GlaxoSmithKline&#44; AstraZeneca&#44; Boehringer Ingelheim and Mundipharma&#46;</p></span></span>"
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        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Introduction</span><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Geographical variations may impact outcomes in chronic obstructive pulmonary disease &#40;COPD&#41;&#46; We evaluated differences in baseline characteristics and outcomes between patients enrolled in Latin America compared with the rest of the world &#40;RoW&#41; in the TIOtropium Safety and Performance In Respimat<span class="elsevierStyleSup">&#174;</span> &#40;TIOSPIR<span class="elsevierStyleSup">&#174;</span>&#41; trial&#46;</p></span> <span id="abst0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Methods</span><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">TIOSPIR<span class="elsevierStyleSup">&#174;</span>&#44; a 2&#8211;3-year&#44; randomized&#44; double-blind trial &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>17<span class="elsevierStyleHsp" style=""></span>116&#59; treated set&#41;&#44; compared safety and efficacy of once-daily tiotropium Respimat<span class="elsevierStyleSup">&#174;</span> 5 and 2&#46;5<span class="elsevierStyleHsp" style=""></span>&#956;g with tiotropium HandiHaler<span class="elsevierStyleSup">&#174;</span> 18<span class="elsevierStyleHsp" style=""></span>&#956;g&#46; This post-hoc analysis pooled data from all treatment arms to assess mortality&#44; exacerbations&#44; cardiac events&#44; and serious adverse events &#40;SAEs&#41; between both regions&#46;</p></span> <span id="abst0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Results</span><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">At baseline&#44; patients enrolled in Latin America &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>1000&#41; versus RoW &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>16<span class="elsevierStyleHsp" style=""></span>116&#41; were older&#44; with higher pack-years of smoking history and more exacerbations&#44; but less cardiac history&#46; In this analysis&#44; patients in Latin America versus RoW had an increased risk of death &#40;hazard ratio &#91;HR&#93; &#91;95&#37; confidence interval &#40;CI&#41;&#93;&#58; 1&#46;52 &#91;1&#46;24&#8211;1&#46;86&#93;&#59; <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>&#46;0001&#41; or moderate-to-severe exacerbation &#40;HR &#91;95&#37; CI&#93;&#58; 1&#46;29 &#91;1&#46;18&#8211;1&#46;41&#93;&#59; <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>&#46;0001&#41;&#44; but a lower risk of severe exacerbation &#40;HR &#91;95&#37; CI&#93;&#58; 0&#46;82 &#91;0&#46;68&#8211;0&#46;98&#93;&#59; <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;0333&#41;&#46; SAE rates in Latin America were lower versus RoW &#40;incidence rate ratio &#91;IRR&#93; &#91;95&#37; CI&#93;&#58; 0&#46;82 &#91;0&#46;72&#8211;0&#46;92&#93;&#41;&#44; including cardiac disorders &#40;IRR &#91;95&#37; CI&#93;&#58; 0&#46;68 &#91;0&#46;48&#8211;0&#46;97&#93;&#41;&#46; Risk of major adverse cardiovascular events were similar &#40;HR &#91;95&#37; CI&#93;&#58; 0&#46;99 &#91;0&#46;71&#8211;1&#46;40&#93;&#59; <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;9677&#41;&#46;</p></span> <span id="abst0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Conclusions</span><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">TIOSPIR<span class="elsevierStyleSup">&#174;</span> patients in Latin America had a higher risk of death or moderate-to-severe exacerbation&#44; but a lower risk of severe exacerbation than those in RoW&#46; Geographical differences may impact outcomes in COPD trials&#46;</p></span>"
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        "resumen" => "<span id="abst0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Introducci&#243;n</span><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Las variaciones geogr&#225;ficas pueden afectar a los resultados en la enfermedad pulmonar obstructiva cr&#243;nica &#40;EPOC&#41;&#46; Evaluamos las diferencias en las caracter&#237;sticas basales y los resultados de los pacientes incluidos en Latinoam&#233;rica en comparaci&#243;n con el resto del mundo &#40;RdM&#41; en el ensayo <span class="elsevierStyleItalic">TIOtropium Safety and Performance In Respimat</span><span class="elsevierStyleSup">&#174;</span> &#40;TIOSPIR<span class="elsevierStyleSup">&#174;</span>&#41;&#46;</p></span> <span id="abst0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">M&#233;todos</span><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">TIOSPIR<span class="elsevierStyleSup">&#174;</span>&#44; es un estudio aleatorizado&#44; doble ciego de 2-3 a&#241;os de duraci&#243;n &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>17&#46;116&#59; conjunto tratado&#41;&#44; compar&#243; la seguridad y la eficacia del tiotropio Respimat<span class="elsevierStyleSup">&#174;</span> una vez al d&#237;a en dosis de 5 y 2&#44;5<span class="elsevierStyleHsp" style=""></span>&#956;g con respecto al tiotropio HandiHaler<span class="elsevierStyleSup">&#174;</span> 18<span class="elsevierStyleHsp" style=""></span>&#956;g&#46; Este an&#225;lisis post-hoc reuni&#243; datos de todos los brazos de tratamiento para evaluar la mortalidad&#44; las exacerbaciones&#44; los acontecimientos card&#237;acos y los acontecimientos adversos graves &#40;AAG&#41; entre ambas regiones&#46;</p></span> <span id="abst0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Resultados</span><p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Al inicio del estudio&#44; los pacientes reclutados en Am&#233;rica Latina &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>1&#46;000&#41; versus RdM &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>16&#46;116&#41; eran de mayor edad&#44; con m&#225;s paquetes&#47;a&#241;o de consumo de tabaco en sus antecedentes y m&#225;s exacerbaciones&#44; pero menos antecedentes card&#237;acos&#46; En este an&#225;lisis&#44; los pacientes de Latinoam&#233;rica versus RdM ten&#237;an un mayor riesgo de muerte &#40;raz&#243;n de riesgo &#91;HR&#93; intervalo de confianza del 95&#37; &#91;IC 95&#37;&#93;&#58; 1&#44;52 &#91;1&#44;24-1&#44;86&#93;&#59; p<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#44;0001&#41; y de exacerbaci&#243;n moderada a grave &#40;HR &#91;IC 95&#37;&#93;&#58; 1&#44;29 &#91;1&#44;18-1&#44;41&#93;&#59; p<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#44;0001&#41;&#44; pero menor riesgo de exacerbaci&#243;n grave &#40;HR &#91;IC 95&#37;&#93;&#58; 0&#44;82 &#91;0&#44;68-0&#44;98&#93;&#59; p<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;0333&#41;&#46; Las tasas de AAG en Latinoam&#233;rica fueron m&#225;s bajas frente al RdM &#40;tasa de incidencia &#91;IRR&#93; &#91;IC 95&#37;&#93;&#58; 0&#44;82 &#91;0&#44;72-0&#44;92&#93;&#41;&#44; incluidos los trastornos card&#237;acos &#40;IRR &#91;IC 95&#37;&#93;&#58; 0&#44;68 &#91;0&#44;48-0&#44;97&#93;&#41;&#46; El riesgo de acontecimientos cardiovasculares adversos mayores fue similar &#40;HR &#91;IC 95&#37;&#93;&#58; 0&#44;99 &#91;0&#44;71-1&#44;40&#93;&#59; p<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;9677&#41;&#46;</p></span> <span id="abst0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Conclusiones</span><p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">Los pacientes de TIOSPIR<span class="elsevierStyleSup">&#174;</span> en Latinoam&#233;rica tuvieron un mayor riesgo de muerte y de exacerbaci&#243;n moderada a grave&#44; pero un menor riesgo de exacerbaci&#243;n grave que aquellos en el RdM&#46; Las diferencias geogr&#225;ficas pueden afectar los resultados en los ensayos de la EPOC&#46;</p></span>"
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          "en" => "<p id="spar0060" class="elsevierStyleSimplePara elsevierViewall">Time to death by region and according to baseline characteristics &#40;vital status analysis&#41;&#46;</p> <p id="spar0065" class="elsevierStyleSimplePara elsevierViewall">Data were included if the death occurred up until the end of the study&#46;</p> <p id="spar0070" class="elsevierStyleSimplePara elsevierViewall">BL&#44; baseline&#59; BMI&#44; body mass index&#59; CI&#44; confidence interval&#59; COPD&#44; chronic obstructive pulmonary disease&#59; GOLD&#44; Global Initiative for Chronic Obstructive Lung Disease&#59; HR&#44; hazard ratio&#59; ICS&#44; inhaled corticosteroid&#59; LABA&#44; long-acting &#946;<span class="elsevierStyleInf">2</span>-agonist&#59; RoW&#44; rest of the world&#46;</p>"
        ]
      ]
      2 => array:7 [
        "identificador" => "fig0015"
        "etiqueta" => "Fig&#46; 3"
        "tipo" => "MULTIMEDIAFIGURA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "figura" => array:1 [
          0 => array:4 [
            "imagen" => "gr3.jpeg"
            "Alto" => 1049
            "Ancho" => 1651
            "Tamanyo" => 168884
