Review article
Increased serum interleukin-6 level as a predictive biomarker for atrial fibrillation: A systematic review and meta-analysis
Nível sérico elevado de Interleucina-6 como biomarcador preditivo de fibrilhação auricular: uma revisão sistemática e meta-análise
Peng Zhou, Maieryemu Waresi, Yikai Zhao, Hung-Chen Lin, Bangwei Wu, Nanqing Xiong, Huiyang Li, Qingyu Huang, Xinping Luo, Jian Li
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Department of Cardiology, Huashan Hospital of Fudan University, Shanghai, People's Republic of China
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array:1 [ 0 => array:2 [ "autoresLista" => "António Fiarresga" "autores" => array:1 [ 0 => array:2 [ "nombre" => "António" "apellidos" => "Fiarresga" ] ] ] ] ] "idiomaDefecto" => "en" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S0870255120304431?idApp=UINPBA00004E" "url" => "/08702551/0000003900000012/v1_202012220636/S0870255120304431/v1_202012220636/en/main.assets" ] "en" => array:19 [ "idiomaDefecto" => true "cabecera" => "<span class="elsevierStyleTextfn">Review article</span>" "titulo" => "Increased serum interleukin-6 level as a predictive biomarker for atrial fibrillation: A systematic review and meta-analysis" "tieneTextoCompleto" => true "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "723" "paginaFinal" => "728" ] ] "autores" => array:1 [ 0 => array:4 [ "autoresLista" => "Peng Zhou, Maieryemu Waresi, Yikai Zhao, Hung-Chen Lin, Bangwei Wu, Nanqing Xiong, Huiyang Li, Qingyu Huang, Xinping Luo, Jian Li" "autores" => array:10 [ 0 => array:2 [ "nombre" => "Peng" "apellidos" => "Zhou" ] 1 => array:2 [ "nombre" => "Maieryemu" "apellidos" => "Waresi" ] 2 => array:2 [ "nombre" => "Yikai" "apellidos" => "Zhao" ] 3 => array:2 [ "nombre" => "Hung-Chen" "apellidos" => "Lin" ] 4 => array:2 [ "nombre" => "Bangwei" "apellidos" => "Wu" ] 5 => array:2 [ "nombre" => "Nanqing" "apellidos" => "Xiong" ] 6 => array:2 [ "nombre" => "Huiyang" "apellidos" => "Li" ] 7 => array:2 [ "nombre" => "Qingyu" "apellidos" => "Huang" ] 8 => array:2 [ "nombre" => "Xinping" "apellidos" => "Luo" ] 9 => array:4 [ "nombre" => "Jian" "apellidos" => "Li" "email" => array:1 [ 0 => "13816066763@163.com" ] "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">*</span>" "identificador" => "cor0005" ] ] ] ] "afiliaciones" => array:1 [ 0 => array:2 [ "entidad" => "Department of Cardiology, Huashan Hospital of Fudan University, Shanghai, People's Republic of China" "identificador" => "aff0005" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "pt" => array:1 [ "titulo" => "Nível sérico elevado de Interleucina-6 como biomarcador preditivo de fibrilhação auricular: uma revisão sistemática e meta-análise" ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0015" "etiqueta" => "Figure 3" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr3.jpeg" "Alto" => 1847 "Ancho" => 2508 "Tamanyo" => 474152 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0055" class="elsevierStyleSimplePara elsevierViewall">Association of IL-6 and other adverse events in atrial fibrillation (AF). (A) Forest plots of risk ratio (RR) and CI 95% for the association between IL-6 and major bleeding events in AF. (B) Forest plots of RR and CI 95% for the association between IL-6 and acute coronary syndrome events in AF. (C) Forest plots of RR and CI 95% for the association between IL-6 and all-cause mortality in AF.</p>" ] ] ] "textoCompleto" => "<span class="elsevierStyleSections"><p id="par0005" class="elsevierStylePara elsevierViewall">Atrial fibrillation (AF) is the most common sustained arrhythmia in clinical practice which can cause thromboembolic events such as stroke.<a class="elsevierStyleCrossRefs" href="#bib0150"><span class="elsevierStyleSup">1–3</span></a> So far, anticoagulation therapy is the major strategy for AF treatment.<a class="elsevierStyleCrossRef" href="#bib0165"><span class="elsevierStyleSup">4</span></a> We applied CHA<span class="elsevierStyleInf">2</span>DS<span class="elsevierStyleInf">2</span>-VASc (Congestive Heart Failure, Hypertension, Age (≥75 years), Diabetes, Stroke/Transient Ischemic Attack, Vascular Disease, Age (65-74 years), Sex (Female)) score to assess the risk of stroke in AF patients. The patients with a high score (male ≥2, female ≥3) require anti-coagulation therapy.