Original Article
Chronic Use of Theophylline and Mortality in Chronic Obstructive Pulmonary Disease: A Meta-analysis
Uso crónico de teofilina y mortalidad en la enfermedad pulmonar obstructiva crónica: un metaanálisis
Nobuyuki Horitaa,b,
, Naoki Miyazawaa,b, Ryota Kojimaa,b, Miyo Inouea,b, Yoshiaki Ishigatsuboa, Takeshi Kanekoa,c
Corresponding author
a Department of Internal Medicine and Clinical Immunology, Yokohama City University Graduate School of Medicine, Yokohama, Japan
b Department of Respiratory Medicine, Saiseikai Yokohamashi Nanbu Hospital, Yokohama, Japan
c Respiratory Disease Center, Yokohama City University Medical Center, Yokohama, Japan
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class="elsevierStyleSup">c</span>" "identificador" => "aff0015" ] ] ] ] "afiliaciones" => array:3 [ 0 => array:3 [ "entidad" => "Department of Internal Medicine and Clinical Immunology, Yokohama City University Graduate School of Medicine, Yokohama, Japan" "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "Department of Respiratory Medicine, Saiseikai Yokohamashi Nanbu Hospital, Yokohama, Japan" "etiqueta" => "b" "identificador" => "aff0010" ] 2 => array:3 [ "entidad" => "Respiratory Disease Center, Yokohama City University Medical Center, Yokohama, Japan" "etiqueta" => "c" "identificador" => "aff0015" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Uso crónico de teofilina y mortalidad en la enfermedad pulmonar obstructiva crónica: un metaanálisis" ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0010" "etiqueta" => "Fig. 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 752 "Ancho" => 2917 "Tamanyo" => 194718 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">Forest plot evaluating hazard ratio (HR) for all-cause death by theophylline administration.</p>" ] ] ] "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 (COPD), now the fourth leading cause of death worldwide, is a systemic disease characterized by chronic airflow limitation.<a class="elsevierStyleCrossRef" href="#bib0195"><span class="elsevierStyleSup">1</span></a> As such, bronchodilator medications, namely theophylline, long-acting muscarinic antagonists (LAMA), and long-acting beta-agonists (LABA), are understandably used as key medications for treating stable COPD patients.<a class="elsevierStyleCrossRef" href="#bib0195"><span class="elsevierStyleSup">1</span></a> Among these 3 subclasses of bronchodilators, LAMAs and LABAs have repeatedly been reported as safe and effective in randomized controlled trials (RCT) and large observational studies.<a class="elsevierStyleCrossRefs" href="#bib0195"><span class="elsevierStyleSup">1–7</span></a> LAMAs and LABAs are, therefore, now regarded as first-line medications for stable COPD.<a class="elsevierStyleCrossRef" href="#bib0195"><span class="elsevierStyleSup">1</span></a> The efficacy of theophylline, meanwhile, has been shown in many observational studies and relatively small RCTs.<a class="elsevierStyleCrossRefs" href="#bib0230"><span class="elsevierStyleSup">8–18</span></a> These studies generally indicated that theophylline improves values in respiratory function tests and arterial blood gas analyses, but that it may negatively affect the risk of exacerbation and side effects.<a class="elsevierStyleCrossRefs" href="#bib0230"><span class="elsevierStyleSup">8–18</span></a> Even though clinicians are usually interested in patient survival, death was not used as the main outcome. Other surrogate outcomes such as oxygenation or respiratory function were used instead, because an insufficient number of deaths was observed during the follow-up period. However, these surrogate markers do not always reflect the mortality of respiratory disease with airflow obstruction. For example, short-acting beta-agonists improve airflow obstruction, dyspnea, and quality of life in bronchial asthma patients, but regular use of these agents increases the number of deaths from bronchial asthma.<a class="elsevierStyleCrossRefs" href="#bib0285"><span class="elsevierStyleSup">19,20</span></a> Accordingly, the impact of theophylline on mortality in COPD patients is still an important research question.</p><p id="par0010" class="elsevierStylePara elsevierViewall">Some observational studies have investigated the impact of theophylline treatment on mortality in COPD patients.<a class="elsevierStyleCrossRefs" href="#bib0295"><span class="elsevierStyleSup">21–26</span></a> However, the results of these studies varies widely. The association between theophylline and mortality risk is still an important matter for all clinicians, as theophylline is a common bronchodilator that has been used for decades.