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Background
Few data are available on long-term drug therapy and its potential prognostic impact after Takotsubo syndrome (TTS). Aim of the study is to evaluate clinical characteristics and long-term outcome of TTS patients on Renin Angiotensin system inhibitors (RASi).
MethodsTTS patients were enrolled in the international multicenter GEIST (GErman Italian Spanish Takotsubo) registry. Median follow-up was 31 (Interquartile range 12-56) months. Comparison of RASi treated vs. untreated patients was performed within the overall population and after 1:1 propensity score matching for age, sex, comorbidities, type of trigger and in-hospital complications.
Registrationclinicaltrials.gov, NCT04361994, https://clinicaltrials.gov/study/NCT04361994
ResultsOf the 2453 TTS patients discharged alive, 1683 (68%) received RASi therapy. Patients with RASi were older (age 71 ± 11 vs 69 ± 13 years, P = .01), with higher prevalence of hypertension (74% vs 53%, P < .01) and diabetes (19% v s15%, P = .01), higher admission left ventricular ejection fraction (LVEF) (41 ± 11% vs 39 ± 12%, P < .01) and lower rates of in-hospital complications (18.9% vs 29.6%, P < .01). At multivariable analysis, RASi therapy at discharge was independently associated with lower mortality (HR 0.63, 95% CI 0.45-0.87, P < .01). Survival analysis showed that at long term, patients treated with RASi had lower mortality rates in the overall cohort (log-rank P = .001). However, this benefit was not found among patients treated with RASi in the matched cohort (log-rank P = .168). Potential survival benefit of RASi were present, both in the overall and matched cohort, in 2 subgroups: patients with admission LVEF ≤ 40% (HR 0.54 95% CI 0.38-0.78, P = .001; HR 0.59, 95% CI 0.37-0.95, P = .030) and diabetes (HR 0.41, 95% CI 0.23-0.73, P = .002; HR 0.41, 95% CI 0.21-0.82, P = .011).
ConclusionsLong-term therapy with RASi after a TTS episode was not associated with lower mortality rates at propensity score analysis. However, potential survival benefit can be found among patients with admission LVEF ≤ 40% or diabetes.
Central illustration
RASi discharge therapy and long-term outcome among TTS patients. Legend LVEF = left ventricular ejection fraction, RASi = renin-angiotensin system inhibitors, TTS = Takotsubo syndrome.
BackgroundTakotsubo syndrome (TTS) is an acute heart failure condition characterized by a transient left ventricular (LV) dysfunction1 and burdened by high rate of in hospital complications and mortality.2
Myocardial toxicity due to increased levels of local3 and systemic4 catecholamines mainly acting on beta 2 adrenergic receptors of mid-apical segments of left ventricle5,6 has been reported as a potential pathophysiological mechanism. However, also acute ischemia due to severe microvascular dysfunction can be found in TTS.7
Despite the recovery of LV ejection fraction (LVEF) within weeks to months after the onset, unexpectedly increased long-term mortality has been described at follow-up, with rates comparable to those observed after acute myocardial infarction (AMI).8,9 Recent studies showed that patients with TTS after the acute event could develop a persistent, long-term heart failure phenotype10 including cardiac abnormalities due to global microscopic fibrosis,11 but few data currently exist on the use and effect of long-term heart failure treatments in these patients.
Ancillary findings from 2 large multicentric registries showed that renin angiotensin system inhibitor (RASi) therapy was associated with a better prognosis at the long-term, either in terms of all-cause12 and cardiovascular13 mortality. However, no study to date was specifically targeted to report on the subgroup of TTS patients discharged on RASi, and no randomized controlled trial has been performed so far.
The aim of the present study is to describe the clinical characteristics and long-term outcome of patients receiving RASi after an acute TTS event.
MethodsThis study included data from 2813 consecutive TTS patients enrolled in the GErman Italian Spanish Takotsubo (GEIST) Registry, a multicenter, international registry which collects TTS patients from Italy, Germany and Spain (NCT04361994). Patients were enrolled from January 2006 until September 2022 and median follow-up was 31 (Interquartile range 12-56) months. We performed an analysis on 2453 patients within the registry who were discharged alive and had available data regarding RASi therapy prescription (Figure 1).