<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">5</span></a> We used HAS-BLED (Hypertension, Abnormal renal and liver function, Stroke, Bleeding, Labile INRs, Elderly, Drugs or alcohol) to estimate the bleeding risk in AF patients. A score ≥3 means there is a high risk of bleeding.</p><p id="par0010" class="elsevierStylePara elsevierViewall">However, the area under curve (AUC) for CHA<span class="elsevierStyleInf">2</span>DS<span class="elsevierStyleInf">2</span>-VASc is approximately 0.660.<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">5</span></a> In our previous investigation, less than 30% patients received anticoagulation therapy before stroke. One of the important reasons was that the score before stroke was <2. There must be other factors such as biomarkers which lead to stroke and thromboembolism. Similarly, the AUC for HAS-BLED is approximately 0.60.<a class="elsevierStyleCrossRef" href="#bib0295"><span class="elsevierStyleSup">6</span></a> We also are unable to estimate the risk of other adverse events, such as cerebral infarction and mortality in AF patients by using these scores. It is necessary to discover other methods to assess the prognosis of AF patients.</p><p id="par0015" class="elsevierStylePara elsevierViewall">Inflammation can cause AF and thrombosis. Several biomarkers have been studied in AF patients such as C-reactive protein (CRP)<a class="elsevierStyleCrossRefs" href="#bib0175"><span class="elsevierStyleSup">7,8</span></a> and interleukin (IL),<a class="elsevierStyleCrossRef" href="#bib0185"><span class="elsevierStyleSup">9</span></a> while the role of IL-6 in AF and adverse events, especially thrombotic risk, remains controversial.<a class="elsevierStyleCrossRefs" href="#bib0190"><span class="elsevierStyleSup">10,11</span></a> We therefore conducted a systematic review and meta-analysis to provide an overview of the association between IL-6 with thromboembolic and other adverse events in AF.</p><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Methods</span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Search strategy</span><p id="par0020" class="elsevierStylePara elsevierViewall">We used electronic databases to identify relevant studies. The PubMed, EMBASE, Web of Science, and Cochrane databases were systematically searched for studies published up to January 2020. We used mesh terms including “atrial fibrillation” and “interleukin 6” and “inflammation”.</p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Study selection</span><p id="par0025" class="elsevierStylePara elsevierViewall">We enrolled the studies according to the the following criteria: (1) cohort studies (both retrospective and prospective) about stroke or thromboembolic risk in AF patients and (2) studies which focused on IL-6. In case of multiple publications, the most recent studies or studies of a larger population were used. Citations were selected by initially screening the title and abstract of the studies. We assessed the study quality using the Newcastle-Ottawa scale. The total scores ranged from 0 (worst) to 9 (best) for case-control or cohort studies.</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Data extraction</span><p id="par0030" class="elsevierStylePara elsevierViewall">Using standard data extraction forms, two reviewers (Zhou and Zhao) extracted data from the relevant studies. The following data were independently extracted: author's name, year of publication, type of study design, study population, sample size, mean duration of follow-up, study end points, risk ratio (RR) with 95% confidence interval (CI), cut-off value and reported adjustment for potential confounders. If the study provided the IL-6 level, we extracted the means and standard deviations in each group. If the study provided the medians and ranges instead of the means and standard deviations, we imputed the means and standard deviations using the method developed by Hozo et al.<a class="elsevierStyleCrossRef" href="#bib0200"><span class="elsevierStyleSup">12</span></a></p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Data analysis</span><p id="par0035" class="elsevierStylePara elsevierViewall">For cohort studies, we used pooled hazard ratio (HR) as a summary statistic to estimate the prognostic effect of IL-6 level on thromboembolic events in AF patients. An HR>1 indicated the correlation between elevated IL-6 and stroke and thromboembolic events.