<a class="elsevierStyleCrossRefs" href="#bib0195"><span class="elsevierStyleSup">1,27</span></a> The aim of this systematic review and meta-analysis, then, was to evaluate the impact of theophylline on all-cause death in COPD patients.</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 Search Criteria</span><p id="par0015" class="elsevierStylePara elsevierViewall">Requirements for institutional review board approval and informed consent were waived for this study because of the anonymous nature of the data and the fact that it was a review study.</p><p id="par0020" class="elsevierStylePara elsevierViewall">The eligibility criterion for the meta-analysis was an original research article that provided a hazard ratio (HR) for theophylline for all-cause death in COPD patients. Both RCTs and observational studies were accepted. For observational studies, adjusted HR was preferred to non-adjusted HR. Follow-up duration had to be >6 months. Duplicate use of the same data was excluded.</p><p id="par0025" class="elsevierStylePara elsevierViewall">Two investigators independently searched for eligible articles using the MEDLINE, Web of Science, EMBASE, and Cochrane Databases as of January 2014. The search formula for MEDLINE was ((“COPD”[title] OR “chronic obstructive pulmonary disease”[title] OR “chronic obstructive airway disease”[title] OR “emphysema”[title] OR “chronic bronchitis”[title] OR “chronic airflow obstruction”[title]) OR ((“COPD” OR “chronic obstructive pulmonary disease” OR “chronic obstructive airway disease” OR “emphysema” OR “chronic bronchitis” OR “chronic airflow obstruction”) and (“theophylline” OR “xanthine” OR “theophyllines” OR “xanthines” OR “aminophylline” OR “diprophylline” OR “proxyphylline” OR “diprophylline”))) and (“mortality” OR “prognosis” OR “death” OR “mortalities” OR “prognoses” OR “deaths”) and (“hazard ratio” OR “HR” OR “hazard ratios”).</p><p id="par0030" class="elsevierStylePara elsevierViewall">The quality of eligible studies was evaluated using a scale comprising 4 subscales with a maximum of 2 points for each subscale.<a class="elsevierStyleCrossRef" href="#bib0330"><span class="elsevierStyleSup">28</span></a> The subscales were cohort entry, exposure definition, outcome, and cofounding assessment. The scores ranged from 0 to 8, where a higher score signified better quality<a class="elsevierStyleCrossRef" href="#bib0330"><span class="elsevierStyleSup">28</span></a></p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Statistics</span><p id="par0035" class="elsevierStylePara elsevierViewall">We extracted HR for all-cause mortality in each study. HR and its 95% confidence interval [95% confidence interval (CI)] had to be clearly demonstrated in a text, a table, or a figure in each original study. Additionally, data for number of patients, concomitant administration of beta-stimulants and anti-cholinergic agents, and covariables adjusted for the Cox model were extracted.</p><p id="par0040" class="elsevierStylePara elsevierViewall">The fixed-model method with generic inverse variance was used for meta-analysis to estimate pooled value, after no significant heterogeneity was confirmed (<span class="elsevierStyleItalic">I</span><span class="elsevierStyleSup">2</span><50%).<a class="elsevierStyleCrossRefs" href="#bib0335"><span class="elsevierStyleSup">29–31</span></a> Heterogeneity among the original studies was evaluated with (i) the Chi-square distribution test with a rejection region of <span class="elsevierStyleItalic">P</span>=.1, and (ii) the <span class="elsevierStyleItalic">I</span><span class="elsevierStyleSup">2</span> statistics test whereby <span class="elsevierStyleItalic">I</span><span class="elsevierStyleSup">2</span>=0% indicates no heterogeneity, <span class="elsevierStyleItalic">I</span><span class="elsevierStyleSup">2</span>=25% indicates mild heterogeneity, <span class="elsevierStyleItalic">I</span><span class="elsevierStyleSup">2</span>=50% indicates moderate heterogeneity, <span class="elsevierStyleItalic">I</span><span class="elsevierStyleSup">2</span>=75% indicates strong heterogeneity.<a class="elsevierStyleCrossRefs" href="#bib0340"><span class="elsevierStyleSup">30,31</span></a> Publication bias was evaluated with a funnel plot, and with Begg's test using the Spearman's rank correlation test with a rejection region of <span class="elsevierStyleItalic">P</span>=.1.<a class="elsevierStyleCrossRef" href="#bib0350"><span class="elsevierStyleSup">32</span></a> All analyses were performed using Excel Toukei 2012 (SSRI, Tokyo. Japan), and Review Manager version 5.3 (Cochrane Collaboration, Oxford, UK).