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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Background</span><p id="par0005" class="elsevierStylePara elsevierViewall">Beta-blockers are one of the medical therapies most frequently prescribed to patients with Takotsubo syndrome &#40;TTS&#41; at discharge&#46;<a class="elsevierStyleCrossRef" href="#bib0125"><span class="elsevierStyleSup">1</span></a> Taking into account its physiopathology&#44; it seems logical to use beta-blockers in order to protect against stressful triggers and subsequent catecholamine surges&#46;<a class="elsevierStyleCrossRef" href="#bib0130"><span class="elsevierStyleSup">2</span></a> However&#44; clinical uncertainty exists regarding their effectiveness in reducing mortality in TTS patients&#44; since there is no evidence of any survival benefit of using beta-blockers after hospital discharge&#46;<a class="elsevierStyleCrossRefs" href="#bib0135"><span class="elsevierStyleSup">3&#44;4</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">Moreover&#44; post-discharge beta-blocker therapy does not appear to prevent recurrence&#46; Up to a third of patients experienced a TTS recurrence during treatment with beta-blockers&#44; suggesting that other receptors such as alpha-receptors might be involved&#46;<a class="elsevierStyleCrossRefs" href="#bib0145"><span class="elsevierStyleSup">5&#8211;7</span></a> The International Expert Consensus Document on Takotsubo Syndrome suggests that beta-blockers might be useful for preventing recurrence of TTS in selected patients&#44; especially those with persistent anxiety and elevated sympathetic tone&#46;<a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">8</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">To the best of our knowledge&#44; to date there are no analyses of large-scale datasets that have specifically investigated the impact of beta-blockers on survival after hospital discharge for TTS&#46; The aim of this study is to fill this gap by assessing the long-term prognostic impact of beta-blockers in TTS patients according to the pattern and trigger&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Methods</span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Study population</span><p id="par0020" class="elsevierStylePara elsevierViewall">The analyses were based on data from the national multicenter RETAKO &#40;Registry on Takotsubo Syndrome&#41; trial&#44; supported by the Ischemic Heart Disease and Acute Cardiovascular Care Section of the Spanish Society of Cardiology&#46; It is a partially retrospective and prospective &#40;from January 1&#44; 2012&#44; onwards&#41;&#44; voluntary&#44; observational study that enrolled TTS patients from 38 centers in Spain&#46; Data were collected at each hospital&#44; electronically encrypted and anonymized&#44; and transferred online to a central database&#46; Its rationale and design have been previously described&#46;<a class="elsevierStyleCrossRefs" href="#bib0165"><span class="elsevierStyleSup">9&#44;10</span></a></p><p id="par0025" class="elsevierStylePara elsevierViewall">The main inclusion criteria required a definitive TTS diagnosis based on the modified Mayo Clinic criteria<a class="elsevierStyleCrossRef" href="#bib0175"><span class="elsevierStyleSup">11</span></a>&#58; &#40;1&#41; transient left ventricular dysfunction with apical&#44; midventricular&#44; or basal segmental alterations extending beyond the territory supplied by a single coronary artery&#59; &#40;2&#41; angiographic absence of significant obstructive coronary disease &#40;luminal narrowing &#62;50&#37;&#41; or a complicated &#40;ruptured&#47;thrombosed&#41; atheroma&#59; &#40;3&#41; new electrocardiographic changes &#40;ST-segment elevation and&#47;or negative T waves&#41; and moderate elevation of cardiac troponins&#46; Complete normalization of wall motion abnormalities and left ventricular ejection fraction &#40;LVEF&#41; was required&#44; except in cases that died before complete normalization of LVEF&#46;</p><p id="par0030" class="elsevierStylePara elsevierViewall">Our cohort &#40;N&#61;970&#41; was obtained from 1095 patients with final diagnosis of TTS admitted between January 1&#44; 2003&#44; and July 31&#44; 2018 &#40;see <a class="elsevierStyleCrossRef" href="#fig0005">Figure 1</a>&#41;&#46; We excluded 19 &#40;1&#46;7&#37;&#41; patients who died in the hospital&#59; 14 &#40;1&#46;3&#37;&#41; with missing mortality data&#59; 24 &#40;2&#46;2&#37;&#41; with pheochromocytoma&#59; 21 &#40;1&#46;9&#37;&#41; with left ventricular outflow tract obstruction &#40;LVOTO&#41;&#44; defined as a resting peak instantaneous gradient &#62;25 mmHg in absence of inotropics&#59; 27 &#40;2&#46;5&#37;&#41; with sustained ventricular arrhythmias&#59; and 20 &#40;1&#46;8&#37;&#41; with baseline heart rate &#8804;45 bpm or high degree atrial-ventricular heart block&#46; For the present study&#44; beta-blocker use was determined according to whether eligible patients had received beta-blockers on discharge from the hospital&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0035" class="elsevierStylePara elsevierViewall">The study complied with the Declaration of Helsinki and was approved by the Institutional Ethics Committee of Hospital Cl&#237;nico San Carlos &#40;Madrid&#44; Spain&#41;&#46; All patients provided written informed consent&#46;</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Triggers and pattern of takotsubo syndrome</span><p id="par0040" class="elsevierStylePara elsevierViewall">All the possible triggers in each patient were collected&#46; Patients were categorized into groups according to the types of preceding stressors &#8211; emotional stress&#44; physical stress&#44; and no identifiable trigger &#8211; based on the recently proposed classification&#46;<a class="elsevierStyleCrossRef" href="#bib0180"><span class="elsevierStyleSup">12</span></a> The pattern of LV dysfunction based on angiography or echocardiographic evaluation was classified as apical and non-apical types&#46;<a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">8</span></a> Apical type is characterized by hypokinesia&#44; akinesia or dyskinesia of midventricular and apical parts of the anterior&#44; septal&#44; inferior and lateral walls of the left ventricle&#44; associated with hyperkinesia of basal segments&#46; Non-apical pattern includes all the remaining types &#40;basal&#44; midventricular&#44; and focal types&#41;&#46;</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Follow-up and outcomes</span><p id="par0045" class="elsevierStylePara elsevierViewall">Follow-up after hospital discharge was conducted either by outpatient clinical visits or structured telephone interviews with patients or relatives&#46; Follow-up outcomes were pre-specified and defined