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0075" class="elsevierStyleSimplePara elsevierViewall">Time to first moderate-to-severe exacerbation by region &#40;on-treatment analysis&#41;&#46;</p> <p id="spar0080" class="elsevierStyleSimplePara elsevierViewall">Events were counted from randomization to drug stop date<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>1 day&#46;</p> <p id="spar0085" class="elsevierStyleSimplePara elsevierViewall">COPD&#44; chronic obstructive pulmonary disease&#59; RoW&#44; rest of the world&#46;</p>"
        ]
      ]
      3 => array:7 [
        "identificador" => "fig0020"
        "etiqueta" => "Fig&#46; 4"
        "tipo" => "MULTIMEDIAFIGURA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "figura" => array:1 [
          0 => array:4 [
            "imagen" => "gr4.jpeg"
            "Alto" => 2369
            "Ancho" => 2893
            "Tamanyo" => 564120
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0090" class="elsevierStyleSimplePara elsevierViewall">Time to first moderate-to-severe COPD exacerbation by region and according to baseline characteristics &#40;on-treatment analysis&#41;&#46;</p> <p id="spar0095" class="elsevierStyleSimplePara elsevierViewall">Events were counted from randomization to drug stop date<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>1 day&#46;</p> <p id="spar0100" class="elsevierStyleSimplePara elsevierViewall">BL&#44; baseline&#59; BMI&#44; body mass index&#59; CI&#44; confidence interval&#59; COPD&#44; chronic obstructive pulmonary disease&#59; GOLD&#44; Global Initiative for Chronic Obstructive Lung Disease&#59; HR&#44; hazard ratio&#59; ICS&#44; inhaled corticosteroid&#59; LABA&#44; long-acting &#946;<span class="elsevierStyleInf">2</span>-agonist&#59; RoW&#44; rest of the world&#46;</p>"
        ]
      ]
      4 => array:7 [
        "identificador" => "fig0025"
        "etiqueta" => "Fig&#46; 5"
        "tipo" => "MULTIMEDIAFIGURA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "figura" => array:1 [
          0 => array:4 [
            "imagen" => "gr5.jpeg"
            "Alto" => 1044
            "Ancho" => 1658
            "Tamanyo" => 153088
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0105" class="elsevierStyleSimplePara elsevierViewall">Time to first severe exacerbation &#40;hospitalization&#41; by region &#40;on-treatment analysis&#41;&#46;</p> <p id="spar0110" class="elsevierStyleSimplePara elsevierViewall">Events were counted from randomization to drug stop date<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>1 day&#46;</p> <p id="spar0115" class="elsevierStyleSimplePara elsevierViewall">COPD&#44; chronic obstructive pulmonary disease&#59; RoW&#44; rest of the world&#46;</p>"
        ]
      ]
      5 => array:7 [
        "identificador" => "fig0030"
        "etiqueta" => "Fig&#46; 6"
        "tipo" => "MULTIMEDIAFIGURA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "figura" => array:1 [
          0 => array:4 [
            "imagen" => "gr6.jpeg"
            "Alto" => 2400
            "Ancho" => 2917
            "Tamanyo" => 460204
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0120" class="elsevierStyleSimplePara elsevierViewall">Time to first severe COPD exacerbation by region adjusted for relevant covariates<span class="elsevierStyleSup">a</span> &#40;on-treatment analysis&#41;&#46;</p> <p id="spar0125" class="elsevierStyleSimplePara elsevierViewall">Events were counted from randomization to drug stop date<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>1 day&#46;</p> <p id="spar0130" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleSup">a</span>Adjusted for age&#44; FEV<span class="elsevierStyleInf">1</span>&#37; predicted&#44; gender&#44; exacerbation history&#44; smoking history &#40;pack-years&#41;&#44; BMI&#44; history of cardiac disorders&#44; myocardial infarction&#44; coronary artery disease&#47;ischaemic heart disease&#44; cardiac arrhythmia&#44; heart failure &#40;class I&#8211;IV&#41;&#44; and stroke&#47;transient ischemic attack&#46; Patients with missing covariates &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>6 for Latin America and <span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>45 for RoW&#41; are excluded&#46;</p> <p id="spar0135" class="elsevierStyleSimplePara elsevierViewall">BL&#44; baseline&#59; BMI&#44; body mass index&#59; CI&#44; confidence interval&#59; COPD&#44; chronic obstructive pulmonary disease&#59; FEV<span class="elsevierStyleInf">1</span>&#44; forced expiratory volume in 1 second&#59; GOLD&#44; Global Initiative for Chronic Obstructive Lung Disease&#59; HR&#44; hazard ratio&#59; ICS&#44; inhaled corticosteroid&#59; LABA&#44; long-acting &#946;<span class="elsevierStyleInf">2</span>-agonist&#59; RoW&#44; rest of the world&#46;</p>"
        ]
      ]
      6 => array:7 [
        "identificador" => "fig0035"
        "etiqueta" => "Fig&#46; 7"
        "tipo" => "MULTIMEDIAFIGURA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "figura" => array:1 [
          0 => array:4 [
            "imagen" => "gr7.jpeg"
            "Alto" => 1013
            "Ancho" => 1611
            "Tamanyo" => 146216
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0140" class="elsevierStyleSimplePara elsevierViewall">Time to first MACE by region &#40;on-treatment analysis&#41;&#46;</p> <p id="spar0145" class="elsevierStyleSimplePara elsevierViewall">Events were counted from randomization to drug stop date<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>30 days&#46;</p> <p id="spar0150" class="elsevierStyleSimplePara elsevierViewall">MACE includes stroke&#44; transient ischaemic attack&#44; MI&#44; sudden death&#44; cardiac death&#44; sudden cardiac death&#44; or fatal event in SOCs for cardiac and vascular disorders&#46;</p> <p id="spar0155" class="elsevierStyleSimplePara elsevierViewall">SOCs were defined according to MedDRA and PT&#46;</p> <p id="spar0160" class="elsevierStyleSimplePara elsevierViewall">MACE&#44; major adverse cardiovascular event&#59; MedDRA&#44; Medical Dictionary for Regulatory Activities&#59; MI&#44; myocardial infarction&#59; PT&#44; preferred term&#59; RoW&#44; rest of the world&#59; SOC&#44; system organ class&#46;</p>"
        ]
      ]
      7 => array:8 [
        "identificador" => "tbl0005"
        "etiqueta" => "Table 1"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "detalles" => array:1 [
          0 => array:3 [
            "identificador" => "at1"
            "detalle" => "Table "
            "rol" => "short"
          ]
        ]
        "tabla" => array:2 [
          "leyenda" => "<p id="spar0170" class="elsevierStyleSimplePara elsevierViewall">Patients with missing baseline characteristics are not shown&#46;</p><p id="spar0175" class="elsevierStyleSimplePara elsevierViewall">Cardiac history was defined as history of MI&#44; CAD&#47;IHD&#44; cardiac arrhythmia&#44; or heart failure&#46; Any CV medication includes &#946;-blockers&#44; calcium channel blockers&#44; cardiac glycosides &#40;digoxin&#41;&#44; angiotensin-converting enzyme inhibitors&#44; angiotensin receptor blockers&#44; nitrates&#44; anti-arrhythmics class I or III &#40;sodium or potassium channel blockers&#41;&#44; adenosine&#44; acetylsalicylic acid&#44; anticoagulants &#40;vitamin K antagonists&#44; direct thrombin inhibitors&#44; and factor Xa inhibitors&#41;&#44; and antiplatelets&#46;</p><p id="spar0180" class="elsevierStyleSimplePara elsevierViewall">BD&#44; bronchodilator&#59; BMI&#44; body mass index&#59; CAD&#44; coronary artery disease&#59; COPD&#44; chronic obstructive pulmonary disease&#59; CV&#44; cardiovascular&#59; FEV<span class="elsevierStyleInf">1</span>&#44; forced expiratory volume in 1 second&#59; GOLD&#44; Global Initiative for Chronic Obstructive Lung Disease&#59; ICS&#44; inhaled corticosteroids&#59; IHD&#44; ischaemic heart disease&#59; LABA&#44; long-acting &#946;<span class="elsevierStyleInf">2</span>-agonist&#59; LAMA&#44; long-acting muscarinic antagonist&#59; MI&#44; myocardial infarction&#59; mMRC&#44; Modified Medical Research Council&#59; RoW&#44; rest of the world&#59; SD&#44; standard deviation&#46;</p>"
          "tablatextoimagen" => array:1 [
            0 => array:2 [