</p></span></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Results</span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Study Search Results</span><p id="par0045" class="elsevierStylePara elsevierViewall">We screened 364 potentially eligible articles. Of the 364 articles, 259 were excluded on the basis of title and abstract, 99 were excluded after the full text was examined. Lee reported 4 articles analyzing overlapping data reporting risk of death by treatment regimen using HR,<a class="elsevierStyleCrossRefs" href="#bib0315"><span class="elsevierStyleSup">25,33–35</span></a> of which we included 1 article that focused on impact of theophylline on death<a class="elsevierStyleCrossRef" href="#bib0315"><span class="elsevierStyleSup">25</span></a> and excluded the others<a class="elsevierStyleCrossRefs" href="#bib0355"><span class="elsevierStyleSup">33–35</span></a> due to duplicate use of the same data. Six studies were finally included in our analysis (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>).<a class="elsevierStyleCrossRefs" href="#bib0295"><span class="elsevierStyleSup">21–26</span></a> These 6 were published between 2003 and 2011. Macie grouped COPD cases into patients aged under 65, and those aged 65 or older.<a class="elsevierStyleCrossRef" href="#bib0310"><span class="elsevierStyleSup">24</span></a> Lee reported some HRs for theophylline for all-cause death.<a class="elsevierStyleCrossRef" href="#bib0315"><span class="elsevierStyleSup">25</span></a> One HR was calculated with a time-varying exposure analysis in which patients were treated with variety of medications. Each of the other HRs in Lee's study was calculated with specific regimen. Duplicate data was found in these calculations; for this study, therefore, we used HR by time-varying exposure analysis.</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0050" class="elsevierStylePara elsevierViewall">The main meta-analysis included 7 cohorts. The number of patients in each cohort ranged from 47 to 46<span class="elsevierStyleHsp" style=""></span>403, for a total of 60<span class="elsevierStyleHsp" style=""></span>692 COPD patients (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>). The quality score of Lee's study was 6 out of 8. The quality scores of the other studies included were 7 out of 8. Those scores meant that the quality of these observational studies was generally good (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>). Adjusted co-variables in the Cox model are also summarized in <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>. No study provided succinct data concerning theophylline dose or blood levels.</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0055" class="elsevierStylePara elsevierViewall">The proportion of patients prescribed other bronchodilators, such as beta-agonists and anticholinergics, are shown in <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>. There was no specific association between HR for all-cause death and prescription of these bronchodilators in any of the studies (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>)</p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Meta-analysis</span><p id="par0060" class="elsevierStylePara elsevierViewall">Each of the 7 cohorts presented an HR of 0.79–1.41, suggesting weak or moderate heterogeneity without significance (<span class="elsevierStyleItalic">I</span><span class="elsevierStyleSup">2</span>=42%, <span class="elsevierStyleItalic">P</span>=.11). Fixed-model meta-analysis yielded a pooled HR for theophylline for all-cause death of 1.07 (95% CI 1.02–1.13, <span class="elsevierStyleItalic">P</span>=.003) (<a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>). Neither a funnel plot nor Begg's test (<span class="elsevierStyleItalic">r</span>=0.21, <span class="elsevierStyleItalic">P</span>=.662) suggested the existence of publication bias (<a class="elsevierStyleCrossRef" href="#fig0015">Fig. 3</a>).</p><elsevierMultimedia ident="fig0010"></elsevierMultimedia><elsevierMultimedia ident="fig0015"></elsevierMultimedia></span></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Discussion</span><p id="par0065" class="elsevierStylePara elsevierViewall">We conducted a systematic review and meta-analysis of observational studies to evaluate the impact of theophylline on mortality in COPD patients. Fixed-model meta-analysis yielded a pooled HR for theophylline for all-cause death of 1.07 (95% CI 1.02–1.13, <span class="elsevierStyleItalic">P</span>=.003) (<a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>). This suggests that theophylline may be associated with a slight increase in all-cause death in COPD subjects.</p><p id="par0070" class="elsevierStylePara elsevierViewall">Pharmacologic therapy for COPD is used to reduce symptoms, frequency of exacerbations, and death. To date, few of the existing agents have been sufficiently shown to modify long-term deterioration in lung function.