As previously reported 14, patient's inclusion was performed in accordance with the following TTS diagnostic criteria: 1) transient regional wall motion abnormalities of the left or right ventricle, frequently preceded by a stressful trigger and usually extending beyond a single epicardial coronary artery distribution; 2) absence of culprit coronary artery disease at coronary angiogram; 3) new and reversible electrocardiography abnormalities; 4) significantly elevated serum natriuretic peptide (BNP or NT-proBNP) during the acute phase and positive but relatively small elevation in cardiac troponin; and 5) recovery of ventricular systolic function at follow-up in all surviving patients 15. The evaluation of patients and subsequent inclusion in the registry was performed by the physicians in charge only after all diagnostic criteria were met. All patients underwent coronary angiogram with different timing according to the European Society of Cardiology guidelines on acute coronary syndrome 16,17. Coronary artery disease was defined as the presence of coronary calcifications, atherosclerosis, plaques, and/or stenoses, with stenoses >50% of the lumen diameter in arteries with a diameter amenable to percutaneous intervention. Data regarding demographic characteristics, clinical presentation, laboratory measures, electrocardiography, echocardiography, parameters, treatment and medication were collected.
For the purpose of the present research, we provided a stepwise comparison of patients with and without RASi prescription at discharge (Figure 1).
Initially (step 1), the comparison was made for patients within the overall population. Then (step 2), a propensity score matching analysis was used to identify subgroups of patients with and without RASi therapy with a 1:1 matching. The matched cohort consisted of 583 patients per group for whom additional comparison was carried out. Baseline clinical characteristics, including demographic details, cardiovascular risk factors and comorbidities, the presence and kind of stressful trigger were recorded on admission. Ballooning patterns were classified as apical (typical), mid-ventricular, basal, or focal,18,19 with or without concomitant right ventricular involvement.20 In-hospital complications included were death, pulmonary edema, need for invasive mechanical ventilation, and cardiogenic shock, as previously described.2 Recovery of left ventricular systolic function was documented in all the study patients. Drug treatments were reported as prescribed at the moment of hospital discharge. Primary endpoint of the study was all cause-mortality. Long-term outcome was verified by outpatient visits, medical records, or phone interviews.
The consistency of the main results for the primary outcome of the study was investigated in prespecified subgroups of clinical interest: age > 70 or ≤ 70 years, male or female, presence or not of hypertension, diabetes, malignancies, physical trigger, admission LVEF > 40% or < 40%, development or not of in-hospital complications and, cardiogenic shock during the acute phase.
All patients were managed in accordance with the Declaration of Helsinki and signed informed consent for the processing of personal data for scientific research purposes. The study received approval by institutional review board and ethical committee.
Statistical analysisChi-square analysis or Fisher exact-test, as appropriate, were used to compare categorical variables. Continuous variables were presented as mean SD or as median (IQR). The student's t-test for independent samples or Mann-Whitney U test were used to compare continuous variables. Univariable and multivariable logistic regression analysis were used to calculate estimated ORs and 95% CIs for factors associated with the prescription of RASi at hospital discharge, while univariable and multivariable Cox regression analyses were performed to assess factors independently associated with long-term mortality in the overall cohort. Matching between patients with and without RASi prescription was performed using propensity-score matching and included the following variables: age, sex, hypertension, diabetes, physical and emotional trigger, LVEF, in-hospital complications, beta-blocker therapy at discharge; match tolerance was set at 0.003. Kaplan-Meier curves and log-rank test were used to assess survival function at follow-up in both the overall and matched cohort. Schoenfeld residuals test was used to assess the proportional hazard assumption. All data were analyzed with SPSS software version 25.0 (SPSS Inc).
Results Clinical characteristicsBaseline demographic and clinical characteristics within the overall and matched cohorts stratified by RASi prescription at discharge are reported in Table 1 and summarized in Figure 2.