              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Characteristic&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Latin America &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>1000&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">RoW &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>16<span class="elsevierStyleHsp" style=""></span>116&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" 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</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">Male&#44; n &#40;&#37;&#41;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">687 &#40;68&#46;7&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">11<span class="elsevierStyleHsp" style=""></span>550 &#40;71&#46;7&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;0437&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="4" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="3" align="left" valign="top"><span class="elsevierStyleItalic">Age&#44; n &#40;&#37;&#41;</span></td><td class="td" title="table-entry  " rowspan="4" align="left" valign="top"><span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>&#46;0001</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>&#60;60 years&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">225 &#40;22&#46;5&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">4538 &#40;28&#46;2&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>60&#8211;&#60;70 years&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">377 &#40;37&#46;7&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">6325 &#40;39&#46;2&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>&#8805;70 years&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">398 &#40;39&#46;8&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">5253 &#40;32&#46;6&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="4" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="3" align="left" valign="top"><span class="elsevierStyleItalic">BMI&#44; kg&#47;m</span><span class="elsevierStyleSup"><span class="elsevierStyleItalic">2</span></span><span class="elsevierStyleItalic">&#44; n &#40;&#37;&#41;</span></td><td class="td" title="table-entry  " rowspan="5" align="left" valign="top"><span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">&#61;</span><span class="elsevierStyleHsp" style=""></span>&#46;0061</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Underweight&#44; BMI<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>18&#46;5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">60 &#40;6&#46;0&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1038 &#40;6&#46;4&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Normal&#44; 18&#46;5<span class="elsevierStyleHsp" style=""></span>&#8804;<span class="elsevierStyleHsp" style=""></span>BMI<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>25&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">434 &#40;43&#46;4&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">6252 &#40;38&#46;8&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Pre-obese&#44; 25<span class="elsevierStyleHsp" style=""></span>&#8804;<span class="elsevierStyleHsp" style=""></span>BMI<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>30&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">321 &#40;32&#46;1&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">5188 &#40;32&#46;2&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Obese&#44; BMI<span class="elsevierStyleHsp" style=""></span>&#8805;<span class="elsevierStyleHsp" style=""></span>30&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">185 &#40;18&#46;5&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">3638 &#40;22&#46;6&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="4" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">Duration of COPD&#44; years&#44; mean &#40;SD&#41;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">6&#46;9 &#40;5&#46;4&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">7&#46;5 &#40;6&#46;2&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;1064&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">Smoking history&#44; pack-years&#44; mean &#40;SD&#41;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">48&#46;1 &#40;28&#46;6&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">43&#46;5 &#40;24&#46;5&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">&#60;</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">&#46;</span>0001&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">Current smoker&#44; n &#40;&#37;&#41;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">207 &#40;20&#46;7&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">6312 &#40;39&#46;2&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">&#60;</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">&#46;</span>0001&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">Post-BD FEV</span><span class="elsevierStyleInf"><span class="elsevierStyleItalic">1</span></span><span class="elsevierStyleItalic">&#44; l&#44; mean &#40;SD&#41;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1&#46;24 &#40;0&#46;46&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1&#46;35 &#40;0&#46;48&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">&#60;</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">&#46;</span>0001&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">Post-BD FEV</span><span class="elsevierStyleInf"><span class="elsevierStyleItalic">1</span></span><span class="elsevierStyleItalic">&#44; &#37; of predicted value&#44; mean &#40;SD&#41;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">47&#46;0 &#40;14&#46;3&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">48&#46;4 &#40;13&#46;8&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;0021&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="4" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="3" align="left" valign="top"><span class="elsevierStyleItalic">GOLD stage&#44; n &#40;&#37;&#41;</span></td><td class="td" title="table-entry  " rowspan="4" align="left" valign="top"><span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;0020</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>I<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>II&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">465 &#40;46&#46;5&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">7727 &#40;47&#46;9&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>III&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">397 &#40;39&#46;7&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">6449 &#40;40&#46;0&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>IV&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">130 &#40;13&#46;0&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1712 &#40;10&#46;6&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="4" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="3" align="left" valign="top"><span class="elsevierStyleItalic">mMRC scale&#44; n &#40;&#37;&#41;</span></td><td class="td" title="table-entry  " rowspan="4" align="left" valign="top"><span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;0471</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">102 &#40;10&#46;2&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1303 &#40;8&#46;1&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">354 &#40;35&#46;4&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">6020 &#40;37&#46;4&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>&#62;1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">542 &#40;54&#46;2&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">8773 &#40;54&#46;4&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="4" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">History of cardiac disorder&#44; n &#40;&#37;&#41;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">182 &#40;18&#46;2&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">4287 &#40;26&#46;6&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">&#60;</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">&#46;</span>0001&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">History of MI&#44; n &#40;&#37;&#41;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">38 &#40;3&#46;8&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">988 &#40;6&#46;1&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;0026&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">History of CAD&#47;IHD&#44; n &#40;&#37;&#41;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">50 &#40;5&#46;0&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">2544 &#40;15&#46;8&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">&#60;</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">&#46;</span>0001&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">History of cardiac arrhythmia&#44; n &#40;&#37;&#41;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">120 &#40;12&#46;0&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1705 &#40;10&#46;6&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">&#61;</span><span class="elsevierStyleHsp" style=""></span>&#46;1597&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">History of heart failure&#44; class I&#8211;IV&#44; n &#40;&#37;&#41;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">21 &#40;2&#46;1&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1317 &#40;8&#46;2&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">&#60;</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">&#46;</span>0001&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="4" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="3" align="left" valign="top"><span class="elsevierStyleItalic">Number of COPD exacerbations treated in last year&#44; n &#40;&#37;&#41;</span></td><td