<a class="elsevierStyleCrossRef" href="#bib0195"><span class="elsevierStyleSup">1</span></a> Bronchodilators increase forced expiratory volume in one second, usually by altering the smooth muscle tone of the airway. Among bronchodilators, theophylline is less effective and less well tolerated than LAMAs and LABAs, and is not recommended as a first-choice medication. Toxicity is dose-related and the therapeutic index is small. Most of the benefit occurs only when near-toxic doses are used.<a class="elsevierStyleCrossRef" href="#bib0195"><span class="elsevierStyleSup">1</span></a> Furthermore, it theoretically more easily causes systemic side effects than LAMAs and LABAs, as it has to be administrated systematically.<a class="elsevierStyleCrossRef" href="#bib0195"><span class="elsevierStyleSup">1</span></a></p><p id="par0075" class="elsevierStylePara elsevierViewall">The therapeutic effects of theophylline are still being debated. It acts as a non-selective phosphodiesterase inhibitor, but also has non-bronchodilator action, i.e. improvement of inspiratory muscle function and an anti-inflammatory effect. Zhou conducted a double-blind, parallel-group, placebo-controlled RCT in 110 subjects to evaluate the therapeutic effect of low-dose treatment (100<span class="elsevierStyleHsp" style=""></span>mg twice daily).<a class="elsevierStyleCrossRef" href="#bib0370"><span class="elsevierStyleSup">36</span></a> This low dose of theophylline was not considered as a bronchodilator, but as an anti-inflammatory agent.<a class="elsevierStyleCrossRef" href="#bib0375"><span class="elsevierStyleSup">37</span></a> In the study, even though low-dose theophylline did not improve post-bronchodilator lung function, theophylline-treated subjects showed improved quality of life, and lower rates of exacerbation and hospitalization.<a class="elsevierStyleCrossRef" href="#bib0370"><span class="elsevierStyleSup">36</span></a> Considering recent emerging consensus on the link between exacerbations and mortality, low-dose theophylline may hint at a new treatment strategy.</p><p id="par0080" class="elsevierStylePara elsevierViewall">Limitations of the current study should be discussed. The current meta-analysis included limited numbers of cohorts. In addition, all studies included in the meta-analysis were observational studies, not RCT. However, meta-analysis using non-RCT articles has recently become widely accepted.<a class="elsevierStyleCrossRef" href="#bib0380"><span class="elsevierStyleSup">38</span></a> Another limitation is that no original article provided sufficient data on theophylline dosing and blood levels. Nonetheless, we still believe that the results of this analysis are reliable, given that the observational studies included showed neither heterogeneity nor publication bias.</p><p id="par0085" class="elsevierStylePara elsevierViewall">In conclusion, current guidelines supporting the chronic use of theophylline for COPD cases are based on a few studies focusing on respiratory function tests and arterial blood gas analyses.<a class="elsevierStyleCrossRefs" href="#bib0230"><span class="elsevierStyleSup">8,9</span></a> No RCT has evaluated the impact of theophylline on all-cause death. This meta-analysis of 7 observational studies suggests that theophylline slightly increases all-cause death in COPD patients with a pooled HR for theophylline for all-cause death of 1.07 (95% CI 1.02–1.13). These results should be taken into account when deciding on the use of theophylline in some COPD patients.</p></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">Financial Statement</span><p id="par0090" class="elsevierStylePara elsevierViewall">No support in the form of grants, gifts, equipment, and/or drugs was received.</p></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0110">Conflict of Interest</span><p id="par0095" class="elsevierStylePara elsevierViewall">The authors declare no conflict of interest.