as the first non-fatal TTS recurrence or the occurrence of all-cause death&#46; Recurrence was considered if a documented new non-fatal episode met the diagnostic criteria for TTS&#46;<a class="elsevierStyleCrossRef" href="#bib0175"><span class="elsevierStyleSup">11</span></a> If a pre-specified outcome was observed&#44; review of electronic medical records and consensus of two experienced local investigators were mandatory for event adjudication&#46; Patients were censored if they did not experience the outcome of interest or were lost to follow-up&#46;</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Statistical analysis</span><p id="par0050" class="elsevierStylePara elsevierViewall">Baseline characteristics according to treatment with beta-blockers were described by using number and percentage for categorical data and mean<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>standard difference for continuous data&#46; Differences in characteristics were assessed by using Chi-square tests and two-sample Student t-tests&#44; for categorial and continuous variables&#44; respectively&#46;</p><p id="par0055" class="elsevierStylePara elsevierViewall">The association between beta-blocker therapy and survival free of TTS recurrence was studied in robust Cox regression analysis&#46; Multivariable model risk adjustments were performed with all variables associated with the combined outcome of post-discharge mortality or TTS recurrence based on clinical plausibility or p-value &#60;0&#46;1 in the univariate Cox analyses &#40;<a class="elsevierStyleCrossRef" href="#sec0095">Table 1 of the supplementary data</a>&#41;&#46; Estimates were expressed as hazard ratios &#40;HRs&#41; with their 95&#37; confidence interval &#40;CI&#41;&#46; Proportionality of risk assumption of survival models was evaluated by plotting Schoenfeld residuals or by studying the interaction of covariates with time for the Cox proportional hazard models&#46;</p><p id="par0060" class="elsevierStylePara elsevierViewall">Given the substantial differences in key baseline characteristics depending on prescription of beta-blocker therapy&#44; we performed a sensitivity analysis using a propensity score &#40;PS&#41; analysis&#46; PSs were estimated using a non-parsimonious multivariable logistic regression model&#44; with beta-blocker therapy as the dependent variable and those characteristics that differed between patients treated and not treated with beta-blockers &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41; as covariates&#46; Survival time inverse probability weighting &#40;IPW&#41; PS analysis was used to evaluate the association between beta-blocker therapy and survival free of TTS recurrence&#46; The effect of beta-blockers was graphically represented in Kaplan-Meier curves adjusted by IPW&#44; to balance the covariate distribution between the treatment and control observations&#46;<a class="elsevierStyleCrossRef" href="#bib0185"><span class="elsevierStyleSup">13</span></a> We complemented the analysis with an augmented IPW &#40;AIPW&#41; to estimate the average treatment effect &#40;ATE&#41; of beta-blockers in one-year survival free of TTS recurrence&#44; using a doubly robust method that combined both the properties of the regression-based estimator and the IPW estimator&#46;<a class="elsevierStyleCrossRef" href="#bib0190"><span class="elsevierStyleSup">14</span></a> Subsequent PS matching &#40;PSM&#41; was performed to assemble a cohort in which all the measured covariates would be well balanced across the comparator group&#46; PSM was performed with 1&#58;1 nearest-neighbor matching without replacement and with a caliper width of 0&#46;2 of the standard deviation of all PSs&#46; Standard mean differences were estimated for all covariates before and after matching to assess pre-matching imbalance and post-matching balance&#59; standard mean differences of &#60;10&#37; for a given covariate were considered as indicators of adequate balance &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#41;&#46; In the PS-matched population&#44; the reduction in mortality and&#47;or TTS recurrence was compared using a stratified Cox regression model&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><elsevierMultimedia ident="tbl0010"></elsevierMultimedia><p id="par0065" class="elsevierStylePara elsevierViewall">Analysis of follow-up mortality and TTS recurrence was also performed in subgroups defined according to age &#40;&#60;75 years or &#8805;75 years&#41;&#44; sex&#44; presence of coronary artery disease&#44; atrial fibrillation&#47;flutter&#44; chronic obstructive pulmonary disease &#40;COPD&#41;&#44; Killip class&#44; status of cardiogenic shock&#44; and therapy with angiotensin-converting enzyme inhibitors or angiotensin receptor blockers &#40;ACEI&#47;ARB&#41; on discharge&#46; Treatment-by-subgroup interactions were tested using a Cox proportional hazards model adjusted by IPW&#44; containing the beta-blocker therapy&#44; subgroup&#44; and the treatment-by-subgroup interaction&#46;</p><p id="par0070" class="elsevierStylePara elsevierViewall">A two-tailed p&#60;0&#46;05 indicated statistical significance&#46; Statistical analyses were performed using Stata 15&#46;1 &#40;StataCorp&#44; College Station&#44; Texas&#41;&#46;</p></span></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">Results</span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0110">Comparison of Takotsubo patients treated and untreated with beta-blockers</span><p id="par0075" class="elsevierStylePara elsevierViewall">Among the 970 patients with TTS included in this study&#44; 582 patients &#40;60&#46;0&#37;&#41; were treated with beta-blockers&#46; There were significant differences in baseline characteristics between patients with and without beta-blocker treatment &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#46; In particular&#44; patients who did not receive beta-blockers were more frequently comorbid&#44; including COPD &#40;20&#46;6&#37; vs&#46; 11&#46;9&#37;&#41; and history of cancer &#40;13&#46;9&#37; vs&#46; 9&#46;3&#37;&#41;&#46; Compared with patients untreated with beta-blockers&#44; those who received beta-blockers tended to be treated with higher rates of aspirin &#40;56&#46;5&#37; vs&#46; 32&#46;2&#37;&#59; p&#60;0&#46;001&#41;&#44; ACEI&#47;ARB &#40;73&#46;2&#37; vs&#46; 43&#46;3&#37;&#59; p&#60;0&#46;001&#41;&#44; and statins &#40;59&#46;3&#37; vs&#46; 34&#46;0&#37;&#59; p&#60;0&#46;001&#41;&#46;</p></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0115">Prognosis according to beta-blocker therapy</span><p id="par0080" class="elsevierStylePara elsevierViewall">For the entire cohort&#44; during a mean follow-up of 2&#46;5<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>3&#46;3 years&#44; there were 87 deaths &#40;3&#46;6 