Of the 2453 patients discharged alive and with the available data included in the GEIST registry, 1683 (68%) were discharged with RASi. Patients receiving RASi therapy were older (age 71 ± 11 vs 69 ± 13 years, P = .01), more often of female sex (90% vs 86%, P = .01), with higher prevalence of hypertension (74.5% vs 53.2%, P < .01) and diabetes (19.4% vs 15.2%, P = .01).
Patients with RASi therapy at discharge were more likely to have been admitted following an emotional triggered TTS (38.9% vs 31.2%, P < .01) and having higher admission LVEF (41 ± 11% vs 39 ± 12%, P < .01) with lower rates of in-hospital complications (18.9% vs 29.6%, P < .01), including cardiogenic shock (5.2% vs 11.5%, P < .01).
At multivariable analysis, the following factors were independently associated with the prescription of RASi: age (OR: 1.01, 95% CI [1-1.02)], P = .035), hypertension (OR: 2.5, 95% CI [2.06-3.03], P < .01), physical trigger (OR: 0.71, 95% CI [0.59-0.86], P < .01), LVEF (OR: 1.01, 95% CI [1-1.02], P = .01) and in-hospital complications (OR: 0.6, 95% CI [0.48-0.74], P < .01) (Supplementary Table 1).
Long-term OutcomeAt multivariable analysis, including age, male sex, diabetes, pulmonary disease, malignancies, physical trigger, LVEF ≤ 40%, in-hospital complication, RASi therapy at discharge was independently associated with lower mortality risk (HR: 0.63, 95% CI 0.45-0.87, P = .005) (Table 2).
Other variable associated with increased mortality rates were: age (HR: 1.35, 95% CI 1.24-1.47, P = < .001), male sex (HR: 1.72, 95% CI 1.14-2.62, P = .01), diabetes (HR: 2.53, 95% CI 1.82-3.49 P ≤ .001), pulmonary disease (HR: 1.49, 95% CI 1.02-2.19 P = .041), malignancies (HR: 2.44, 95% CI 1.71-3.47, P ≤ .001), physical trigger (HR: 2.14, 95% CI 1.56-2.93, P ≤ .001), LVEF ≤ 40% (1.44, 95% CI 1.04-1.99, P = .029) and in-hospital complications (HR: 1.72, 95% CI 1.23-2.41, P = .001) (Table 2).
At long term follow-up, patients treated with RASi had lower mortality rate in the overall cohort (log rank P = .001). However, no survival benefits were found among patients treated with RASi in the matched cohort (log rank P = .168) (Figure 3). The association between RASi prescription and mortality was tested within relevant subgroups, with results reported in Table 3. Survival analysis showed that patients treated with RASi and admission LVEF ≤ 40% had better long-term outcome both in the overall and matched cohort (log rank P = .001 and P = .043, respectively) (Figure 4). No benefits were found among patients with admission LVEF ≥ 40% in both cohorts (log-rank P = .592 and P = .842) (Supplementary Figure 1).
The survival benefit of RASi was found in patients with age ≥ 70 and hypertension (HR 0.54, 95% CI 0.37-0.77, P = .001, P for interaction = .001 and HR: 0.53, 95% CI 0.36-0.78, P = .001, P for interaction < .01 respectively) in the overall cohort. The subgroups of patients with admission LVEF ≤ 40% and diabetes retained higher survival benefit both in the overall (HR: 0.54 95% CI 0.38-0.78, P = .013, P for interaction = .001 and HR: 0.41, 95% CI 0.23-0.73, P = .002, P for interaction = .002 respectively) and matched cohort (HR: 0.59, 95% CI 0.37-0.95, P = .030, p for interaction = .013 and HR: 0.41, 95% CI 0.21-0.82, P = .11, P for interaction = .044 respectively) (Figure 5, Table 3). At long term follow-up overall rate of TTS recurrence was 4,6% and there were no differences in term of TTS recurrence among patients treated with RASi or not (4.8% vs 4.5% P = .55).