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:11 [ 0 => array:3 [ "identificador" => "xres631365" "titulo" => "Abstract" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0005" "titulo" => "Background" ] 1 => array:2 [ "identificador" => "abst0010" "titulo" => "Method" ] 2 => array:2 [ "identificador" => "abst0015" "titulo" => "Results" ] 3 => array:2 [ "identificador" => "abst0020" "titulo" => "Conclusion" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec644192" "titulo" => "Keywords" ] 2 => array:3 [ "identificador" => "xres631364" "titulo" => "Resumen" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0025" "titulo" => "Antecedentes" ] 1 => array:2 [ "identificador" => "abst0030" "titulo" => "Método" ] 2 => array:2 [ "identificador" => "abst0035" "titulo" => "Resultados" ] 3 => array:2 [ "identificador" => "abst0040" "titulo" => "Conclusión" ] ] ] 3 => array:2 [ "identificador" => "xpalclavsec644193" "titulo" => "Palabras clave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 5 => array:3 [ "identificador" => "sec0010" "titulo" => "Methods" "secciones" => array:2 [ 0 => array:2 [ "identificador" => "sec0015" "titulo" => "Study Search Criteria" ] 1 => array:2 [ "identificador" => "sec0020" "titulo" => "Statistics" ] ] ] 6 => array:3 [ "identificador" => "sec0025" "titulo" => "Results" "secciones" => array:2 [ 0 => array:2 [ "identificador" => "sec0030" "titulo" => "Study Search Results" ] 1 => array:2 [ "identificador" => "sec0035" "titulo" => "Meta-analysis" ] ] ] 7 => array:2 [ "identificador" => "sec0040" "titulo" => "Discussion" ] 8 => array:2 [ "identificador" => "sec0045" "titulo" => "Financial Statement" ] 9 => array:2 [ "identificador" => "sec0050" "titulo" => "Conflict of Interest" ] 10 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2014-11-12" "fechaAceptado" => "2015-02-11" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec644192" "palabras" => array:5 [ 0 => "Emphysema" 1 => "Death" 2 => "Adverse effect" 3 => "Drug toxicity" 4 => "Bronchodilator" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec644193" "palabras" => array:5 [ 0 => "Enfisema" 1 => "Muerte" 2 => "Efectos adversos" 3 => "Toxicidad de los fármacos" 4 => "Broncodilatador" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:3 [ "titulo" => "Abstract" "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Background</span><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Theophylline has been shown to improve respiratory function and oxygenation in patients with chronic obstruction pulmonary disease (COPD). However, the impact of theophylline on mortality in COPD patients has not been not sufficiently evaluated.</p></span> <span id="abst0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Method</span><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Two investigators independently searched for eligible articles in 4 databases. The eligibility criterion for this meta-analysis was an original research article that provided a hazard ratio for theophylline for all-cause mortality of COPD patients. Both randomized controlled trials and observational studies were accepted. After we confirmed no substantial heterogeneity (<span class="elsevierStyleItalic">I</span><span class="elsevierStyleSup">2</span><50%), the fixed-model method with generic inverse variance was used for meta-analysis to estimate the pooled hazard ratio.</p></span> <span id="abst0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Results</span><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">We screened 364 potentially eligible articles. Of the 364 articles, 259 were excluded on the basis of title and abstract, and 99 were excluded after examination of the full text. Our final analysis included 6 observational studies and no randomized controlled trials. One study reported 2 cohorts. The number of patients in each cohort ranged from 47 to 46<span class="elsevierStyleHsp" style=""></span>403. Heterogeneity (<span class="elsevierStyleItalic">I</span><span class="elsevierStyleSup">2</span>=42%, <span class="elsevierStyleItalic">P</span>=.11) and publication bias (Begg's test <span class="elsevierStyleItalic">r</span>=0.21, <span class="elsevierStyleItalic">P</span>=.662) were not substantial. Fixed-model meta-analysis yielded a pooled hazard ratio for theophylline for all-cause death of 1.07 (95% confidence interval: 1.02–1.13, <span class="elsevierStyleItalic">P</span>=.003).</p></span> <span id="abst0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Conclusion</span><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">This meta-analysis of 7 observational cohorts suggests that theophylline slightly increases all-cause death in COPD patients.</p></span>" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0005" "titulo" => "Background" ] 1 => array:2 [ "identificador" => "abst0010" "titulo" => "Method" ] 2 => array:2 [ "identificador" => "abst0015" "titulo" => "Results" ] 3 => array:2 [ "identificador" => "abst0020" "titulo" => "Conclusion" ] ] ] "es" => array:3 [ "titulo" => "Resumen" "resumen" => "<span id="abst0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Antecedentes</span><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Se ha demostrado que la teofilina mejora la función respiratoria y la oxigenación en pacientes con enfermedad pulmonar obstructiva crónica (EPOC). Sin embargo, no está suficientemente evaluado el impacto de la teofilina sobre la mortalidad de los pacientes con EPOC.