per 100 patients&#47;year&#41; and 29 TTS recurrences &#40;1&#46;2 per 100 patients&#47;year&#41;&#46; Unadjusted mortality rates were similar for patients who received beta-blockers compared with those who did not &#91;3&#46;3 &#40;95&#37; CI 2&#46;4&#8211;4&#46;3&#41; vs&#46; 4&#46;2 &#40;95&#37; CI 3&#46;1&#8211;5&#46;7&#41; per 100 patients&#47;year&#44; respectively&#59; p&#61;0&#46;254&#41;&#93;&#46; A similar result was found for TTS recurrence &#91;1&#46;4 &#40;95&#37; CI 0&#46;9&#8211;2&#46;1&#41; vs&#46; 0&#46;9 &#40;95&#37; CI 0&#46;4&#8211;1&#46;8&#41; per 100 patients&#47;year&#44; respectively&#59; p&#61;0&#46;278&#41;&#93;&#46; After multivariate adjustment &#40;including age&#44; sex&#44; hypertension&#44; diabetes mellitus&#44; smoking&#44; coronary artery disease&#44; prior stroke&#44; prior beta-blocker therapy&#44; COPD&#44; history of cancer&#44; Killip&#8805;II on admission&#44; atrial fibrillation&#47;flutter&#44; creatinine &#8805;1&#46;5 mg&#47;dl&#44; apical vs&#46; non-apical TTS&#44; emotional or physical trigger&#44; and medication at discharge &#8211; aspirin&#44; P2Y12 inhibitors&#44; oral anticoagulation&#44; ACEI&#47;ARB&#44; calcium channel blockers&#44; diuretics&#44; statins&#44; anxiolytics&#44; and antidepressants&#41;&#44; there were no significant differences in the composite outcome of mortality or TTS recurrence between patients treated and untreated with beta-blockers &#40;adjusted HR 0&#46;95&#44; 95&#37; CI 0&#46;57&#8211;1&#46;53&#59; p&#61;0&#46;794&#41;&#46;</p></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0120">Propensity score analysis</span><p id="par0085" class="elsevierStylePara elsevierViewall">For the balanced PS analysis&#44; 566 patients were removed &#40;380 from the beta-blocker group and 186 from the non-beta-blocker group&#41;&#44; leaving 404 patients &#40;202 in each group&#41;&#46; Overlap assumption assessment and balance checks were conducted and the results are summarized in <a class="elsevierStyleCrossRef" href="#sec0095">Table 2 of the supplementary data</a>&#46; The area under the curve for the PS model was 0&#46;87 &#40;95&#37; CI 0&#46;85&#8211;0&#46;89&#41;&#44; which indicated a good discrimination for the model&#46; Beta-blocker therapy was not associated with significant differences in dmortality or TTS recurrence neither after adjusting by IPW &#40;<a class="elsevierStyleCrossRef" href="#fig0010">Figure 2</a>&#41; nor after PS matching &#40;HR 0&#46;85&#44; 95&#37; CI 0&#46;46&#8211;1&#46;60&#44; p&#61;0&#46;621&#41;&#46; After weighting and adjustment&#44; differences in one-year survival free of TTS recurrence between patients treated and untreated with beta-blockers were not found &#40;average treatment effect &#40;ATE&#41; 95&#37; &#8722;0&#46;01 95&#37; CI &#8722;0&#46;07 to 0&#46;04&#59; p&#61;0&#46;621&#41; &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#41;&#46;</p><elsevierMultimedia ident="fig0010"></elsevierMultimedia></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0125">Impact of beta-blocker therapy according to Takotsubo syndrome type and trigger</span><p id="par0090" class="elsevierStylePara elsevierViewall">Beta-blocker therapy was similarly prescribed in the four major TTS types &#40;<a class="elsevierStyleCrossRef" href="#fig0015">Figure 3</a>A&#41;&#46; Lack of benefit of beta-blockers in terms of follow-up mortality and&#47;or TTS recurrence was consistent across different TTS types &#40;<a class="elsevierStyleCrossRef" href="#fig0020">Figure 4</a>&#58; central illustration&#41;&#46; In the PS-matched population&#44; the HR for mortality or TTS recurrence of beta-blockers in patients with apical TTS was 0&#46;68 &#40;95&#37; CI 0&#46;34&#8211;1&#46;36&#44; p-value&#61;0&#46;277&#41;&#44; and in patients with non-apical TTS was 2&#46;62 &#40;95&#37; CI 0&#46;54&#8211;12&#46;65&#44; p-value&#61;0&#46;231&#41;&#46; Regarding to the trigger&#44; beta-blocker therapy was most frequently prescribed in patients with TTS related to emotional stress &#40;68&#46;4&#37; vs&#46; 52&#46;5&#37; in TTS related to physical stress&#44; and 57&#46;7&#37; in TTS without an identifiable triggering factor&#41; &#40;<a class="elsevierStyleCrossRef" href="#fig0015">Figure 3</a>B&#41;&#46; However&#44; no differences in mortality and TTS recurrence were found between patients treated and untreated with beta-blockers&#44; neither after PSM &#40;<a class="elsevierStyleCrossRef" href="#fig0020">Figure 4</a>&#58; central illustration&#41; nor after IPW &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#41;&#46;</p><elsevierMultimedia ident="fig0015"></elsevierMultimedia><elsevierMultimedia ident="fig0020"></elsevierMultimedia></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0130">Subgroup analysis</span><p id="par0095" class="elsevierStylePara elsevierViewall">Subgroup analysis after adjusting by IPW has not found a benefit of beta-blockers in any group &#40;<a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>&#41;&#46; Even in patients with COPD&#44; beta-blockers were associated with higher rates of mortality or TTS recurrence &#40;HR 2&#46;42&#44; 95&#37; CI 1&#46;07&#8211;5&#46;49&#59; p&#61;0&#46;034&#41; &#40;<a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>&#41;&#46;</p><elsevierMultimedia ident="tbl0015"></elsevierMultimedia></span></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0135">Discussion</span><p id="par0100" class="elsevierStylePara elsevierViewall">In this observational nationwide cohort study of TTS survivors&#44; the use of beta-blockers was not associated with mortality or TTS recurrence&#46;</p><p id="par0105" class="elsevierStylePara elsevierViewall">A major role of excessive adrenergic overstimulation leading to myocardial stunning has been advocated as possible explanation of the pathophysiology of TTS&#46;<a class="elsevierStyleCrossRef" href="#bib0130"><span class="elsevierStyleSup">2</span></a> In this context&#44; beta-blockers could potentially reduce the myocardial damage caused by a sympathetic drive&#46; However&#44; our results have not confirmed this hypothesis&#46; Moreover&#44; our lack of association between beta-blockers in TTS and poor outcomes are consistent with other previous studies&#46; In this sense&#44; Isogai et al&#46; examined whether early beta-blocker therapy in patients with TTS was associated with lower in-hospital mortality&#46;<a class="elsevierStyleCrossRef" href="#bib0135"><span class="elsevierStyleSup">3</span></a> Using PSM and instrumental variable analyses in 2672 TTS patients&#44; they did not find significant association between early beta-blocker use and in-hospital mortality &#40;odds ratio &#40;OR&#41; 1&#46;08&#44; 95&#37; CI 0&#46;59&#8211;1&#46;96&#44; p&#61;0&#46;812&#41;&#46; In addition to the results of the Japanese