DiscussionWe report the long-term outcome of TTS patients discharged on RASi enrolled in a large multicenter European (GEIST) registry. The main findings of the present study are as follow:
- 1)More than 2 thirds of TTS patients were discharged on RASi, this prescription was associated with higher admission LVEF and was more common in patients with emotional triggers and lower rates of in-hospital complications;
- 2)RASi therapy was not associated with lower long-term mortality in the matched cohort, after propensity score analysis;
- 3)Survival benefit of RASi emerged in the overall and matched cohorts among the subgroup of patients with admission LVEF ≤ 40% or diabetes.
TTS is a challenging diagnosis, having a clinical presentation almost consistent with an acute coronary syndrome (ACS) and could require serial echocardiographic evaluations or cardiac magnetic resonance.21 Hence, the majority of the patients receive a medical therapy similar to that prescribed in ACS. Most of the patients receive at discharge RASi (75%-80%), aspirin (62%-67%), dual antiplatelet therapy (9.5%-11%), beta-blockers (77%-78%) and statin (51% - 57%).7 22,23
These data are in line with the present study, where more than two thirds of TTS patients were prescribed RASi at discharge. A selection bias in treatment assignment is likely present. RASi was more likely prescribed in older patients with hypertension, possibly reflecting a clinical indication to this treatment irrespective of the TTS event.24 However, these patients had higher admission LVEF, higher prevalence of emotional triggers and experienced lower rates of in-hospital complications. On the other side, high risk TTS features, like presenting with a physical trigger,25 lower LVEF26 and developing in-hospital complications including cardiogenic shock27,28 were all factors associated with a lower prescription rate of the drug. It might be the case that clinicians were less prone to prescribe a RASi in those patients with low blood pressure value or who have developed a severe in-hospital course possibly with hemodynamic instability. A similar trend has been described in heart failure patients, who are less likely to receive an ACE-inhibitor or betablocker if they have higher BNP, lower blood pressure and a previous hospitalization in the past year.29
RASi therapy at discharge in our population was not associated with lower long-term mortality in the matched cohort, after propensity score analysis, where survival benefit was found only among patients with admission LVEF ≤ 40% or diabetes. At the state of the art, 2 studies evaluated the potential benefit of RASi in TTS patients. Templin et al.12 found in a large international registry of 1,750 patients, survival benefit of RASi at 1 year follow-up. Meanwhile, Citro et al.13 in an Italian registry of 326 patients, found that patients with RASi therapy at discharge had lower rates of cardiac death at long-term follow-up, albeit with no differences in terms of overall mortality.
One possible explanation of these findings is that TTS is characterized by a large burden of comorbidities 30 in which RASi has a renown benefit, such as diabetes,31 hypertension,19 or even cancer when associated.32,33 Accordingly, on subgroup analysis within the overall population, we found that older patients, with hypertension, diabetes or admission LVEF ≤ 40% seemed to gain more benefit from RASi therapy. However, a potential confounding remains the modality of allocation to RASi treatment, since patients receiving this drug in our population were those displaying a less severe acute TTS along with several other markers of a better long-term prognosis.