</p></span> <span id="abst0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Método</span><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Dos investigadores buscaron de forma independiente artículos elegibles en 4 bases de datos. Los artículos seleccionados para el presente metaanálisis debían ser artículos de investigación originales que proporcionaran el cociente de riesgos instantáneos (HR) de la mortalidad por cualquier causa en pacientes con EPOC tratados con teofilina. Se permitió incluir tanto ensayos controlados aleatorizados como estudios observacionales. Después de confirmar que la heterogeneidad no era significativa (I<span class="elsevierStyleSup">2</span><span class="elsevierStyleHsp" style=""></span><<span class="elsevierStyleHsp" style=""></span>50%), para estimar el cociente de riesgos instantáneos del metaanálisis se empleó un modelo fijo con un método de varianza inversa genérica.</p></span> <span id="abst0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Resultados</span><p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Se seleccionaron 364 artículos potencialmente elegibles. De los 364 artículos, 259 fueron excluidos basándose en el título y el resumen, y 99 fueron excluidos después de considerar sus textos completos. Finalmente, nuestro análisis incluyó 6 estudios observacionales y ningún ensayo controlado aleatorizado. Un estudio estaba realizado con 2 cohortes. El número de pacientes en cada cohorte varió de 47 a 46.403. La heterogeneidad (I<span class="elsevierStyleSup">2</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>42%, p<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0,11) y el sesgo de publicación (r<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0,21, p<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0,662 en la prueba de Begg) no fueron significativos. El metaanálisis del modelo fijo arrojó un cociente de riesgos instantáneos combinado de mortalidad por cualquier causa con teofilina de 1,07 (intervalo de confianza del 95%: 1,2-1,13, p<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0,003).</p></span> <span id="abst0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Conclusión</span><p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">El presente metaanálisis de 7 cohortes observacionales sugiere que la teofilina aumenta ligeramente la mortalidad por cualquier causa de los pacientes con EPOC.</p></span>" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0025" "titulo" => "Antecedentes" ] 1 => array:2 [ "identificador" => "abst0030" "titulo" => "Método" ] 2 => array:2 [ "identificador" => "abst0035" "titulo" => "Resultados" ] 3 => array:2 [ "identificador" => "abst0040" "titulo" => "Conclusión" ] ] ] ] "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as: Horita N, Miyazawa N, Kojima R, Inoue M, Ishigatsubo Y, Kaneko T. Uso crónico de teofilina y mortalidad en la enfermedad pulmonar obstructiva crónica: un metaanálisis. Arch Bronconeumol. 2016;52:233–238.</p>" ] ] "multimedia" => array:4 [ 0 => array:7 [ "identificador" => "fig0005" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 3070 "Ancho" => 2378 "Tamanyo" => 350215 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">PRISMA flow chart for meta-analysis</p>" ] ] 1 => array:7 [ "identificador" => "fig0010" "etiqueta" => "Fig. 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 752 "Ancho" => 2917 "Tamanyo" => 194718 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">Forest plot evaluating hazard ratio (HR) for all-cause death by theophylline administration.</p>" ] ] 2 => array:7 [ "identificador" => "fig0015" "etiqueta" => "Fig. 3" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr3.jpeg" "Alto" => 1075 "Ancho" => 1601 "Tamanyo" => 44638 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0055" class="elsevierStyleSimplePara elsevierViewall">Funnel plot evaluating publication bias</p>" ] ] 3 => array:7 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "tabla" => array:2 [ "leyenda" => "<p id="spar0065" class="elsevierStyleSimplePara elsevierViewall">SQ, study quality, wherein 8 is the best score; Pro, prospective cohort study; Ret, retrospective cohort study; ICD-9, International Classification of Diseases, 9th revision; ATS, American Thoracic Society. Macie grouped cases into cases aged under 65, and cases aged 65 or higher. SABA, short-acting beta agonist; LABA, long-acting beta agonist; LAMA, long-acting muscarinic antagonist; SGRQ, total score of St. George Respiratory Questionnaire.