TTS registry&#44; in the InterTAK study there was no evidence of any survival benefit at one year for the use of beta-blockers&#46;<a class="elsevierStyleCrossRef" href="#bib0140"><span class="elsevierStyleSup">4</span></a> Moreover&#44; of 57 patients with recurrent TTS in the InterTAK&#44; 29 were taking beta-blockers at the time of the second event&#46; And two meta-analyses were consistent with the neutral effect of beta-blockers in survival free of TTS recurrence&#46; In the meta-analysis of Singh et al&#46;&#44; with 847 patients&#44; there was no significant association between the rate of TTS recurrence and use of beta-blockers &#40;p&#61;0&#46;280&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0155"><span class="elsevierStyleSup">7</span></a> Similarly&#44; in the meta-analysis of clinical non-randomized registries conducted by Santoro et al&#46;&#44; with 471 subjects&#44; the recurrence rate was 1&#46;81&#37; &#40;6 of 331&#41; in those treated with beta-blockers&#44; compared with 2&#46;86&#37; &#40;4 of 140&#41; in controls &#40;OR&#58; 0&#46;44&#44; 95&#37; CI&#58; 0&#46;15&#8211;1&#46;31&#44; p&#61;0&#46;790&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">6</span></a> All these data suggest that beta-blockers are not effective in preventing TTS&#46;</p><p id="par0110" class="elsevierStylePara elsevierViewall">One possible pathophysiological explanation justifying our findings might be that the potential protective effect of beta-blockers might be hampered by some paradox phenomena&#46; Paur et al&#46; have proved that beta-blockers that activate beta2 adrenoceptor &#40;AR&#41; to inhibitory G &#40;G<span class="elsevierStyleInf">i</span>&#41; protein signaling &#40;beta<span class="elsevierStyleInf">2</span>AR-G<span class="elsevierStyleInf">i</span>&#41; might exacerbate the epinephrine-induced negative inotropic effect&#46;<a class="elsevierStyleCrossRef" href="#bib0195"><span class="elsevierStyleSup">15</span></a> High doses of epinephrine can act as a negative inotrope via ligand-mediated trafficking of the beta<span class="elsevierStyleInf">2</span>-AR from stimulatory G &#40;G<span class="elsevierStyleInf">s</span>&#41; protein to G<span class="elsevierStyleInf">i</span> protein subcellular signaling pathways&#44; a process described as biased agonism&#46;<a class="elsevierStyleCrossRef" href="#bib0200"><span class="elsevierStyleSup">16</span></a> This switch would be favored in conditions of high catecholamine stress because it depends on beta<span class="elsevierStyleInf">2</span>-AR phosphorylation by both protein kinase A &#40;PKA&#41; and G-protein receptor-coupled kinases &#40;GRKs&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0205"><span class="elsevierStyleSup">17</span></a> This is particularly relevant given the increased frequency of the L41Q GRK5 polymorphism&#44; known to increase cardiac GRK5 activity and beta-AR phosphorylation&#44; in a recent study that genotyped patients with Takotsubo cardiomyopathy&#46;<a class="elsevierStyleCrossRef" href="#bib0210"><span class="elsevierStyleSup">18</span></a> The G<span class="elsevierStyleInf">i</span>-dependent negative effect of beta-blockers was most readily seen in myocytes from failing human hearts &#40;in which G<span class="elsevierStyleInf">i</span> is increased&#41;&#44; but the group of Paur et al&#46; also analyzed it in TTS patients&#46;<a class="elsevierStyleCrossRef" href="#bib0195"><span class="elsevierStyleSup">15</span></a> They evaluated the response of a TTS animal model induced by epinephrine bolus infusion to a propranolol&#44; carvedilol and bisoprolol&#46; Propranolol&#44; a beta-blocker with higher beta<span class="elsevierStyleInf">2</span>-AR-G<span class="elsevierStyleInf">i</span> agonism&#44; enhanced the negative effects of epinephrine at both apex and base&#44; whereas carvedilol&#44; with lower beta<span class="elsevierStyleInf">2</span>-AR-G<span class="elsevierStyleInf">i</span> agonism&#44; had little effect on the apex but decreased the base contraction&#46; In contrast&#44; the beta<span class="elsevierStyleInf">1</span>-AR selective blocker bisoprolol reduced the positive effect of epinephrine at the base but without effect on the apical epinephrine response&#46; Therefore&#44; drugs with high beta<span class="elsevierStyleInf">2</span>-AR-G<span class="elsevierStyleInf">i</span> agonism &#40;e&#46;g&#46;&#44; propranolol&#44; carvedilol&#41; should be avoided in TTS patients&#46; In this sense&#44; there are very few studies that evaluated the impact of the type of beta-blocker on clinical outcomes in this context&#46; A retrospective study by Palla et al&#46; found that&#44; in 64 patients with TTS&#44; of which 16 were taking a beta-blocker on presentation &#40;metoprolol succinate &#91;50&#37;&#93;&#44; metoprolol tartrate &#91;37&#46;5&#37;&#93;&#44; or atenolol &#91;12&#46;5&#37;&#93;&#41;&#44; pretreatment with low dose beta-adrenergic antagonist therapy does not affect severity of TTS presentation&#46;<a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">19</span></a> Another important issue that remains to be elucidated is the role of beta-blockers dose&#46; The adrenergic blockade achieved with commonly used doses of beta-adrenergic antagonists may not be sufficient to effectively antagonize the supraphysiologic&#46; Unfortunately&#44; we lack information about the type and dose of beta-blocker therapy&#46;</p><p id="par0115" class="elsevierStylePara elsevierViewall">In our subgroup analysis&#44; there was a significant interaction between beta-blocker therapy and COPD on follow-up mortality or TTS recurrence&#46; In COPD patients with TTS&#44; beta-blockers were associated with higher rates of mortality or TTS recurrence&#44; whereas in non-COPD patients&#44; survival free of TTS recurrence was similar in patients treated and untreated with beta-blockers&#46; Although this result should be interpreted cautiously because of the number of patients and the observational &#8211; non-randomized &#8211; nature of our study&#44; these findings are consistent with the results from the prospective&#44; randomized&#44; BLOCK COPD trial&#44; that showed metoprolol treatment was associated with almost double the risk of experiencing an exacerbation leading to hospitalization &#40;HR 1&#46;91&#44; 95&#37; CI 1&#46;29&#8211;2&#46;83&#41; in COPD patients without cardiovascular disease&#46;<a class="elsevierStyleCrossRef" href="#bib0220"><span class="elsevierStyleSup">20</span></a></p><p id="par0120" class="elsevierStylePara elsevierViewall">Regarding cardiogenic shock&#44; we have not found an interaction or benefit of beta-blockers in TTS patient with or without cardiogenic shock&#46; Almendro-Delia et al&#46; have previously found a possible association between beta-blockers