</p><p id="par0040" class="elsevierStylePara elsevierViewall">Statistical heterogeneity across studies was assessed using the I<span class="elsevierStyleSup">2</span> statistic. An I<span class="elsevierStyleSup">2</span>≥50% suggests that there is significant heterogeneity between studies. The HR was pooled using a fixed-effects model to manage heterogeneity if it was insignificant (I<span class="elsevierStyleSup">2</span><50%); otherwise, a random-effects model was applied. A p value <0.05 was considered to be statistically significant. Statistical analyses were performed using the RevMan 5.3 software.</p></span></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Results</span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Study characteristics</span><p id="par0045" class="elsevierStylePara elsevierViewall">In total, 471 records were retrieved in our primary literature search by using the mesh term atrial fibrillation and interleukin-6. 402 records were excluded after screening the titles and abstracts. 69 potentially relevant full-text articles were reviewed, and five studies with a total of 22 928 participants were included in the final analysis (<a class="elsevierStyleCrossRef" href="#fig0005">Figure 1</a>), including two retrospective cohort studies and three prospective cohort studies (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>). Quality assessment is reported in <a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>.</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><elsevierMultimedia ident="tbl0010"></elsevierMultimedia></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Association between IL-6, stroke and thromboembolic events in AF</span><p id="par0050" class="elsevierStylePara elsevierViewall">Where IL-6 was affected by other factors, such as antithrombotic therapy or comorbidity, the researchers adjusted the outcomes to determine whether IL-6 was an independent risk factor for stroke and thromboembolic events. We used the data after adjustment. Meta-analysis showed that elevated IL-6 meant a higher risk of long-term stroke and thromboembolic risk in AF patients with a pooled RR 1.44 (CI 95% 1.09-1.90, p=0.01) (<a class="elsevierStyleCrossRef" href="#fig0010">Figure 2</a>).</p><elsevierMultimedia ident="fig0010"></elsevierMultimedia></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">Association between IL-6 and other adverse events in AF</span><p id="par0055" class="elsevierStylePara elsevierViewall">We conducted the analysis of major bleeding events (<a class="elsevierStyleCrossRef" href="#fig0015">Figure 3</a>A), acute coronary syndrome (ACS) (<a class="elsevierStyleCrossRef" href="#fig0015">Figure 3</a>B), all-cause mortality (<a class="elsevierStyleCrossRef" href="#fig0015">Figure 3</a>C) in AF and the level of IL-6. Three studies were eligible for the analysis. Meta-analysis showed that elevated IL-6 meant a higher risk of long-term bleeding risk (RR 1.36, CI 95% 1.06-1.74, p=0.02), ACS risk (RR 1.81, CI 95% 1.43-2.30, P<0.001) and all-cause death (RR 2.35, CI 95% 2.09-2.65, p<0.001).</p><elsevierMultimedia ident="fig0015"></elsevierMultimedia></span></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0110">Discussion</span><p id="par0060" class="elsevierStylePara elsevierViewall">IL-6 is one of the inflammatory cytokines with a pleiotropic effect on immune response and inflammation. It is synthesized in immune cells such as macrophages and monocytes.<a class="elsevierStyleCrossRef" href="#bib0225"><span class="elsevierStyleSup">16</span></a> When pattern recognition receptors of immune cells are activated, a range of signaling pathways including factor kappa B are initiated to enhance the transcription of the message RNA of inflammatory cytokines such as IL-6, tumor necrosis factor (TNF), and IL-1β.<a class="elsevierStyleCrossRef" href="#bib0230"><span class="elsevierStyleSup">17</span></a> IL-6 can also be produced in endothelial cells as a result of the stimulation of IL-1, TNF and interferon-γ.<a class="elsevierStyleCrossRef" href="#bib0235"><span class="elsevierStyleSup">18</span></a></p><p id="par0065" class="elsevierStylePara elsevierViewall">IL-6 synthesized in the inflammatory lesion is released to the blood and moves to the liver, which means IL-6 is the major regulator of acute phase response in human hepatocytes.