In the matched cohort of the present study the survival benefit of patients receiving RASi was blunted, keeping a similar, though not significant, trend as compared with that found in the whole population. It might be hypothesized that when baseline differences associated with RASi treatment allocation are more homogeneously distributed between groups, as it was in the matched cohort, the long-term survival advantage of patients under this therapy could be reduced. On subgroup analysis within the matched cohort, we found a survival benefit of RASi in patients with diabetes and in those presenting with LVEF ≤ 40%. Although not statistically significant there was a trend for potential benefit of RASi therapy also in patients with history of malignancy, an important risk factor among TTS patients34 as previously reported by Nguyen TH et al.35
Diabetes has been described as a marker of worse prognosis in TTS,36 and the beneficial effects of RASi in this endocrine disorder are well established,37 justifying our observation. Moreover, diabetic patients have severe damage of coronary microvasculature, a subset that may benefit of RASi therapy that could improve microvascular function.38
On the other hand, a relatively unexpected finding was that admission LV systolic function influenced the beneficial association of the treatment with prognosis, that was significant in both cohorts for an LVEF ≤ 40% while negligible in the other subgroup. Following the acute phase, LVEF in TTS recovers after days to weeks, but admission LVEF remains a well-known prognostic marker of in-hospital complication2 and long-term survival.13,22 Moreover, long-term myocardial changes have been reported in TTS, including abnormality on cardiac magnetic resonance imaging (native T1 values), impaired cardiac deformation and energetic status that were associated with poor exercise tolerance,10 especially in patients within the most severe acute disease spectrum11 and in those with persisting symptoms.10 Additionally, in TTS a long-term maladaptive activation of the renin-angiotensin system has been described,39 with serum renin and angiotensin II concentrations persistently elevated after the acute event. All together this indicates, at least in a subset of patients, the presence of a persisting heart failure phenotype that could be either a consequence of TTS10,11 or also a predating condition characterizing TTS predisposition40,41 and unmasked by the acute event.42,43 In any case, a heart failure condition associated with a clinical history of LVEF ≤ 40%, subsequently recovered, would qualify these patients as having heart failure with improved ejection fraction.44 There is the consensus that this subgroup of patients could be considered for chronic medical therapy, including a RASi, though this indication is currently debated specifically in patients with a previous TTS episode.45,46 Results from our study suggest that long-term treatment with RASi might represent a valuable option after the acute phase in patients experiencing a TTS event, not only in the presence of a guideline directed indication such as hypertension, but also in those admitted with a reduced LVEF or with diabetes.
Additional studies are needed to test the survival benefit of betablockers and RASi combined together. At the state of the art this has been evaluated in the context of TTS recurrence with some potential benefit.47,48
LimitationsThis is an observational study where the discharge therapy was at the discretion of the treating physician; randomized controlled trials are needed to fully assess beneficial impact of RASi treatment in patients recovering after a TTS event. Data on drug therapy before admission for TTS were not routinely assessed. Drug dosage, compliance to therapy and changes of treatment regimen were not routinely assessed at follow-up. Data on cardiovascular and non-cardiovascular mortality were not prospectively collected, hence, the primary end-point was all-cause mortality.
ConclusionsRASi are commonly prescribed after a TTS event, with the prescription rate influenced by underlying clinical characteristics and in-hospital course of the patients. Treatment with RASi at discharge was not associated with lower long-term mortality after PSM analysis, where survival benefit was found only among patients with admission LVEF ≤40% or diabetes.
Data availability statementThe data are available for research upon reasonable request to the corresponding author.
Ethics approvalThe study received approval by an institutional review board and ethics committee in each center (approval number 143/2019 of the ethics committee for the coordinating center).
General data protection regulationThe study is fully compliant with all legal and ethical requirements, and there are no further processes available regarding such studies.
CRediT authorship contribution statementFrancesco Santoro: Writing – original draft, Project administration, Methodology, Investigation, Formal analysis, Data curation, Conceptualization. Thomas Stiermaier: Investigation, Data curation. Iván J. Núñez Gil: . Ibrahim El-Battrawy: Investigation, Data curation. Toni Pätz: . Luca Cacciotti: Investigation, Data curation. Federico Guerra: Investigation, Data curation. Giuseppina Novo: Investigation, Data curation. Beatrice Musumeci: Writing – review & editing. Massimo Volpe: Investigation, Data curation. Enrica Mariano: Investigation, Data curation. Pasquale Caldarola: Investigation, Data curation. Roberta Montisci: Investigation, Data curation. Ilaria Ragnatela: Investigation, Data curation. Rosa Cetera: Investigation, Data curation. Ravi Vazirani: Investigation, Data curation. Carmen Lluch: Investigation, Data curation. Aitor Uribarri: Investigation, Data curation. Miguel Corbi-Pascual: Investigation, Data curation. David Aritza Conty Cardona: Investigation, Data curation. Ibrahim Akin: Investigation, Data curation. Emanuele Barbato: Investigation, Data curation. Holger Thiele: Investigation, Data curation. Natale Daniele Brunetti: Methodology, Visualization, Writing – original draft. Ingo Eitel: Writing – review & editing, Validation, Supervision, Project administration, Methodology, Investigation, Formal analysis, Data curation, Conceptualization, Supervision. Luca Arcari: Writing – original draft, Visualization, Validation, Supervision, Software, Project administration, Methodology, Investigation, Formal analysis, Data curation, Conceptualization.