and a better long-term prognosis of TTS patients&#46;<a class="elsevierStyleCrossRef" href="#bib0165"><span class="elsevierStyleSup">9</span></a> Individuals prone to developing hemodynamic instability and cardiogenic shock in the acute phase of TTS may constitute a high-risk phenotype in which predisposing factors could converge&#58; &#40;1&#41; an exaggerated sympathetic activation in response to triggering events&#59; &#40;2&#41; greater susceptibility to catecholamine mediated myocardial injury&#59; or &#40;3&#41; the presence of a decreased cardiac reserve masking a long-term heart failure phenotype as a marker for underlying disease severity&#46;<a class="elsevierStyleCrossRef" href="#bib0165"><span class="elsevierStyleSup">9</span></a> The preceding features could lead to a potential long-term prognostic benefit of beta-blockers in TTS patients who present with cardiogenic shock&#46; However&#44; our results&#44; after excluding patients with LVOTO and ventricular arrhythmias&#44; have not confirmed those hypotheses&#46;</p><p id="par0125" class="elsevierStylePara elsevierViewall">To date neither the short- nor long-term prognostic impact of beta-blockers according to the type and trigger of TTS has been proven&#46;<a class="elsevierStyleCrossRef" href="#bib0225"><span class="elsevierStyleSup">21</span></a> Previous studies have suggested the existence of different phenotypes within the clinical spectrum of TTS&#44; with different prognosis&#46;<a class="elsevierStyleCrossRefs" href="#bib0140"><span class="elsevierStyleSup">4&#44;12</span></a> In our study&#44; we have assessed the prognosis of beta-blocker therapy in patients with apical versus non-apical TTS&#46; It has been recently shown that the apical ventricular region has a greater beta2&#58;beta1&#160;adrenoceptor ratio&#44; with a higher responsiveness and vulnerability to sympathetic stimulation&#46;<a class="elsevierStyleCrossRef" href="#bib0230"><span class="elsevierStyleSup">22</span></a> The different occurrence of wall motion abnormalities could be explained by interindividual anatomical differences in the distribution of beta-adrenergic receptors&#46; Although in our study treatment with beta-blockers was associated with better prognosis in patients with apical TTS and worse prognosis in those with non-apical TTS&#44; the differences were not significant&#46; Regarding the trigger&#44; we have not found a benefit of beta-blockers in any of the three groups &#40;emotional stress&#44; physical stress&#44; and no identifiable trigger&#41;&#46;</p><p id="par0130" class="elsevierStylePara elsevierViewall">Finally&#44; although the present study did not investigate the underlying pathophysiology of TTS&#44; our results regarding beta-blocker therapy might suggest that other pathophysiological pathways such as an inflammatory<a class="elsevierStyleCrossRef" href="#bib0235"><span class="elsevierStyleSup">23</span></a> or energetic-metabolic pathway<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">24</span></a> need to be explored to identify a suitable therapy for TTS&#46;</p><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0140">Study limitations</span><p id="par0135" class="elsevierStylePara elsevierViewall">Our results should be interpreted in the context of several limitations&#46; First&#44; it is possible that various subclasses&#44; doses and durations of beta-blocker therapy were used in this study&#46; This heterogeneity of beta-blocker therapy might have affected the outcomes&#46; However&#44; those data were not collected in our registry&#46; In addition&#44; we have no data about rates of discontinuation or new prescriptions during follow-up&#46; Second&#44; because of its observational nature&#44; unmeasured confounders constrain causal inference in the present study&#46; Although propensity scoring and further adjustments were made for many additional confounders in the survival models&#44; residual confounding is likely to happen anyway&#46; So cautious interpretation is encouraged and&#44; therefore&#44; prognostic associations should be considered exploratory&#46; Nonetheless&#44; our results are consistent with other non-randomized data&#46; Clearly&#44; a randomized controlled trial is necessary to further investigate the issues surrounding beta-blocker use in TTS&#46;</p></span></span><span id="sec0075" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0145">Conclusions</span><p id="par0140" class="elsevierStylePara elsevierViewall">Among TTS patients who survived hospitalization&#44; beta-blocker therapy was not associated with lower mortality and TTS recurrence after addressing potential confounding by adjusting and using PS methods&#46; This result adds to the increasing body of evidence that the routine prescription of beta-blockers might not be indicated in patients with TTS&#46;</p></span><span id="sec0080" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0150">Funding</span><p id="par0145" class="elsevierStylePara elsevierViewall">The Retako webpage was funded by a non-conditional <span class="elsevierStyleGrantSponsor" id="gs1">Astrazeneca scholarship</span>&#46;</p></span><span id="sec0085" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0155">Conflict of interest</span><p id="par0150" class="elsevierStylePara elsevierViewall">None declared&#46;</p></span></span>"
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        "titulo" => "Abstract"
        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Background</span><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">No evidence-based therapy has yet been established for Takotsubo syndrome &#40;TTS&#41;&#46; Given the putative harmful effects of catecholamines in patients with TTS&#44; beta-blockers may potentially decrease the intensity of the detrimental cardiac effects in those patients&#46;</p></span> <span id="abst0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Objective</span><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">The purpose of this study was to assess the impact of beta-blocker therapy on long-term mortality and TTS recurrence&#46;</p></span> <span id="abst0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Methods</span><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">The cohort study used the national Spanish Registry on TakoTsubo Syndrome &#40;RETAKO&#41;&#46; A total of 970 TTS post-discharge survivors&#44; without pheochromocytoma&#44; left ventricular outflow tract obstruction&#44; sustained ventricular arrhythmias&#44; and significant bradyarrhythmias&#44; between January 1&#44; 2003&#44; and July 31&#44; 2018&#44; were assessed&#46; Cox regression analysis and inverse probability weighting &#40;IPW&#41; propensity score analysis were used to evaluate the association between beta-blocker