<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">19</span></a> A series of acute phase proteins were then induced such as CRP, fibrinogen and plasminogen activator inhibitor-1.<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">19</span></a> IL-6 promotes megakaryocyte maturation after reaching the bone marrow, thus leading to the release of platelets and thrombocytosis.<a class="elsevierStyleCrossRef" href="#bib0245"><span class="elsevierStyleSup">20</span></a> IL-6 may induce the expression of tissue factor,<a class="elsevierStyleCrossRefs" href="#bib0250"><span class="elsevierStyleSup">21,22</span></a> factor VIII<a class="elsevierStyleCrossRef" href="#bib0260"><span class="elsevierStyleSup">23</span></a> and von Willebrand factor.<a class="elsevierStyleCrossRef" href="#bib0265"><span class="elsevierStyleSup">24</span></a> In addition, an increased interleukin-6 level decreases the natural inhibitors of hemostasis such as antithrombin, protein S<a class="elsevierStyleCrossRef" href="#bib0270"><span class="elsevierStyleSup">25</span></a> and thrombomodulin.<a class="elsevierStyleCrossRef" href="#bib0275"><span class="elsevierStyleSup">26</span></a> Elevated IL-6 is related to enhanced coagulation function and weakened anticoagulation function to establish a prothrombotic state, which in turn is linked to thrombotic risk and ACS. IL-6 also induces excess production of vascular endothelial growth factor, leading to enhanced angiogenesis and increased risk of bleeding.<a class="elsevierStyleCrossRef" href="#bib0225"><span class="elsevierStyleSup">16</span></a></p><p id="par0070" class="elsevierStylePara elsevierViewall">Emerging studies have proved that AF is a kind of inflammation, containing inflammatory cells and inflammatory cytokines. Thrombogenesis of AF is also associated with inflammation. CRP level is significantly associated with stroke risk in AF patients.<a class="elsevierStyleCrossRef" href="#bib0175"><span class="elsevierStyleSup">7</span></a> In AF patients, platelet P-selectin levels and adenosine diphosphate -induced platelet aggregation are significantly higher in the left atrium compared to the right atrium,<a class="elsevierStyleCrossRef" href="#bib0280"><span class="elsevierStyleSup">27</span></a> which may be related to the different inflammation level. IL-6 level is positively related to the CHA<span class="elsevierStyleInf">2</span>DS<span class="elsevierStyleInf">2</span> score, while anticoagulation therapy can decrease the IL-6 level.<a class="elsevierStyleCrossRefs" href="#bib0285"><span class="elsevierStyleSup">28,29</span></a> Inflammation can cause endothelial dysfunction, platelet and endothelial cell activation, and coagulation cascade activation.<a class="elsevierStyleCrossRef" href="#bib0185"><span class="elsevierStyleSup">9</span></a></p><p id="par0075" class="elsevierStylePara elsevierViewall">In our meta-analysis, a higher IL-6 level may predict a higher thrombotic risk as well as a higher bleeding risk, ACS risk and mortality risk in AF patients. It is possible to assess the thromboembolic risk and bleeding risk by adding IL-6 into theCHA<span class="elsevierStyleInf">2</span>DS<span class="elsevierStyleInf">2</span>-VASc score and HAS-BLED score. Anti-inflammation or anti-IL-6 therapy may be administered in AF patients. Further research needs to be conducted such as the cut-off point of IL-6.</p><p id="par0080" class="elsevierStylePara elsevierViewall">There are several limitations in our study. The participants’ baseline characteristics, such as age and complications were various and the mean follow-up time and cut-off point were all different among the studies. Publication bias was not detected because of the limited number of studies. Publication bias might exist in this study.</p></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0115">Conclusion</span><p id="par0085" class="elsevierStylePara elsevierViewall">Our meta-analysis showed that higher level of IL-6 may predict a greater number of long-term thromboembolic events, as well as bleeding events, ACS events and mortality in AF patients. Further studies such as the cut-off point of IL-6 need to be conducted in the future.