class="td" title="table-entry  " rowspan="4" align="left" valign="top"><span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>&#46;0001</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">385 &#40;38&#46;5&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">8434 &#40;52&#46;3&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">384 &#40;38&#46;4&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">4492 &#40;27&#46;9&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>&#62;1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">230 &#40;23&#46;0&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">3179 &#40;19&#46;7&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="4" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">Sputum-producing cough &#62;3</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">mo for 2 years&#44; n &#40;&#37;&#41;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">579 &#40;58&#46;0&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">10<span class="elsevierStyleHsp" style=""></span>307 &#40;64&#46;0&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">&#46;</span>0001&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">Any pulmonary medication&#44; n &#40;&#37;&#41;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">927 &#40;92&#46;7&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">14<span class="elsevierStyleHsp" style=""></span>573 &#40;90&#46;4&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;0170&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">LAMA&#44; n &#40;&#37;&#41;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">242 &#40;24&#46;2&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">7781 &#40;48&#46;3&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">&#60;</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">&#46;</span>0001&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="4" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="3" align="left" valign="top"><span class="elsevierStyleItalic">ICS&#44; LABA&#44; or both&#44; n &#40;&#37;&#41;</span></td><td class="td" title="table-entry  " rowspan="5" align="left" valign="top"><span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">&#60;</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">&#46;</span>0001</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>LABA &#40;but not ICS&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">81 &#40;8&#46;1&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1625 &#40;10&#46;1&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>ICS &#40;but not LABA&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">126 &#40;12&#46;6&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1105 &#40;6&#46;9&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>LABA and ICS&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">566 &#40;56&#46;6&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">8306 &#40;51&#46;5&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Neither &#40;ICS nor LABA&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">227 &#40;22&#46;7&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">5080 &#40;31&#46;5&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="4" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">Any CV medication&#44; n &#40;&#37;&#41;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">447 &#40;44&#46;7&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">8306 &#40;51&#46;5&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">&#60;</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">&#46;</span>0001&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
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                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head  " align="" valign="top" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Latin America &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>1000&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">RoW &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>16<span class="elsevierStyleHsp" style=""></span>116&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Latin America vs RoW&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="table-entry  " colspan="4" align="left" valign="top"><span class="elsevierStyleBold">&#40;A&#41; Death</span><a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Patients with deaths&#44; n &#40;&#37;&#41;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">100 &#40;10&#46;0&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1200 &#40;7&#46;4&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Median time to death&#44; days</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>HR &#40;95&#37; CI&#41;&#59; <span class="elsevierStyleItalic">P</span>-value &#40;without additional covariates&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1&#46;52 &#40;1&#46;24&#8211;1&#46;86&#41;&#59;<br><span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>&#46;0001&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>HR &#40;95&#37; CI&#41;&#59; <span class="elsevierStyleItalic">P</span>-value &#40;with additional covariates&#41;<a class="elsevierStyleCrossRef" href="#tblfn0020"><span class="elsevierStyleSup">d</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1&#46;37 &#40;1&#46;11&#8211;1&#46;69&#41;&#59;<br><span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;0031&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="4" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="4" align="left" valign="top"><span class="elsevierStyleBold">&#40;B&#41; Moderate-to-severe exacerbation</span><a class="elsevierStyleCrossRef" href="#tblfn0010"><span class="elsevierStyleSup">b</span></a></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Patients with moderate-to-severe exacerbations&#44; n &#40;&#37;&#41;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">548 &#40;54&#46;8&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">7647 &#40;47&#46;4&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Total number of moderate-to-severe exacerbations&#44; n</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1278&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">17<span class="elsevierStyleHsp" style=""></span>815&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Median time to moderate-to-severe exacerbation&#44; days</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">536&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">779&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>Estimated annual rate&#44; mean &#40;95&#37; CI&#41;&#44; and RR &#40;95&#37; CI&#41;&#59; <span class="elsevierStyleItalic">P</span>-value &#40;without additional covariates&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#46;71 &#40;0&#46;65&#8211;0&#46;78&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#46;57 &#40;0&#46;56&#8211;0&#46;58&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1&#46;25 &#40;1&#46;13&#8211;1&#46;38&#41;&#59;<br><span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>&#46;0001&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>Estimated annual rate&#44; mean &#40;95&#37; CI&#41;&#44; and RR &#40;95&#37; CI&#41;&#59; <span class="elsevierStyleItalic">P</span>-value &#40;with additional covariates&#41;<a class="elsevierStyleCrossRef" href="#tblfn0020"><span class="elsevierStyleSup">d</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#46;59 &#40;0&#46;52&#8211;0&#46;68&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#46;55 &#40;0&#46;50&#8211;0&#46;61&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1&#46;07 &#40;0&#46;97&#8211;1&#46;18&#41;&#59;<br><span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;1650&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>HR &#40;95&#37; CI&#41;&#59; <span class="elsevierStyleItalic">P</span>-value &#40;without additional covariates&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1&#46;29 &#40;1&#46;18&#8211;1&#46;41&#41;&#59;<br><span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>&#46;0001&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>HR &#40;95&#37; CI&#41;&#59; <span class="elsevierStyleItalic">P</span>-value &#40;with additional covariates&#41;<a class="elsevierStyleCrossRef" href="#tblfn0020"><span class="elsevierStyleSup">d</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1&#46;13 &#40;1&#46;03&#8211;1&#46;23&#41;&#59;<br><span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;0081&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="4" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="4" align="left" valign="top"><span class="elsevierStyleBold">&#40;C&#41; Severe exacerbation</span><a class="elsevierStyleCrossRef" href="#tblfn0010"><span class="elsevierStyleSup">b</span></a></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Patients with severe exacerbations&#44; n &#40;&#37;&#41;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">114 &#40;11&#46;4&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2392 &#40;14&#46;8&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Total number of severe exacerbations&#44; n</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">156&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">3660&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Median time to first severe exacerbation&#44; days</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>Estimated annual rate&#44; mean &#40;95&#37; CI&#41;&#44; and RR &#40;95&#37; CI&#41;&#59; <span class="elsevierStyleItalic">P</span>-value &#40;without additional covariates&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#46;09 &#40;0&#46;07&#8211;0&#46;11&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#46;12 &#40;0&#46;12&#8211;0&#46;13&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#46;76 &#40;0&#46;61&#8211;0&#46;94&#41;&#59;<br><span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;0111&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>Estimated annual rate&#59; mean &#40;95&#37; CI&#41;&#44; and RR &#40;95&#37; CI&#41;&#59; <span class="elsevierStyleItalic">P</span>-value &#40;with additional covariates&#41;<a class="elsevierStyleCrossRef" href="#tblfn0020"><span class="elsevierStyleSup">d</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#46;08 &#40;0&#46;06&#8211;0&#46;10&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#46;12 &#40;0&#46;10&#8211;0&#46;15&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#46;62 &#40;0&#46;50&#8211;0&#46;77&#41;&#59;<br><span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>&#46;0001&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>HR &#40;95&#37; CI&#41;&#59; <span class="elsevierStyleItalic">P</span>-value &#40;without additional covariates&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#46;82 &#40;0&#46;68&#8211;0&#46;98&#41;&#59;<br><span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;0333&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>HR &#40;95&#37; CI&#41;&#59; <span class="elsevierStyleItalic">P</span>-value &#40;with additional covariates&#41;<a class="elsevierStyleCrossRef" href="#tblfn0020"><span class="elsevierStyleSup">d</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#46;67 &#40;0&#46;55&#8211;0&#46;81&#41;&#59;<br><span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>&#46;0001&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="4" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="4" align="left" valign="top"><span class="elsevierStyleBold">&#40;D&#41; MACE</span><a class="elsevierStyleCrossRef" href="#tblfn0015"><span class="elsevierStyleSup">c</span></a><span class="elsevierStyleBold">and fatal MACE</span><a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Patients with MACE&#44; n &#40;&#37;&#41;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">35 &#40;3&#46;5&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">613 &#40;3&#46;8&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>HR &#40;95&#37; CI&#41;&#59; <span class="elsevierStyleItalic">P</span>-value &#40;without additional covariates&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#46;99 &#40;0&#46;71&#8211;1&#46;40&#41;&#59;<br><span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;9677&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>HR &#40;95&#37; CI&#41;&#59; <span class="elsevierStyleItalic">P</span>-value &#40;with additional covariates&#41;<a class="elsevierStyleCrossRef" href="#tblfn0020"><span class="elsevierStyleSup">d</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1&#46;01 &#40;0&#46;71&#8211;1&#46;42&#41;&#59;<br><span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">&#61;</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">&#46;9633</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Patients with fatal MACE&#44; n &#40;&#37;&#41;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">24 &#40;2&#46;4&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">308 &#40;1&#46;9&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>HR &#40;95&#37; CI&#41;&#59; <span class="elsevierStyleItalic">P</span>-value &#40;without additional covariates&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1&#46;41 &#40;0&#46;93&#8211;2&#46;13&#41;&#59;<br><span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;1082&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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            0 => array:3 [
              "identificador" => "tblfn0005"
              "etiqueta" => "a"
              "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Vital status analysis &#40;data were included if the death occurred up until the end of the study&#41;&#46;</p>"
            ]
            1 => array:3 [
              "identificador" => "tblfn0010"
              "etiqueta" => "b"
              "nota" => "<p class="elsevierStyleNotepara" id="npar0010">On-treatment analysis &#40;events were counted from randomization to drug stop date<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>1 day&#41;&#46;</p>"
            ]
            2 => array:3 [
              "identificador" => "tblfn0015"
              "etiqueta" => "c"
              "nota" => "<p class="elsevierStyleNotepara" id="npar0015">On-treatment analysis &#40;from randomization to drug stop date<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>30 days&#41;&#46;</p>"
            ]
            3 => array:3 [
              "identificador" => "tblfn0020"
              "etiqueta" => "d"
              "nota" => "<p class="elsevierStyleNotepara" id="npar0020">Adjusted for age&#44; FEV<span class="elsevierStyleInf">1</span>&#37; predicted&#44; gender&#44; exacerbation history&#44; smoking history &#40;pack-years&#41;&#44; body mass index&#44; and history of cardiac disorders&#44; myocardial infarction&#44; coronary artery disease&#47;ischaemic heart disease&#44; cardiac arrhythmia&#44; heart failure &#40;class I&#8211;IV&#41;&#44; and stroke&#47;transient ischemic attack&#46; Patients with missing covariates &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>6 for Latin America and <span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>45 for RoW&#41; are excluded&#46;</p> <p class="elsevierStyleNotepara" id="npar0025">CI&#44; confidence interval&#59; COPD&#44; chronic obstructive pulmonary disease&#59; FEV<span class="elsevierStyleInf">1</span>&#44; forced expiratory volume in 1 second&#59; HR&#44; hazard ratio&#59; MACE&#44; major adverse cardiovascular events&#59; RoW&#44; rest of the world&#59; RR&#44; rate ratio&#46;</p>"
            ]
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0185" class="elsevierStyleSimplePara elsevierViewall">Number of&#44; and time to&#58; &#40;A&#41; deaths&#44;<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a> &#40;B&#41; moderate-to-severe exacerbations&#44;<a class="elsevierStyleCrossRef" href="#tblfn0010"><span class="elsevierStyleSup">b</span></a> &#40;C&#41; severe &#40;hospitalized&#41; exacerbations&#44;<a class="elsevierStyleCrossRef" href="#tblfn0010"><span class="elsevierStyleSup">b</span></a> and &#40;D&#41; MACE<a class="elsevierStyleCrossRef" href="#tblfn0015"><span class="elsevierStyleSup">c</span></a> and fatal MACE<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a> by region&#46;</p>"
        ]
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        "etiqueta" => "Table 3"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
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        "tabla" => array:2 [
          "leyenda" => "<p id="spar0200" class="elsevierStyleSimplePara elsevierViewall">CI&#44; confidence interval&#59; COPD&#44; chronic obstructive pulmonary disease&#59; IRR&#44; incidence rate ratio&#59; RoW&#44; rest of the world&#46;</p>"
          "tablatextoimagen" => array:1 [