</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">Study \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col">Design SQ \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " colspan="4" align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Patients</th><th class="td" title="table-head " align="left" valign="top" scope="col">Follow-up duration \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col">Co-variables adjusted for Cox model \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col">Hazard ratio (95% CI) \t\t\t\t\t\t\n \t\t\t\t</th></tr><tr title="table-row"><th class="td" title="table-head " align="" valign="top" scope="col" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="" valign="top" scope="col" style="border-bottom: 2px solid black"> \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">Recruitment, definition \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">No. \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">Inhaled beta-agonist \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">Inhaled anti-cholinergic \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="" valign="top" scope="col" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="" valign="top" scope="col" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="" valign="top" scope="col" style="border-bottom: 2px solid black"> \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 " align="left" valign="top">Fan (2003)<a class="elsevierStyleCrossRef" href="#bib0295"><span class="elsevierStyleSup">21</span></a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Pro 7 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Outpatients on inhaled corticosteroids. ICD-9 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">8052 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">88.0% (SABA) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">72.8% (not specified) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">544 days \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Pulmonary medication, age, hospital site, prior COPD visits, comorbidity, distance to hospital \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1.00 (0.84–1.20) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Nizet (2005)<a class="elsevierStyleCrossRef" href="#bib0300"><span class="elsevierStyleSup">22</span></a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Pro 7 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Hypercapnic, ATS \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">47 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Not available \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Not available \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">3.8 years \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Age, sex, comorbidity, diuretics \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1.10 (0.40–3.10) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Gudmundsson (2006)<a class="elsevierStyleCrossRef" href="#bib0305"><span class="elsevierStyleSup">23</span></a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Pro 7 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Post exacerbation \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">416 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">39.6% (LABA) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">35.1% (Ipratropium) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">2 years \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Age, sex, center, smoking, FEV<span class="elsevierStyleInf">1</span>, previous hospitalization, SGRQ, comorbidity, pulmonary medication, long-term oxygen \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">0.79 (0.48–1.30) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Macie (2006)<a class="elsevierStyleCrossRef" href="#bib0310"><span class="elsevierStyleSup">24</span></a><br><65 years old;<br>≥65 years old \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Ret 7 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Post admission, ICD-9 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top"><br>965<br>4022 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top"><br>54.9% (not specified)<br>61.2% (not specified) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top"><br>30.6% (Ipratropium)<br>44.7% (Ipratropium) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">365 days \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Selected covariates \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top"><br>1.41 (0.60–3.34)<br>1.40 (1.10–1.79) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Lee (2009)<a class="elsevierStyleCrossRef" href="#bib0315"><span class="elsevierStyleSup">25</span></a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Ret 6 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Veterans, ICD-9 