</p></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0120">Funding sources</span><p id="par0090" class="elsevierStylePara elsevierViewall">This work was supported by the <span class="elsevierStyleGrantSponsor" id="gs1">Science and Technology Research and Development Program of Shanghai</span> (No. <span class="elsevierStyleGrantNumber" refid="gs1">17ZR1403700</span>).</p></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0125">Conflicts of interest</span><p id="par0095" class="elsevierStylePara elsevierViewall">The authors have no conflicts of interest to declare.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:11 [ 0 => array:3 [ "identificador" => "xres1438452" "titulo" => "Abstract" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0005" "titulo" => "Background" ] 1 => array:2 [ "identificador" => "abst0010" "titulo" => "Methods" ] 2 => array:2 [ "identificador" => "abst0015" "titulo" => "Results" ] 3 => array:2 [ "identificador" => "abst0020" "titulo" => "Conclusion" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec1313048" "titulo" => "Keywords" ] 2 => array:3 [ "identificador" => "xres1438451" "titulo" => "Resumo" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0025" "titulo" => "Introdução" ] 1 => array:2 [ "identificador" => "abst0030" "titulo" => "Métodos" ] 2 => array:2 [ "identificador" => "abst0035" "titulo" => "Resultados" ] 3 => array:2 [ "identificador" => "abst0040" "titulo" => "Conclusão" ] ] ] 3 => array:2 [ "identificador" => "xpalclavsec1313049" "titulo" => "Palavras-chave" ] 4 => array:3 [ "identificador" => "sec0005" "titulo" => "Methods" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "sec0010" "titulo" => "Search strategy" ] 1 => array:2 [ "identificador" => "sec0015" "titulo" => "Study selection" ] 2 => array:2 [ "identificador" => "sec0020" "titulo" => "Data extraction" ] 3 => array:2 [ "identificador" => "sec0025" "titulo" => "Data analysis" ] ] ] 5 => array:3 [ "identificador" => "sec0030" "titulo" => "Results" "secciones" => array:3 [ 0 => array:2 [ "identificador" => "sec0035" "titulo" => "Study characteristics" ] 1 => array:2 [ "identificador" => "sec0040" "titulo" => "Association between IL-6, stroke and thromboembolic events in AF" ] 2 => array:2 [ "identificador" => "sec0045" "titulo" => "Association between IL-6 and other adverse events in AF" ] ] ] 6 => array:2 [ "identificador" => "sec0050" "titulo" => "Discussion" ] 7 => array:2 [ "identificador" => "sec0055" "titulo" => "Conclusion" ] 8 => array:2 [ "identificador" => "sec0060" "titulo" => "Funding sources" ] 9 => array:2 [ "identificador" => "sec0065" "titulo" => "Conflicts of interest" ] 10 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2020-05-07" "fechaAceptado" => "2020-07-09" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec1313048" "palabras" => array:4 [ 0 => "Atrial fibrillation" 1 => "Interleukin-6" 2 => "Stroke" 3 => "Prognosis" ] ] ] "pt" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palavras-chave" "identificador" => "xpalclavsec1313049" "palabras" => array:4 [ 0 => "Firilhação auricular" 1 => "Interleucina-6" 2 => "Acidente vascular cerebral" 3 => "Prognóstico" ] ] ] ] "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">Atrial fibrillation (AF) is related to a higher risk of thromboembolic events and mortality. Some studies have demonstrated that the inflammatory biomarker interleukin-6 (IL-6) is associated with a higher risk of higher thrombosis in AF patients, but the real effect of IL-6 remains a controversy.</p></span> <span id="abst0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Methods</span><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">We conducted a systematic review and meta-analysis to investigate the association between IL-6 and thromboembolic events, as well as bleeding events, acute coronary syndrome (ACS) events and all-cause mortality in AF.</p></span> <span id="abst0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Results</span><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">A total of five studies involving 22 928 patients met our inclusion criteria for the systematic review. The higher level of IL-6 in AF patients is related to long-term thromboembolic events including stroke (RR 1.44, CI 95% 1.09-1.90, p=0.01). IL-6 meant a higher risk of long-term bleeding risk (RR 1.36, CI 95% 1.06-1.74, p=0.02), ACS risk (RR 1.81, CI 95% 1.43-2.30, p<0.001) and all-cause mortality (RR 2.35, CI 95% 2.09-2.65, p<0.001).