Conflict of interestNone reported.
Supplementary materialsSupplementary material associated with this article can be found, in the online version, at doi:10.1016/j.ahj.2024.08.019.
Appendix Supplementary materialsImage, application 1
| Variable | Overall cohort | SMD | Matched cohort | SMD | ||||
| RASi (n = 1683) | No RASi (n = 770) | RASi (n = 583) | No RASi (n = 583) | |||||
| Age (years)* | 71 ± 11 | 69 ± 13 | .01 | 0.182 | 70 ± 12 | 70 ± 13 | .62 | 0.029 |
| Male sex (%)* | 170/1683 (10%) | 108/770 (14%) | < .01 | 0.124 | 78/583 (13.4%) | 63/583 (10.8%) | .21 | 0.079 |
| Comorbidities | ||||||||
| Hypertension (%)* | 1254/ 1683 (74.5%) | 409/768 (53.2%) | < .01 | 0.455 | 341/583 (58.5%) | 337/583 (57.8%) | .85 | 0.014 |
| Diabetes Mellitus (%)* | 328/1683 (19.4%) | 117/768 (15.2%) | < .01 | 0.111 | 95/583 (16.3%) | 94/583 (16.1%) | .99 | 0.005 |
| Dyslipidemia (%) | 673/1594 (42,2%) | 303/702 (43.2%) | .34 | 0.019 | 224/551 (40.6%) | 234/529 (44.2%) | .24 | 0.072 |
| Current Smoker (%) | 290/1683 (17.2%) | 139/766 (18.1%) | .60 | 0.024 | 115/583 (19.7%) | 93/581 (16%) | .11 | 0.097 |
| Pulmonary disease (%) | 225/1490 (15.1%) | 99/688 (14.4%) | .69 | 0.020 | 75/516 (14.5%) | 76/528 (14.4%) | .99 | 0.004 |
| Neurological disease | 221/1359 (16.3%) | 118/614 (19.2%) | < .01 | 0.078 | 74/462 (16%) | 82/472 (17.4%) | .59 | 0.036 |
| Malignancies (%) | 220/1480 (14.9%) | 95/635 (15%) | .94 | 0.003 | 89/507 (17.5%) | 73/490 (14.9%) | .04 | 0.072 |
| Coronary artery disease (%) | 167/1576 (10.6%) | 64/715 (8.9%) | .23 | 0.054 | 52/541 (9.6%) | 48/541 (8.9%) | .75 | 0.025 |
| Clinical Presentation | ||||||||
| Dyspnea (%) | 549/1581 (34,7%) | 273/749 (36.4%) | .43 | 0.036 | 209/556 (37.6%) | 214/568 (37.7%) | .99 | 0.002 |
| Stressful Trigger (%) | 1160/1677 (69.2%) | 546/770 (71%) | .39 | 0.034 | 400/583 (68.6%) | 406/583 (69.6%) | .75 | 0.022 |
| -Emotional (%)* | 653/1677 (38.9%) | 241/770 (31.2%) | < .01 | 0.160 | 191/583 (32.8%) | 207/583 (35.5%) | .35 | 0.058 |
| -Physical (%)* | 510/1677 (30.4%) | 308/770 (40%) | < .01 | 0.204 | 213/583 (36.5%) | 203/583 (34.8%) | .58 | 0.036 |
| Admission electrocardiographic findings | ||||||||
| Atrial Fibrillation (%) | 225/1504 (14.9%) | 102/647 (15.8%) | .64 | 0.022 | 74/548 (13.5%) | 82/526 (15.6%) | .38 | 0.059 |
| ST-changes (%) | 1136/1459 (77.8%) | 528/649 (81.3%) | .07 | 0.086 | 379/507 (74.7%) | 406/502 (80.9%) | .02 | 0.147 |