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                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black"><span class="elsevierStyleItalic">n</span> &#40;incidence rate&#47;100 patient-years&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Latin America &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>1000&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">RoW &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>16<span class="elsevierStyleHsp" style=""></span>116&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Latin America vs RoW IRR &#40;95&#37; CI&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleBold">Patients with death due to any cause</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">100 &#40;4&#46;8&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1200 &#40;3&#46;2&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1&#46;49 &#40;1&#46;21&#8211;1&#46;82&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="4" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="4" align="left" valign="top"><span class="elsevierStyleBold">Adjudicated causes of death</span></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Cardiac disorders</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">5 &#40;0&#46;2&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">61 &#40;0&#46;2&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1&#46;46 &#40;0&#46;59&#8211;3&#46;64&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Gastrointestinal disorders</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">5 &#40;0&#46;2&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">27 &#40;0&#46;1&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">3&#46;30 &#40;1&#46;27&#8211;8&#46;58&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">General disorders and administration site conditions</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">25 &#40;1&#46;2&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">294 &#40;0&#46;8&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1&#46;52 &#40;1&#46;01&#8211;2&#46;28&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>Death&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">9 &#40;0&#46;4&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">90 &#40;0&#46;2&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1&#46;78 &#40;0&#46;90&#8211;3&#46;54&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>Sudden cardiac death&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">9 &#40;0&#46;4&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">79 &#40;0&#46;2&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">2&#46;03 &#40;1&#46;02&#8211;4&#46;05&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>Sudden death&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">7 &#40;0&#46;3&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">121 &#40;0&#46;3&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1&#46;03 &#40;0&#46;48&#8211;2&#46;21&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Hepatobiliary disorders</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1 &#40;0&#46;0&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">5 &#40;0&#46;0&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">3&#46;57 &#40;0&#46;42&#8211;30&#46;53&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Infections and infestations</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">12 &#40;0&#46;6&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">90 &#40;0&#46;2&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">2&#46;38 &#40;1&#46;30&#8211;4&#46;34&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Injury&#44; poisoning&#44; and procedural complications</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1 &#40;0&#46;0&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">37 &#40;0&#46;1&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;48 &#40;0&#46;07&#8211;3&#46;51&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Neoplasms&#58; benign&#44; malignant&#44; and unspecified</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">17 &#40;0&#46;8&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">287 &#40;0&#46;8&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1&#46;06 &#40;0&#46;65&#8211;1&#46;72&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Nervous system disorders</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">3 &#40;0&#46;1&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">39 &#40;0&#46;1&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1&#46;37 &#40;0&#46;42&#8211;4&#46;44&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Psychiatric disorders</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1 &#40;0&#46;0&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">6 &#40;0&#46;0&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">2&#46;97 &#40;0&#46;36&#8211;24&#46;69&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Respiratory&#44; thoracic&#44; and mediastinal disorders</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">29 &#40;1&#46;4&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">340 &#40;0&#46;9&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1&#46;52 &#40;1&#46;04&#8211;2&#46;22&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>COPD&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">27 &#40;1&#46;3&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">315 &#40;0&#46;8&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1&#46;53 &#40;1&#46;03&#8211;2&#46;26&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Vascular disorders</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1 &#40;0&#46;0&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">12 &#40;0&#46;0&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1&#46;49 &#40;0&#46;19&#8211;11&#46;43&#41;&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="spar0195" class="elsevierStyleSimplePara elsevierViewall">Adjudicated causes of death by region &#40;vital status analysis&#41;&#46;</p>"
        ]
      ]
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        "tipo" => "MULTIMEDIAECOMPONENTE"
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        "mostrarDisplay" => true
        "Ecomponente" => array:2 [
          "fichero" => "mmc1.docx"
          "ficheroTamanyo" => 14094
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    "bibliografia" => array:2 [
      "titulo" => "References"
      "seccion" => array:1 [
        0 => array:2 [
          "identificador" => "bibs0015"
          "bibliografiaReferencia" => array:28 [
            0 => array:3 [
              "identificador" => "bib0145"
              "etiqueta" => "1"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Worldwide burden of COPD in high- and low-income countries&#46; Part II&#46; Burden of chronic obstructive lung disease in Latin America&#58; the PLATINO study"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "A&#46;M&#46; Menezes"
                            1 => "R&#46; Perez-Padilla"
                            2 => "P&#46;C&#46; Hallal"
                            3 => "J&#46;R&#46; Jardim"
                            4 => "A&#46; Muino"
                            5 => "M&#46;V&#46; Lopez"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:7 [
                        "tituloSerie" => "Int J Tuberc Lung Dis"
                        "fecha" => "2008"
                        "volumen" => "12"
                        "numero" => "Suppl&#46; 7"
                        "paginaInicial" => "709"
                        "paginaFinal" => "712"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/18544192"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            1 => array:3 [
              "identificador" => "bib0150"
              "etiqueta" => "2"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Global burden of COPD&#58; systematic review and meta-analysis"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:6 [
                            0 => "R&#46;J&#46; Halbert"
                            1 => "J&#46;L&#46; Natoli"
                            2 => "A&#46; Gano"
                            3 => "E&#46; Badamgarav"
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Original Article
Demographic Characteristics and Clinical Outcomes in Patients from Latin America Versus the Rest of the World: A TIOSPIR® Post-Hoc Analysis
Características demográficas y resultados clínicos en pacientes de Latinoamérica respecto al resto del mundo: un análisis post-hoc de TIOSPIR®
Antonio Anzuetoa,
Corresponding author
anzueto@uthscsa.edu

Corresponding author.
, Peter M.A. Calverleyb, Achim Muellerc, Norbert Metzdorfd, Michaela Haenseld, José R. Jardime, Emilio Pizzichinif, Horacio Giraldog, Alejandra Ramirez-Venegash, Eduardo R. Giugnoi
a Pulmonary/Critical Care, University of Texas and South Texas Veterans Health Care System, San Antonio, TX, USA
b Clinical Science Centre, Institute of Ageing and Chronic Disease, University of Liverpool, Liverpool, UK
c Biostatistics and Data Sciences Europe, Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach an der Riss, Germany
d Respiratory Medicine, Boehringer Ingelheim Pharma GmbH & Co. KG, Ingelheim am Rhein, Germany
e Respiratory Division, Federal University of São Paulo, São Paulo, Brazil
f The Federal University of Santa Catarina, Florianópolis, Brazil
g Almirante Colón Medical Center, Clínica del Country, Bogotá, Colombia
h Tobacco Smoking and COPD Research Department, National Institute of Respiratory Diseases, Mexico City, Mexico
i Hospital Zonal Especializado de Agudos y Crónicos “Dr. Antonio Cetrángolo”, Buenos Aires, Argentina
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    "titulo" => "Demographic Characteristics and Clinical Outcomes in Patients from Latin America Versus the Rest of the World&#58; A TIOSPIR<span class="elsevierStyleSup">&#174;</span> Post-Hoc Analysis"