therapy and survival free of TTS recurrence&#46;</p></span> <span id="abst0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Results</span><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">From 970 TTS patients&#44; 582 &#40;60&#46;0&#37;&#41; received beta-blockers&#46; During a mean follow-up of 2&#46;5<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>3&#46;3 years&#44; there were 87 deaths &#40;3&#46;6 per 100 patients&#47;year&#41; and 29 TTS recurrences &#40;1&#46;2 per 100 patient&#47;year&#41;&#46; There was no significant difference in follow-up mortality or TTS recurrence in unadjusted and adjusted Cox analysis &#40;hazard ratio &#91;HR&#93; 0&#46;86&#44; 95&#37; confidence interval &#91;CI&#93; 0&#46;59&#8211;1&#46;27&#44; and 0&#46;95&#44; 95&#37; CI 0&#46;57&#8211;1&#46;13&#44; respectively&#41;&#46; After weighting and adjusting by IPW&#44; differences in one-year survival free of TTS recurrence between patients treated and untreated with beta-blockers were not found &#40;average treatment effect &#8722;0&#46;01&#44; 95&#37; CI &#8722;0&#46;07 to 0&#46;04&#59; p&#61;0&#46;621&#41;&#46;</p></span> <span id="abst0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Conclusions</span><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">In this observational nationwide study from Spain&#44; there was no significant association between beta-blocker therapy and follow-up survival free of TTS recurrence&#46;</p></span>"
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        "resumen" => "<span id="abst0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Introdu&#231;&#227;o</span><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Ainda n&#227;o foi estabelecido um tratamento baseado na evid&#234;ncia para a s&#237;ndrome de Takotsubo &#40;STT&#41;&#46; Dados os efeitos supostamente nocivos das catecolaminas em doentes com STT&#44; os betabloqueantes podem potencialmente diminuir a intensidade dos seus efeitos prejudiciais nesses doentes&#46;</p></span> <span id="abst0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Objetivo</span><p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Avaliar o impacto da terap&#234;utica com betabloqueantes na mortalidade a longo prazo e na recidiva da STT&#46;</p></span> <span id="abst0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">M&#233;todos</span><p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">O estudo coorte utilizou o registo nacional espanhol da s&#237;ndrome de Takotsubo &#40;RETAKO&#41;&#46; Foram avaliados 970 sobreviventes de STT ap&#243;s a alta&#44; sem feocromocitoma&#44; sem obstru&#231;&#227;o do trato de sa&#237;da do ventr&#237;culo esquerdo&#44; sem arritmias ventriculares mantidas e sem bradiarritmias significativas&#44; entre 1 de janeiro de 2003 e 31 de julho de 2018&#46; A an&#225;lise de regress&#227;o de Cox e a an&#225;lise da pondera&#231;&#227;o de probabilidade inversa &#40;PPI&#41; foram utilizadas para avaliar a associa&#231;&#227;o entre a terapia com betabloqueantes e a sobreviv&#234;ncia sem recidiva de STT&#46;</p></span> <span id="abst0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Resultados</span><p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">Dos 970 doentes com STT&#44; 582 &#40;60&#44;0&#37;&#41; foram tratados com betabloqueantes&#46; Durante um seguimento m&#233;dio de 2&#44;5<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>3&#44;3 anos&#44; houve 87 mortes &#40;3&#44;6 por 100 doentes&#47;ano&#41; e 29 recidivas de STT &#40;1&#44;2 por 100 doentes&#47;ano&#41;&#46; N&#227;o se verificaram diferen&#231;as significativas na mortalidade durante o seguimento&#44; nem na recidiva de STT na an&#225;lise Cox n&#227;o ajustada e ajustada &#40;<span class="elsevierStyleItalic">Hazard Ratio</span> &#91;HR&#93; 0&#44;86&#44; Intervalo de Confian&#231;a &#91;IC&#93; 95&#37;&#44; 0&#44;59-1&#44;27 e IC 95&#37;&#8722;0&#44;57-1&#44;13&#44; respetivamente&#41;&#46; Ap&#243;s pondera&#231;&#227;o e ajuste por PPI&#44; n&#227;o foram tamb&#233;m encontradas diferen&#231;as na sobreviv&#234;ncia a um ano e na recidiva de STT entre doentes tratados e n&#227;o tratados com betabloqueantes &#40;efeito m&#233;dio do tratamento &#8722;0&#44;01&#44; IC 95&#37; &#8722;0&#44;07 a 0&#44;04&#59; p&#61;0&#44;621&#41;&#46;</p></span> <span id="abst0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Conclus&#227;o</span><p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">Neste estudo observacional de &#226;mbito nacional em Espanha&#44; n&#227;o houve associa&#231;&#227;o significativa entre a terap&#234;utica com betabloqueantes e a sobreviv&#234;ncia ou recidivas de STT&#46;</p></span>"
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">p-Value&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleItalic">Female sex</span>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleItalic">Cardiovascular risk factors</span></td></tr><tr title="table-row"><td class="td-with-role" title="\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Smoking&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">66 &#40;11&#46;3&#37;&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">59 &#40;15&#46;2&#37;&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Hypertension&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">393 &#40;67&#46;5&#37;&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Dyslipemia&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">272 &#40;46&#46;7&#37;&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">172 &#40;44&#46;3&#37;&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">0&#46;461&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Diabetes mellitus&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">112 &#40;19&#46;2&#37;&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">72 &#40;18&#46;6&#37;&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">0&#46;789&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " colspan="5" align="left" valign="\n
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                  \t\t\t\t"><span class="elsevierStyleItalic">Cardiovascular history</span></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