</p></span> <span id="abst0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Conclusion</span><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">A higher level of IL-6 may predict a greater number of long-term thromboembolic events and bleeding events, ACS events and mortality in AF patients. Further studies such as the cut-off point of IL-6 need to be conducted in the future.</p></span>" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0005" "titulo" => "Background" ] 1 => array:2 [ "identificador" => "abst0010" "titulo" => "Methods" ] 2 => array:2 [ "identificador" => "abst0015" "titulo" => "Results" ] 3 => array:2 [ "identificador" => "abst0020" "titulo" => "Conclusion" ] ] ] "pt" => array:3 [ "titulo" => "Resumo" "resumen" => "<span id="abst0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Introdução</span><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">A fibrilhação auricular (AF) está relacionada com maior risco de eventos tromboembólicos e de mortalidade. Alguns estudos mostraram que o biomarcador inflamatório interleucina-6 (IL-6) estava associado a maior risco trombótico em doentes com AF, mas o efeito real da IL-6 continua controverso.</p></span> <span id="abst0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Métodos</span><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Realizámos uma revisão sistemática e meta-análise para investigar a associação de IL-6 com eventos tromboembólicos assim como eventos hemorrágicos, eventos síndrome coronária aguda e mortalidade total na AF.</p></span> <span id="abst0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Resultados</span><p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Cinco estudos que envolveram 22 928 doentes preencheram os nossos critérios de inclusão para revisão sistemática. Maior nível de IL-6 em doentes com AF relaciona-se com eventos tromboembólicos em longo prazo, incluindo acidente vascular cerebral (RR 1,44, 95% CI 1,09-1,90, P 0,01), risco de ACS (RR 1,81, 95% CI 1,43-2,30, P<0,001) e mortalidade total (RR 2,35, 95% CI 2,09-2,65, P<0,001).</p></span> <span id="abst0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Conclusão</span><p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">Um nível mais elevado de IL-6 pode prever um maior número de eventos tromboembólicos assim como de eventos hemorrágicos, eventos ACS e mortalidade em doentes com AF. Mais estudos sobre o ponto de corte de IL-6 necessitam ser realizados.</p></span>" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0025" "titulo" => "Introdução" ] 1 => array:2 [ "identificador" => "abst0030" "titulo" => "Métodos" ] 2 => array:2 [ "identificador" => "abst0035" "titulo" => "Resultados" ] 3 => array:2 [ "identificador" => "abst0040" "titulo" => "Conclusão" ] ] ] ] "multimedia" => array:5 [ 0 => array:7 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1535 "Ancho" => 2341 "Tamanyo" => 227135 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">Flow diagram of the study selection.</p>" ] ] 1 => array:7 [ "identificador" => "fig0010" "etiqueta" => "Figure 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 469 "Ancho" => 2065 "Tamanyo" => 115272 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">Forest plots of risk ratio (RR) and CI 95% for the association between IL-6 and stroke and thromboembolic events in AF.</p>" ] ] 2 => array:7 [ "identificador" => "fig0015" "etiqueta" => "Figure 3" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr3.jpeg" "Alto" => 1847 "Ancho" => 2508 "Tamanyo" => 474152 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0055" class="elsevierStyleSimplePara elsevierViewall">Association of IL-6 and other adverse events in atrial fibrillation (AF). (A) Forest plots of risk ratio (RR) and CI 95% for the association between IL-6 and major bleeding events in AF. (B) Forest plots of RR and CI 95% for the association between IL-6 and acute coronary syndrome events in AF. (C) Forest plots of RR and CI 95% for the association between IL-6 and all-cause mortality in AF.</p>" ] ] 3 => 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="spar0065" class="elsevierStyleSimplePara elsevierViewall">AF: atrial fibrillation; TIA: transient ischemia attack; ACS: acute coronary syndrome; CHA<span class="elsevierStyleInf">2</span>DS<span class="elsevierStyleInf">2</span>-VASc: Congestive Heart Failure, Hypertension, Age (≥75 years), Diabetes, Stroke/Transient Ischemic Attack, Vascular Disease, Age (65-74 years), Sex (Female).