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          "en" => "<p id="spar0090" class="elsevierStyleSimplePara elsevierViewall">Time to first moderate-to-severe COPD exacerbation by region and according to baseline characteristics &#40;on-treatment analysis&#41;&#46;</p> <p id="spar0095" class="elsevierStyleSimplePara elsevierViewall">Events were counted from randomization to drug stop date<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>1 day&#46;</p> <p id="spar0100" class="elsevierStyleSimplePara elsevierViewall">BL&#44; baseline&#59; BMI&#44; body mass index&#59; CI&#44; confidence interval&#59; COPD&#44; chronic obstructive pulmonary disease&#59; GOLD&#44; Global Initiative for Chronic Obstructive Lung Disease&#59; HR&#44; hazard ratio&#59; ICS&#44; inhaled corticosteroid&#59; LABA&#44; long-acting &#946;<span class="elsevierStyleInf">2</span>-agonist&#59; RoW&#44; rest of the world&#46;</p>"
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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">Chronic obstructive pulmonary disease &#40;COPD&#41; represents an enormous health burden worldwide&#46; Its prevalence is relatively high in Latin America&#44; affecting an estimated 14&#46;3&#37;<a class="elsevierStyleCrossRef" href="#bib0145"><span class="elsevierStyleSup">1</span></a> of the population versus 9&#46;2&#37;<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">2</span></a> in the rest of the world &#40;RoW&#41;&#46; A substantial proportion of Latin American patients had experienced an exacerbation &#40;18&#46;2&#37;&#41;&#44;<a class="elsevierStyleCrossRef" href="#bib0155"><span class="elsevierStyleSup">3</span></a> and respiratory causes&#44; including COPD&#44; are amongst the leading cause of mortality in this region&#46;<a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">4</span></a> Smoking is a behaviour that is seemingly ingrained in Latin American culture&#44;<a class="elsevierStyleCrossRef" href="#bib0165"><span class="elsevierStyleSup">5</span></a> with smokers from Latin America constituting 8&#37;&#8211;10&#37; of tobacco smokers globally&#46;<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">6</span></a> Solid fuels are used by 30&#37;&#8211;75&#37; of households<a class="elsevierStyleCrossRef" href="#bib0175"><span class="elsevierStyleSup">7</span></a> &#40;traditionally in rural areas<a class="elsevierStyleCrossRef" href="#bib0180"><span class="elsevierStyleSup">8</span></a>&#41; and contribute to mortality rates similar to those observed in tobacco smokers&#46;<a class="elsevierStyleCrossRef" href="#bib0185"><span class="elsevierStyleSup">9</span></a> Management guidelines for COPD recognize that curbing the smoking epidemic<a class="elsevierStyleCrossRefs" href="#bib0190"><span class="elsevierStyleSup">10&#44;11</span></a> and reducing exposure to pollutants<a class="elsevierStyleCrossRef" href="#bib0190"><span class="elsevierStyleSup">10</span></a> are necessary to lower COPD risk in developing countries&#44; but do not detail regional differences in risk&#44; outcomes&#44; or treatment options&#46;</p><p id="par0010" class="elsevierStylePara elsevierViewall">The TIOtropium Safety and Performance In Respimat<span class="elsevierStyleSup">&#174;</span> &#40;TIOSPIR<span class="elsevierStyleSup">&#174;</span>&#41; study demonstrated similar efficacy and safety profiles between tiotropium Respimat<span class="elsevierStyleSup">&#174;</span> &#40;2&#46;5 or 5<span class="elsevierStyleHsp" style=""></span>&#956;g&#41; and tiotropium HandiHaler<span class="elsevierStyleSup">&#174;</span> 18<span class="elsevierStyleHsp" style=""></span>&#956;g&#44; with respect to risk of mortality and risk of exacerbation&#46;<a class="elsevierStyleCrossRef" href="#bib0200"><span class="elsevierStyleSup">12</span></a> A recent TIOSPIR<span class="elsevierStyleSup">&#174;</span> subanalysis demonstrated similar mortality rates in Asian patients versus RoW&#46; Although exacerbation rates were lower in Asia&#44; a higher proportion of patients had severe exacerbations than in RoW&#46;<a class="elsevierStyleCrossRef" href="#bib0205"><span class="elsevierStyleSup">13</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">The purpose of this post-hoc analysis was to determine whether there are differences in the baseline characteristics&#44; mortality&#44; exacerbations&#44; cardiac adverse event&#44; and serious adverse event &#40;SAE&#41; outcomes of patients from Latin American geographical region versus RoW in the TIOSPIR<span class="elsevierStyleSup">&#174;</span> trial&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Methods</span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Study design</span><p id="par0020" class="elsevierStylePara elsevierViewall">TIOSPIR<span class="elsevierStyleSup">&#174;</span> &#40;<a id="intr0005" class="elsevierStyleInterRef" href="https://clinicaltrials.gov/NCT01126437">NCT01126437</a>&#41; was a large &#40;<span class="elsevierStyleItalic">N</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>17<span class="elsevierStyleHsp" style=""></span>135&#41;&#44; long-term &#40;2&#8211;3-year&#41;&#44; randomized&#44; double-blind&#44; parallel-group&#44; double-dummy&#44; event-driven trial in patients with COPD comparing the safety and efficacy of once-daily tiotropium &#40;SPIRIVA<span class="elsevierStyleSup">&#174;</span> &#91;Boehringer Ingelheim&#44; Ingelheim am Rhein&#44; Germany&#93;&#41; via Respimat<span class="elsevierStyleSup">&#174;</span> 5<span class="elsevierStyleHsp" style=""></span>&#956;g &#40;2 inhalations of 2&#46;5<span class="elsevierStyleHsp" style=""></span>&#956;g&#41;&#44; and 2&#46;5<span class="elsevierStyleHsp" style=""></span>&#956;g &#40;2 inhalations of 1&#46;25<span class="elsevierStyleHsp" style=""></span>&#956;g&#41;&#44; or via HandiHaler<span class="elsevierStyleSup">&#174;</span> 18<span class="elsevierStyleHsp" style=""></span>&#956;g&#59; 17<span class="elsevierStyleHsp" style=""></span>116 patients constituted the as-treated population and were included in this analysis&#46; The study design&#44; detailed methods&#44; and primary results were published previously&#46;<a class="elsevierStyleCrossRefs" href="#bib0200"><span class="elsevierStyleSup">12&#44;14</span></a></p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Study population</span><p id="par0025" class="elsevierStylePara elsevierViewall">All participants had a confirmed diagnosis of COPD &#40;forced expiratory volume in 1 second &#91;FEV<span class="elsevierStyleInf">1</span>&#93; &#8804;70&#37; predicted and FEV<span class="elsevierStyleInf">1</span>&#47;forced vital capacity &#8804;0&#46;70&#41;&#44; were aged &#8805;40 years&#44; and had &#8805;10 pack-years of smoking history&#46;<a class="elsevierStyleCrossRef" href="#bib0210"><span class="elsevierStyleSup">14</span></a> Patients with concomitant cardiac diseases were included in the study&#44; except those with recent &#40;&#8804;6 months&#41; myocardial infarction &#40;MI&#41;&#44; severe arrhythmia&#44; or a change in drug therapy within the previous year&#59; or hospitalization for cardiac failure within the previous year&#46;<a class="elsevierStyleCrossRef" href="#bib0210"><span class="elsevierStyleSup">14</span></a> All usual background treatments for COPD&#44; except other inhaled anticholinergics&#44; were allowed&#46;<a class="elsevierStyleCrossRef" href="#bib0210"><span class="elsevierStyleSup">14</span></a></p><p id="par0030" class="elsevierStylePara elsevierViewall">The geographical region of Latin America enrolled patients in Argentina&#44; Brazil&#44; Colombia&#44; Guatemala&#44; Mexico&#44; Panama&#44; and Peru&#46;</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Outcome measures</span><p id="par0035" class="elsevierStylePara elsevierViewall">Outcomes of interest in this analysis were time to all-cause death&#44; time to first moderate-to-severe or severe exacerbation&#44; time to major adverse cardiovascular events &#40;MACE&#41; and fatal MACE&#44; and SAEs for patients in Latin America versus RoW&#46;</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Assessments</span><p id="par0040" class="elsevierStylePara elsevierViewall">An independent mortality adjudication committee&#44; blinded to treatment assignments attributed the cause of each death&#46;<a class="elsevierStyleCrossRef" href="#bib0210"><span class="elsevierStyleSup">14</span></a> Non-fatal stroke and MI &#40;included in MACE&#41; were reported by study investigators and verified for classification accuracy by central reviewers who were blinded to treatment assignment&#46;</p><p id="par0045" class="elsevierStylePara elsevierViewall">Exacerbations were defined as the worsening of &#8805;2 major respiratory symptoms &#40;dyspnoea&#44; cough&#44; sputum&#44; chest tightness&#44; or wheezing&#41; for &#8805;3 days and requiring specified treatment changes&#46; Moderate-to-severe exacerbations required a prescription for antibiotics&#44; systemic corticosteroids&#44; or both &#40;with no hospitalization&#41;&#59; severe exacerbations required hospitalization&#46; The onset of exacerbation was defined as the onset of the first recorded symptom&#59; the end of exacerbation was