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Peripheral artery disease&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">32 &#40;3&#46;3&#37;&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">22 &#40;3&#46;8&#37;&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">10 &#40;2&#46;6&#37;&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">0&#46;304&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Coronary artery disease&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">70 &#40;7&#46;2&#37;&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">40 &#40;6&#46;9&#37;&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">30 &#40;7&#46;7&#37;&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">0&#46;612&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Prior stroke&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">70 &#40;7&#46;2&#37;&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">50 &#40;8&#46;6&#37;&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">20 &#40;5&#46;2&#37;&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">0&#46;043&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleVsp" style="height:0.5px"></span></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
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                  \t\t\t\t"><span class="elsevierStyleItalic">Prior beta-blocker therapy</span>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">91 &#40;9&#46;4&#37;&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">72 &#40;12&#46;4&#37;&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">19 &#40;4&#46;9&#37;&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">&#60;0&#46;001&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " colspan="5" align="left" valign="\n
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                  \t\t\t\t"><span class="elsevierStyleItalic">Comorbidities</span></td></tr><tr title="table-row"><td class="td-with-role" title="\n
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                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>COPD&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">149 &#40;15&#46;4&#37;&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">69 &#40;11&#46;9&#37;&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">80 &#40;20&#46;6&#37;&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">&#60;0&#46;001&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>History of cancer&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">108 &#40;11&#46;1&#37;&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">54 &#40;9&#46;3&#37;&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">54 &#40;13&#46;9&#37;&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">0&#46;024&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleItalic">Presenting characteristics</span></td></tr><tr title="table-row"><td class="td-with-role" title="\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Killip&#8805;II at admission&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Atrial fibrillation&#47;flutter&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Bundle brunch block&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Creatinine &#62;1&#46;5 mg&#47;dl&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleItalic">Treatment at discharge</span></td></tr><tr title="table-row"><td class="td-with-role" title="\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Aspirin&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>P2Y12 inhibitor&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Oral anticoagulation&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>ACEI&#47;ARB&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">168 &#40;43&#46;3&#37;&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Calcium channel blockers&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">85 &#40;8&#46;8&#37;&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">47 &#40;12&#46;1&#37;&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Nitrates&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">35 &#40;3&#46;6&#37;&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">21 &#40;3&#46;6&#37;&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">14 &#40;3&#46;6&#37;&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">1&#46;00&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Diuretics&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">227 &#40;23&#46;4&#37;&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">147 &#40;25&#46;3&#37;&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">80 &#40;20&#46;6&#37;&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">0&#46;095&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Statins&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">477 &#40;49&#46;2&#37;&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">345 &#40;59&#46;3&#37;&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">132 &#40;34&#46;0&#37;&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">&#60;0&#46;001&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Anxiolytic medication&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">268 &#40;27&#46;6&#37;&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttop\n
                  \t\t\t\t">81 &#40;20&#46;9&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t">&#60;0&#46;001&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Antidepressant therapy&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">130 &#40;13&#46;4&#37;&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttop\n
                  \t\t\t\t">90 &#40;15&#46;5&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t\ttop\n
                  \t\t\t\t">40 &#40;10&#46;3&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t">0&#46;021&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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          "leyenda" => "<p id="spar0095" class="elsevierStyleSimplePara elsevierViewall">ATE&#58; average treatment effect&#59; TTS&#58; Takotsubo syndrome&#46;</p><p id="spar0100" class="elsevierStyleSimplePara elsevierViewall">The average treatment effects &#40;ATEs&#41; represent the absolute difference in mortality or TTS recurrence at one year between beta-blockers treatment versus no treatment across the whole cohort &#40;comparing mortality and TTS recurrence in a scenario in which all patients were treated versus mortality and TTS recurrence in a scenario in which no patients were treated&#41;&#46;</p>"
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                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col">TTS population and subgroups&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-head\n
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                  \t\t\t\t">0&#46;292&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Non identifiable trigger&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t">0&#46;132&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>&#60;75 years&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">0&#46;55&#8211;2&#46;21&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>&#8805;75 years&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">0&#46;84&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;52&#8211;1&#46;37&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t">0&#46;423&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="5" align="left" valign="\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Female&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t">0&#46;51&#8211;7&#46;44&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;334&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " rowspan="2" align="center" valign="middle">0&#46;136</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"><span class="elsevierStyleHsp" style=""></span>Male&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