</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="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Study, year \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Type of study \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Average follow-up (months) \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">No. of patients, n \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Cut-off point of IL-6 (ng/L) \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">End points \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Variables adjusted for \t\t\t\t\t\t\n \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Aulin, 2015<a class="elsevierStyleCrossRef" href="#bib0205"><span class="elsevierStyleSup">13</span></a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Retrospective cohort study \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">24 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">6187 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2.5 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Stroke/systemic embolism, major bleeding, ACS \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Other inflammation marker level, treatment, CHA2DS2-VASc score \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Conway, 2004<a class="elsevierStyleCrossRef" href="#bib0210"><span class="elsevierStyleSup">14</span></a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Prospective cohort study \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">76.8 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">77 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">20 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Stroke, all-cause mortality \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Age, antithrombotic therapy \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Hijazi, 2016<a class="elsevierStyleCrossRef" href="#bib0195"><span class="elsevierStyleSup">11</span></a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Retrospective cohort study \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">22.8 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">14<span class="elsevierStyleHsp" style=""></span>954 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2.3 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Stroke/systemic embolism, major bleeding, ACS, all-cause mortality \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Other inflammation marker level, study treatment, CHA2DS2-VASc score \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Rivera, 2019<a class="elsevierStyleCrossRef" href="#bib0295"><span class="elsevierStyleSup">6</span></a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Prospective cohort study \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">78 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">940 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">3.7 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Stroke, major bleeding \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Other inflammation marker level, CHA2DS2-VASc and HAS-BLED score \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Roldan, 2012<a class="elsevierStyleCrossRef" href="#bib0220"><span class="elsevierStyleSup">15</span></a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Prospective cohort study \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">31.9 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">770 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">3.35 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Stroke/TIA, ACS, all-cause mortality \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">CHA2DS2-VASc score \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab2474398.png" ] ] ] ] "descripcion" => array:1 [ "en" => "<p id="spar0060" class="elsevierStyleSimplePara elsevierViewall">Studies on association between IL-6 and thromboembolic events in AF.