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">7840 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">48.2% (LABA)<br> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">88.2% (Ipratropium) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">2.5 years \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Baseline propensity to receive theophylline, exacerbation, age \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1.23 (1.09–1.39) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Gershon (2011)<a class="elsevierStyleCrossRef" href="#bib0320"><span class="elsevierStyleSup">26</span></a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Ret 7 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Population based \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">46<span class="elsevierStyleHsp" style=""></span>403 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">38.4% (LABA) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">61.6% (LAMA) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">5.5 years \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Age, sex, resident in a long-term care facility, income, place to live, COPD duration, previous spirometry, physician visits, specialist visit, influenza vaccination, lung volume reduction surgery, COPD medications, coronary medications, comorbidities, recent hospitalization/emergency visit. \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1.01 (0.93–1.10) \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1035912.png" ] ] ] ] "descripcion" => array:1 [ "en" => "<p id="spar0060" class="elsevierStyleSimplePara elsevierViewall">Summary of Original Studies Included for Meta-analysis.</p>" ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => 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| Year/Month | Html | Total | |
|---|---|---|---|
| 2024 November | 8 | 2 | 10 |
| 2024 October | 50 | 33 | 83 |
| 2024 September | 44 | 23 | 67 |
| 2024 August | 77 | 40 | 117 |
| 2024 July | 44 | 24 | 68 |
| 2024 June | 59 | 28 | 87 |
| 2024 May | 103 | 25 | 128 |
| 2024 April | 50 | 30 | 80 |
| 2024 March | 65 | 27 | 92 |
| 2024 February | 43 | 32 | 75 |
| 2023 May | 1 | 0 | 1 |
| 2023 March | 12 | 4 | 16 |
| 2023 February | 80 | 20 | 100 |
| 2023 January | 58 | 32 | 90 |
| 2022 December | 94 | 44 | 138 |
| 2022 November | 83 | 24 | 107 |
| 2022 October | 95 | 34 | 129 |
| 2022 September | 64 | 38 | 102 |
| 2022 August | 90 | 33 | 123 |
| 2022 July | 89 | 48 | 137 |
| 2022 June | 71 | 56 | 127 |
| 2022 May | 81 | 43 | 124 |
| 2022 April | 82 | 37 | 119 |
| 2022 March | 92 | 47 | 139 |
| 2022 February | 105 | 37 | 142 |
| 2022 January | 86 | 44 | 130 |
| 2021 December | 71 | 40 | 111 |
| 2021 November | 73 | 56 | 129 |
| 2021 October | 122 | 56 | 178 |
| 2021 September | 67 | 51 | 118 |
| 2021 August | 62 | 33 | 95 |
| 2021 July | 66 | 37 | 103 |
| 2021 June | 95 | 48 | 143 |
| 2021 May | 96 | 41 | 137 |
| 2021 April | 170 | 99 | 269 |
| 2021 March | 86 | 42 | 128 |
| 2021 February | 46 | 27 | 73 |
| 2021 January | 62 | 27 | 89 |
| 2020 December | 65 | 34 | 99 |
| 2020 November | 50 | 24 | 74 |
| 2020 October | 81 | 23 | 104 |
| 2020 September | 68 | 21 | 89 |
| 2020 August | 93 | 32 | 125 |
| 2020 July | 82 | 28 | 110 |
| 2020 June | 57 | 14 | 71 |
| 2020 May | 79 | 13 | 92 |
| 2020 April | 73 | 52 | 125 |
| 2020 March | 50 | 13 | 63 |
| 2020 February | 58 | 22 | 80 |
| 2020 January | 57 | 24 | 81 |
| 2019 December | 74 | 25 | 99 |
| 2019 November | 56 | 48 | 104 |
| 2019 October | 55 | 22 | 77 |
| 2019 September | 56 | 26 | 82 |
| 2019 August | 52 | 32 | 84 |
| 2019 July | 58 | 29 | 87 |
| 2019 June | 75 | 71 | 146 |
| 2019 May | 60 | 33 | 93 |
| 2019 April | 72 | 65 | 137 |
| 2019 March | 55 | 31 | 86 |
| 2019 February | 53 | 39 | 92 |
| 2019 January | 69 | 34 | 103 |
| 2018 December | 52 | 23 | 75 |
| 2018 November | 79 | 27 | 106 |
| 2018 October | 130 | 40 | 170 |
| 2018 September | 30 | 10 | 40 |
| 2018 May | 14 | 0 | 14 |
| 2018 April | 40 | 8 | 48 |
| 2018 March | 31 | 9 | 40 |
| 2018 February | 24 | 15 | 39 |
| 2018 January | 25 | 7 | 32 |
| 2017 December | 33 | 6 | 39 |
| 2017 November | 18 | 5 | 23 |
| 2017 October | 22 | 17 | 39 |
| 2017 September | 30 | 10 | 40 |
| 2017 August | 24 | 12 | 36 |
| 2017 July | 24 | 10 | 34 |
| 2017 June | 42 | 20 | 62 |
| 2017 May | 33 | 17 | 50 |
| 2017 April | 32 | 17 | 49 |
| 2017 March | 18 | 20 | 38 |
| 2017 February | 23 | 14 | 37 |
| 2017 January | 14 | 11 | 25 |
| 2016 December | 42 | 22 | 64 |
| 2016 November | 53 | 37 | 90 |
| 2016 October | 50 | 35 | 85 |
| 2016 September | 52 | 20 | 72 |
| 2016 August | 63 | 23 | 86 |
| 2016 July | 6 | 2 | 8 |
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