| Admission echocardiographic findings | ||||||||
| Apical Ballooning (%) | 1429/1681 (85%) | 643/758 (84.8%) | .90 | 0.005 | 491/583 (84.2%) | 349/582 (60%) | < .01 | 0.043 |
| Mid-ventricular Ballooning (%) | 211/1681 (12.5%) | 88/758 (11.6%) | .54 | 0.029 | 77/583 (13.2%) | 58/582 (10%) | .09 | 0.046 |
| RV Balloning (%) | 39/1197 (3.2%) | 30/588 (5.1%) | .06 | 0.095 | 10/433 (2.3%) | 19/443 (4.3%) | .12 | 0.110 |
| Basal Ballooning (%) | 25/1681 (1.5%) | 25/758 (3.3%) | < .01 | 0.127 | 6/583 (1%) | 4/582 (0.7%) | .75 | 0.095 |
| Focal (%) | 6/1681 (0.3%) | 2/758 (0.3%) | .99 | 0.016 | 5/583 (0.8%) | 3/582 (0.5%) | .72 | 0.066 |
| LVEF (%)* | 41 ± 11% | 39 ± 12% | .01 | 0.138 | 40 ± 10.1% | 40.1 ± 10.8% | .83 | 0.001 |
| In-hospital course | ||||||||
| In-hospital complications (%)* | 318/1683 (18.9%) | 228/770 (29.6%) | < .01 | 0.257 | 151/583 (25.9%) | 141/583 (24.2%) | .54 | 0.039 |
| -Pulmonary Edema (%) | 122/1667 (7.3%) | 68/742 (9.2%) | .12 | 0.068 | 56/579 (9.7%) | 51/569 (8.9%) | .68 | 0.024 |
| -Cardiogenic Shock (%) | 88/1679 (5.2%) | 89/770 (11.5%) | < .01 | 0.244 | 47/583 (8.1%) | 40/583 (6.9%) | .50 | 0.046 |
| -Arrhythmias (%) | 90/1008 (8.9%) | 58/451 (12.9%) | .02 | 0.130 | 41/378 (10.8%) | 39/359 (10.9%) | .99 | 0.001 |
| -Inotropic drug support (%) | 97/1601 (6%) | 101/749 (1.3%) | < .01 | 0.273 | 48/561 (8.5%) | 51/554 (9.2%) | .75 | 0.022 |
| -OTI (%) | 77/1585 (4.8%) | 63/709 (8.9%) | < .01 | 0.168 | 35/551 (6.3%) | 30/530 (10%) | .70 | 0.029 |
| In-hospital stay (days) | 6 (5, 9) | 7 (5, 11) | < .01 | 0.212 | 7 (5,10) | 7 (5,10) | .09 | 0.094 |
| Discharge therapy and outcome | ||||||||
| Aspirin (%) | 1061/1657 (64%) | 344/767 (44.8%) | < .01 | 0.388 | 348/578 (60.2%) | 282/582 (48.4%) | < .01 | 0.236 |
| DAPT (%) | 142/1147 (12.4%) | 53/535 (9.9%) | .16 | 0.077 | 52/424 (12.3%) | 45/416 (10.8%) | .52 | 0.045 |
| Anticoagulant (%) | 274/1467 (18.7%) | 133/735 (18.1%) | .77 | 0.015 | 93/527 (17.6%) | 108/551 (19.6%) | .43 | 0.050 |
| Beta-blockers (%)* | 1282/1590 (80.6%) | 404/725 (55.7%) | < .01 | 0.559 | 389/583 (66.7%) | 382/583 (65.5%) | .71 | 0.025 |
| Statin (%) | 978/1655 (59%) | 310/766 (40.5%) | < .01 | 0.373 | 328/579 (56.6%) | 259/582 (44.5%) | < .01 | 0.242 |
| Long-term death (%) | 136/1683 (8%) | 82/770 (10.6%) | .04 | 0.090 | 54/583 (9.3%) | 68/583 (11.7%) | .21 | 0.078 |
| Long-term mortality | ||||
| variable | Univariable | Multivariable | ||