</p>" ] ] 4 => array:8 [ "identificador" => "tbl0010" "etiqueta" => "Table 2" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at2" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:1 [ "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-with-role" title="\n \t\t\t\t\ttable-head\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col">Study, year \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " colspan="4" align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Newcastle-Ottawa Scale</th></tr><tr title="table-row"><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Selection \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Comparability \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Outcome/Exposure \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Total \t\t\t\t\t\t\n \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Aulin, 2015 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">*** \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">** \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">*** \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">7 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Conway, 2004 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">** \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">** \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">*** \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">6 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Hijazi, 2016 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">*** \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">* \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">** \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">5 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Rivera, 2019 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">*** \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">* \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">*** \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">7 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Roldan, 2012 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">*** \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">* \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">* \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">5 \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab2474399.png" ] ] ] ] "descripcion" => array:1 [ "en" => "<p id="spar0070" class="elsevierStyleSimplePara elsevierViewall">Newcastle scale for scoring studies.</p>" ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0015" "bibliografiaReferencia" => array:29 [ 0 => array:3 [ "identificador" => "bib0150" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Epidemiology of atrial fibrillation: the Australian and Asia-Pacific perspective" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:3 [ 0 => "C.X. 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| Ano/Mês | Html | Total | |
|---|---|---|---|
| 2024 Novembro | 3 | 7 | 10 |
| 2024 Outubro | 37 | 40 | 77 |
| 2024 Setembro | 45 | 36 | 81 |
| 2024 Agosto | 41 | 31 | 72 |
| 2024 Julho | 36 | 43 | 79 |
| 2024 Junho | 33 | 26 | 59 |
| 2024 Maio | 41 | 20 | 61 |
| 2024 Abril | 34 | 26 | 60 |
| 2024 Maro | 46 | 23 | 69 |
| 2024 Fevereiro | 34 | 23 | 57 |
| 2024 Janeiro | 45 | 36 | 81 |
| 2023 Dezembro | 38 | 14 | 52 |
| 2023 Novembro | 43 | 36 | 79 |
| 2023 Outubro | 37 | 14 | 51 |
| 2023 Setembro | 37 | 21 | 58 |
| 2023 Agosto | 24 | 19 | 43 |
| 2023 Julho | 35 | 17 | 52 |
| 2023 Junho | 39 | 19 | 58 |
| 2023 Maio | 54 | 29 | 83 |
| 2023 Abril | 35 | 6 | 41 |
| 2023 Maro | 65 | 19 | 84 |
| 2023 Fevereiro | 46 | 19 | 65 |
| 2023 Janeiro | 34 | 18 | 52 |
| 2022 Dezembro | 55 | 23 | 78 |
| 2022 Novembro | 43 | 33 | 76 |
| 2022 Outubro | 89 | 22 | 111 |
| 2022 Setembro | 106 | 41 | 147 |
| 2022 Agosto | 68 | 31 | 99 |
| 2022 Julho | 57 | 42 | 99 |
| 2022 Junho | 35 | 36 | 71 |
| 2022 Maio | 22 | 45 | 67 |
| 2022 Abril | 37 | 37 | 74 |
| 2022 Maro | 39 | 41 | 80 |
| 2022 Fevereiro | 23 | 31 | 54 |
| 2022 Janeiro | 21 | 26 | 47 |
| 2021 Dezembro | 15 | 41 | 56 |
| 2021 Novembro | 30 | 38 | 68 |
| 2021 Outubro | 49 | 40 | 89 |
| 2021 Setembro | 42 | 35 | 77 |
| 2021 Agosto | 55 | 41 | 96 |
| 2021 Julho | 25 | 27 | 52 |
| 2021 Junho | 30 | 22 | 52 |
| 2021 Maio | 34 | 36 | 70 |
| 2021 Abril | 46 | 72 | 118 |
| 2021 Maro | 42 | 30 | 72 |
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| 2020 Dezembro | 145 | 62 | 207 |
| 2020 Novembro | 35 | 10 | 45 |
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