decided by the investigator&#44; based on clinical judgment&#46;</p><p id="par0050" class="elsevierStylePara elsevierViewall">A composite endpoint of MACE was included in the analyses&#44; comprising stroke&#44; transient ischaemic attack &#40;TIA&#41;&#44; MI&#44; sudden death&#44; cardiac death&#44; sudden cardiac death&#44; or fatal event in the system organ classes &#40;SOCs&#41; for cardiac and vascular disorders&#46; SOCs were defined according to the Medical Dictionary for Regulatory Activities standardizing attributions of AEs globally&#46;</p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Statistical analysis</span><p id="par0055" class="elsevierStylePara elsevierViewall">Based on similar efficacy and safety results among the tiotropium treatment arms in the primary analysis&#44;<a class="elsevierStyleCrossRef" href="#bib0200"><span class="elsevierStyleSup">12</span></a> data were pooled for this post-hoc exploratory analysis&#46;</p><p id="par0060" class="elsevierStylePara elsevierViewall">Baseline characteristics discriminating between patients in Latin America and RoW were identified and compared descriptively&#46;</p><p id="par0065" class="elsevierStylePara elsevierViewall">Hazard ratios &#40;HRs&#41; and 95&#37; confidence intervals &#40;CIs&#41; for time to events by region were calculated using a Cox proportional hazards regression model without covariate adjustment&#44; and displayed via Kaplan&#8211;Meier plots&#46; A negative binomial regression model was used to estimate the number of exacerbations&#46; HRs for time to death and time to moderate-to-severe exacerbation analyses&#44; by region and baseline characteristics&#44; are shown as forest plots&#46; Additional analyses of time to death and moderate-to-severe exacerbation&#44; severe exacerbations&#44; and MACE were adjusted for covariates including age&#44; post-bronchodilator FEV<span class="elsevierStyleInf">1</span>&#37; predicted&#44; gender&#44; exacerbation history&#44; smoking history &#40;pack-years&#41;&#44; body mass index &#40;BMI&#41;&#44; and history of cardiac disorders&#44; MI&#44; coronary artery disease&#47;ischaemic heart disease &#40;CAD&#47;IHD&#41;&#44; cardiac arrhythmia&#44; heart failure &#40;class I&#8211;IV&#41;&#44; and stroke&#47;TIA&#46;</p><p id="par0070" class="elsevierStylePara elsevierViewall">Incidence rates&#44; incidence rate ratios &#40;IRRs&#41;&#44; and 95&#37; CIs for causes of death were calculated&#46; SAEs are provided in the Supplementary Material&#46;</p><p id="par0075" class="elsevierStylePara elsevierViewall">For the mortality analysis &#40;vital status&#41;&#44; data were included if death occurred up until the study end date&#44; irrespective of treatment discontinuation&#46; For the exacerbation analysis &#40;on-treatment&#41;&#44; events were counted from randomization to drug stop date<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>1 day&#44; and for MACE to drug stop date<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>30 days&#46;</p></span></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Results</span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">Study population</span><p id="par0080" class="elsevierStylePara elsevierViewall">Of the TIOSPIR<span class="elsevierStyleSup">&#174;</span> population&#44; 1000 patients from Latin America and 16<span class="elsevierStyleHsp" style=""></span>116 patients from RoW were included &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#46; Total exposure to tiotropium was 1855 and 32<span class="elsevierStyleHsp" style=""></span>229 patient-years for Latin America and RoW&#44; respectively&#46; A total of 228 &#40;22&#46;8&#37;&#41; patients from Latin America and 3689 &#40;22&#46;9&#37;&#41; patients from RoW discontinued prematurely from trial medication&#46; Reasons for premature discontinuation were similar&#44; and mainly due to AEs&#44; with respiratory disorders &#40;including COPD&#41; being the most common AEs&#44; followed by neoplasms&#44; and infections and infestations&#46;<a class="elsevierStyleCrossRef" href="#bib0200"><span class="elsevierStyleSup">12</span></a> Vital status follow-up was complete for 99&#46;1&#37; and 99&#46;8&#37; of patients from Latin America and RoW&#44; respectively&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0110">Baseline characteristics</span><p id="par0085" class="elsevierStylePara elsevierViewall">At baseline&#44; patients enrolled in Latin America were comparatively older &#40;higher proportion of patients aged &#8805;70 years&#41;&#44; and had higher mean pack-years of smoking history than those in RoW&#44; although a lower percentage were current smokers &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#46; A higher proportion of patients in Latin America had COPD exacerbation in the year prior to the trial than those in RoW&#46; Latin American patients were more likely to have very severe COPD &#40;Global Initiative for Chronic Obstructive Lung Disease &#91;GOLD&#93; Stage IV&#41; versus RoW &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#46; Fewer Latin American patients had a history of cardiac disorders&#44; or were receiving cardiovascular medication at baseline versus RoW &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#46; The proportions of patients receiving long-acting muscarinic antagonist &#40;LAMA&#41; or long-acting &#946;<span class="elsevierStyleInf">2</span>-agonist &#40;LABA&#41; at baseline were lower in Latin America than in RoW&#59; however&#44; they were more likely to receive inhaled corticosteroids &#40;ICS&#41; &#40;with or without LABA&#41; &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#46;</p></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0115">Mortality</span><p id="par0090" class="elsevierStylePara elsevierViewall">During the study&#44; a greater proportion of patients died in the Latin American population &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>100 &#91;10&#46;0&#37;&#93;&#41; versus RoW &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>1200 &#91;7&#46;4&#37;&#93;&#41; &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>A&#41;&#46; Analysis of time to death confirmed that patients in Latin America had a higher risk of death than those in RoW &#40;HR &#91;95&#37; CI&#93;&#58; 1&#46;52 &#91;1&#46;24&#8211;1&#46;86&#93;&#41; &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>A&#59; <a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41;&#46; This was also true when the analysis of time to death was adjusted for age&#44; gender&#44; FEV<span class="elsevierStyleInf">1</span>&#37; predicted&#44; exacerbation history&#44; smoking history &#40;pack-years&#41;&#44; BMI&#44; history of cardiac disorders&#44; MI&#44; CAD&#47;IHD&#44; cardiac arrhythmia&#44; heart failure &#40;class I&#8211;IV&#41;&#44; and stroke&#47;TIA &#40;HR &#91;95&#37; CI&#93;&#58; 1&#46;37 &#91;1&#46;11&#8211;1&#46;69&#93;&#41; &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>A&#41;&#46;</p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0095" class="elsevierStylePara elsevierViewall">While the overall risk of death was increased in patients from Latin America versus RoW&#44; regression analysis according to baseline characteristics showed that the risk of death was similar for Latin America and RoW in patients with BMI &#8805;30<span class="elsevierStyleHsp" style=""></span>kg&#47;m<span class="elsevierStyleSup">2</span> &#40;HR &#91;95&#37; CI&#93;&#58; 1&#46;07 &#91;0&#46;58&#8211;1&#46;96&#93;&#41;&#44; and patients with cardiac arrhythmia &#40;HR &#91;95&#37; CI&#93;&#58; 1&#46;06 &#91;0&#46;62&#8211;1&#46;82&#93;&#41; &#40;<a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>&#41;&#46; The largest HRs were observed in patients with GOLD Stage IV &#40;HR &#91;95&#37; CI&#93;&#58; 1&#46;87 &#91;1&#46;26&#8211;2&#46;77&#93;&#41; and in those who received LABA &#40;but no ICS&#41; &#40;HR &#91;95&#37; CI&#93;&#58; 1&#46;94 &#91;1&#46;05&#8211;3&#46;60&#93;&#41; &#40;<a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>&#41;&#44; however the LABA &#40;no ICS&#41; result is based on small patient number&#46; Causes of death were mainly similar between the regions&#44; except for respiratory&#44; thoracic&#44; and mediastinal disorders&#44; including COPD&#44; gastrointestinal disorders&#44; general disorders including death due to unknown reason &#40;sudden cardiac death and death&#41;&#44; and infections and infestations&#44; where the incidence rate was higher in the Latin American region versus RoW&#46; General disorders&#44; neoplasms&#44; and respiratory disorders&#44; including COPD&#44; contributed the majority of deaths &#40;<a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>&#41;&#46;</p><elsevierMultimedia ident="fig0010"></elsevierMultimedia><elsevierMultimedia ident="tbl0015"></elsevierMultimedia></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0120">COPD exacerbations</span><p id="par0100" class="elsevierStylePara elsevierVi