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                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;50&#8211;1&#46;14&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
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                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="5" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="5" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Coronary artery disease</span></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"><span class="elsevierStyleHsp" style=""></span>Yes&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&#46;64&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;48&#8211;5&#46;67&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;433&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " rowspan="2" align="center" valign="middle">0&#46;339</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"><span class="elsevierStyleHsp" style=""></span>No&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
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                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t">0&#46;53&#8211;1&#46;21&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t\ttop\n
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                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="5" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="5" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Atrial fibrillation&#47;flutter</span></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"><span class="elsevierStyleHsp" style=""></span>Yes&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
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                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;29&#8211;1&#46;45&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;294&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " rowspan="2" align="center" valign="middle">0&#46;628</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"><span class="elsevierStyleHsp" style=""></span>No&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
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                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;56&#8211;1&#46;38&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;568&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="5" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="5" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">COPD</span></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"><span class="elsevierStyleHsp" style=""></span>Yes&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;75&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;47&#8211;1&#46;18&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;212&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " rowspan="2" align="center" valign="middle">0&#46;004</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"><span class="elsevierStyleHsp" style=""></span>No&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2&#46;42&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&#46;07&#8211;5&#46;49&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;034&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="5" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="5" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Killip class</span></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"><span class="elsevierStyleHsp" style=""></span>I&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;94&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;53&#8211;1&#46;64&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;823&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " rowspan="2" align="center" valign="middle">0&#46;644</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"><span class="elsevierStyleHsp" style=""></span>&#8805;II&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
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                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
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                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
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                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="5" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="5" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Cardiogenic shock</span></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"><span class="elsevierStyleHsp" style=""></span>Yes&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;31&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;10&#8211;1&#46;59&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;162&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " rowspan="2" align="center" valign="middle">0&#46;163</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"><span class="elsevierStyleHsp" style=""></span>No&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;93&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;62&#8211;1&#46;40&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;731&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="5" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="5" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">ACEI&#47;ARB</span></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"><span class="elsevierStyleHsp" style=""></span>Yes&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&#46;02&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
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                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;945&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " rowspan="2" align="center" valign="middle">0&#46;866</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"><span class="elsevierStyleHsp" style=""></span>No&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
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                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;53&#8211;1&#46;62&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;794&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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