| HR (95% CI) | HR (95% CI) | |||
| Age (per 5 years increase) | 1.38 (1.29-1.49) | <.001 | 1.35 (1.24-1.47) | < .001 |
| Male sex | 1.83 (1.26-2.66) | .001 | 1.72 (1.14-2.62) | .01 |
| Hypertension | 1.45 (1.05-1.99) | .022 | NS | NS |
| Dyslipidemia | 1.09 (0.82-1.45) | .564 | - | - |
| Diabetes | 2.41 (1.82-3.21) | < .001 | 2.53 (1.82-3.49) | < .001 |
| Current Smoking | 0.78 (0.54-1.13) | .185 | - | - |
| Pulmonary disease | 1.88 (1.31-2.68) | .001 | 1.49 (1.02-2.19) | .041 |
| Malignancies | 2.71 (1.98-3.72) | < .001 | 2.44 (1.71-3.47) | < .001 |
| Physical Trigger | 2.42 (1.85-3.17) | < .001 | 2.14 (1.56-2.93) | < .001 |
| LVEF ≤40% | 1.79 (1.34-2.39) | < .001 | 1.44 (1.04-1.99) | .029 |
| Apical Ballooning | 1.35 (0.91-1.981) | .131 | - | - |
| In-hospital complications | 2.41 (1.81-3.19) | < .001 | 1.72 (1.23-2.41) | .001 |
| RAS-inhibitor | 0.63 (0.48-0.84) | .001 | 0.63 (0.45-0.87) | .005 |
| Betablockers | 0.88 (0.65-1.19) | .408 | - | - |
| Variable | Overall cohort | Matched cohort | ||||
| Adjusted HR (95% CI) | Adjusted HR (95% CI) | |||||
| Age < 70 Age ≥ 70 | 1.13 (0.52-2.43) 0.54 (0.37-0.77) | .758 .001 | .001 | 0.76 (0.32-1.77) 0.63 (0.41-0.97) | .513 .037 | .570 |
| Male sex Female Sex | 0.90 (0.36-2.28) 0.59 (0.41-0.85) | .832 .004 | .741 | 1.71 (0.24-2.04) 0.62 (0.41-0.95) | .520 .030 | .830 |
| Hypertension No hypertension | 0.53 (0.36-0.78) 0.81 ((0.36-1.80) | .001 .895 | < .001 | 0.69 (0.44-1.09) 0.73 (0.37-1.42) | .116 .352 | .458 |
| Diabetes No diabetes | 0.41 (0.23-0.73) 0.83 (0.54-1.26) | .002 .377 | .002 | 0.41 (0.21-0.82) 0.82 (0.52-1.30) | .011 .403 | .044 |
| Malignancies No malignancies | 0.41 (0.23-0.73) 0.70 (0.48-1.01) | .002 .054 | .066 | 0.51 (0.26-0.99) 0.78 (0.50-1.23) | .050 .290 | .079 |
| Physical trigger No Physical | 0.61 (0.40-0.93) 0.63 (0.40-0.98) | .023 .049 | .864 | 0.54 (0.32-0.92) 0.77 (0.44-1.36) | .024 .370 | .344 |
| LVEF > 40% LVEF ≤ 40% | 0.94 (0.19-6.09) 0.54 (0.38-0.78) | .945 .001 | .001 | 0.92 (0.46-1.85) 0.59 (0.37-0.95) | .816 .030 | .013 |
| In-hospital complications No in-hospital complications | 0.68 (0.40-1.17) 0.62 (0.42-0.90) | .168 .013 | .825 | 0.63 (0.33-1.21) 0.66 (0.40-1.08) | .164 .096 | .706 |
| Cardiogenic shock No cardiogenic shock | 0.94 (0.41-1.15) 0.63 (0.48-0.84) | .884 .001 | .402 | 0.79 (0.25-2.50) 0.64 (0.42-0.99) | .700 .043 | .994 |
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