European Journal of Internal Medicine 94 (2021) 73–84 Contents lists available at ScienceDirect European Journal of Internal Medicine journal homepage: www.elsevier.com/locate/ejim Outcomes of patients with heart failure with preserved ejection fraction discharged on treatment with neurohormonal antagonists after an episode of decompensation Josep Tost a, Pere Llorens b, Gad Cotter c, Beth Davison c, Javier Jacob d, Víctor Gil e, Pablo Herrero f, Francisco Javier Martín-Sánchez g, Ruxandra Donea a, Beatriz Rodríguez h, Francisco Javier Lucas-Imbernon i, Juan Antonio Andueza j, Ana Belén Mecina k, Raquel Torres-Gárate l, Pascual Piñera m, Aitor Alquézar-Arbé n, Begoña Espinosa b, Alexandre Mebazaa o, p, Ovidiu Chioncel q, Òscar Miró e, p, *, on behalf of the ICA-SEMES group1 a Emergency Department, Hospital de Terrassa, Barcelona, Catalonia, Spain b Emergency Department, Short Stay Unit and Hospitalitation at Home Unit, Hospital General de Alicante, Instituto de Investigación Sanitaria y Biomédica de Alicante (ISABIAL), Universidad Miguel Hernández, Alicante, Spain c Momentum Research, Durham, North Carolina, United States d Emergency Department, Hospital Universitari de Bellvitge, l’Hospitalet de Llobregat, Barcelona, Catalonia, Spain e Emergency Department, Hospital Clínic, Universitat de Barcelona, Barcelona, Catalonia, Spain f Emergency Department, Hospital Universitario Central de Asturias, Oviedo, Spain g Emergency Department, Hospital Clínico San Carlos, Universidad Complutense, Madrid, Spain h Emergency Department, Hospital Universitario Infanta Leonor, Madrid, Spain i Emergency Department, Hospital General de Albacete, Spain j Emergency Department, Hospital General Universitario Gregorio Marañón, Universidad Complutense, Madrid, Sapin k Emergency Department, Hospital de Alcorcón, Madrid, Spain l Emergency Department, Hospital Severo Ochoa, Madrid, Spain m Emergency Department, Hospital General Universitario Reina Sofía, Murcia, Spain n Emergency Department, Hospital de la Santa Creu i Sant Pau, Barcelona, Catalonia, Spain o Department of Anaesthesiology and Critical Care Medicine, AP-HP, Saint Louis and Lariboisière University Hospitals, INSERM U-942, Paris, France. p The GREAT network, Rome, Italy q Emergency Institute for Cardiovascular Diseases, Prof. C. C. Iliescu, 1 University of Medicine Carol Davila, Bucharest, Romania. A R T I C L E I N F O A B S T R A C T Key words: Aims: To analyze the frequency with which patients with heart failure with preserved ejection fraction (HFpEF) Acute heart failure discharged after an acute heart failure (AHF) episode are treated with antineurohormonal drugs (ANHD), the Antineurohormonal drugs variables related to ANHD prescription and their relationship with outcomes. Preserved ejection fraction Methods: We included consecutive HFpEF patients (left ventricular ejection fraction ≥50%) discharged after an Prognosis Emergency departments AHF episode from 45 Spanish hospitals whose chronic medications and treatment at discharge were available. Patients were classified according to whether they were discharged with or without ANHD, including beta- blockers (BB), renin-angiotensin-aldosterone-system inhibitors (RAASi) and mineralcorticosteroid-receptor an­ tagonists (MRA). Co-primary outcomes consisted of 1-year all-cause mortality and 90-day combined adverse event (revisit to emergency department –ED-, hospitalization due to AHF or all-cause death). Secondary out­ comes were 90-day adverse events taken individually. Adjusted associations of ANHD treatment with outcomes were calculated. Results: We analyzed 3,305 patients with HFpEF (median age: 83, 60% women), 2,312 (70%) discharged with ANHD. The ANHD most frequently prescribed was BB (45.8%). The 1-year mortality was 26.9% (adjusted HR for ANHD patients:1.17, 95%CI=0.98-1.38) and the 90-day combined adverse event was 54.4% (HR=1.14, 95% * Corresponding author. E-mail address: omiro@clinic.cat (Ò. Miró). 1 Consult Appendix 1 to see the complete list of the ICA-SEMES Research Group (Research group on Acute Heart Failure of the Spanish Society of Emergency Medicine) members https://doi.org/10.1016/j.ejim.2021.07.013 Received 10 April 2021; Received in revised form 23 July 2021; Accepted 26 July 2021 Available online 24 August 2021 0953-6205/© 2021 The Authors. Published by Elsevier B.V. on behalf of European Federation of Internal Medicine. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). J. Tost et al. European Journal of Internal Medicine 94 (2021) 73–84 CI=0.99-1.31). ED revisit was significantly increased by ANHD (HR=1.15, 95%CI=1.01-1.32). MRA and BB were associated with worse results in some co-primary or secondary endpoints, while RAASi (alone) reduced 90-day hospitalization (HR=0.73, 98%CI=0.56-0.96). Conclusion: 70% of HFpEF patients are discharged with ANHD after an AHF episode. ANHD do not seem to reduce mortality or adverse events in HFpEF patients, only RAASi could provide some benefits, reducing the risk of hospitalization for AHF. 1. Introduction development of AHF during ST-elevation myocardial infarction (STEMI), as many of these patients go straight to the cath lab for Heart failure (HF) is an important health problem with elevated revascularization, bypassing the ED. socio-health care costs. This disease is highly prevalent in the people over the age of 65 years and constitutes the first cause of hospitalization 2.2. Study design and variables recorded in this population. In addition, mortality and rehospitalization associ­ ated with decompensations such as acute heart failure (AHF) are high, The present analysis included all patients discharged alive after an even in patients with low risk HF (1-3). During the last decades, there episode of AHF with a LVEF of 50% or more recorded in an echocardi­ has been an increase in the percentage of patients with HF with pre­ ography performed during the 6 months prior to decompensation or that served ejection fraction (HFpEF), that it is currently defined by a left had been recorded during the current admission. To be included in the ventricular ejection fraction (LVEF) greater than or equal to 50% (4). present analysis, in addition to the clinical criteria required to be The physiopathology of HFpEF is complex and heterogeneous and is included in the EAHFE registry, determination of natriuretic peptides related to different factors which act independently and converge into a during ED stay or hospitalization was necessary, and blood concentra­ systemic inflammatory state, with the increase in its prevalence being tions > 100 ng/L (for BNP) or 450 ng/L (for NT-proBNP) were required related to the aging of the population (5,6). At present, in many coun­ for final inclusion (4). Of the 6 phases of the EAHFE Registry, only pa­ tries more than 50% of the cases of HF correspond to the HFpEF type. tients included in phases 4, 5 and 6 were considered for this study, as Although the clinical presentation and diagnosis of HFpEF are data regarding chronic treatments before decompensation and treat­ similar to what occurs in HF with reduced ejection fraction (HRrEF, ments provided after discharge for the current episode were only defined by LVEF <40%), it is considered a different entity at both a included in the datasheet from phase 4 onwards. Two groups were physiopathological and prognostic level, and there are significant dif­ formed according to whether patients were discharged with or without ferences in the treatment of both types of HF (4,7). Thus, neurohormonal ANHD. We considered antineurohormonal drugs: RAAS inhibitors, BB antagonists such as beta-blockers (BB), renin angiotensin aldosterone and MRA, either alone or in any combination, and at any dosage. system (RAAS) inhibitors and mineralocorticoid receptor antagonists Forty-eight independent variables were collected including de­ (MRA) are used in the treatment of HFrEF and have shown to improve mographic data, baseline status, acute episode characteristics and disease outcomes. These neurohormonal antagonists are generically management provided in the ED. All the variables were prospectively called disease-modifying drugs as they are able to improve outcomes in recorded in a specific datasheet during ED stay, and the definitions are patients with HFrEF, and the guidelines of clinical practice recommend included in supplemental Table 1. To assess the severity of the current their use (class of recommendation I, level of evidence A) (4,8). On the episode of decompensation we used the MEESSI score, a clinical score other hand, studies and clinical trials evaluating the effects of anti­ that has demonstrated very good prediction of 30-day mortality in pa­ neurohormonal drugs on HFpEF have shown null impact on outcomes. tients with AHF using clinical data recorded in the ED (3,10). The Nonetheless, in the usual clinical practice it is common to find patients MEESSI score is calculated from 13 variables recorded during the first with HFpEF receiving ANHD in order to treat other intercurrent diseases patient assessment in the ED (in order of importance: Barthel index, in which these drugs are indicated or for other less clear reasons (9). systolic blood pressure, age, NT-proBNP, potassium, troponin, NYHA Despite this, very few studies have evaluated their impact on outcomes class, respiratory rate, low output symptoms, oxygen saturation, con­ in the scenario of usual clinical practice. Therefore, the aim of this study current acute coronary syndrome, left ventricular hypertrophy in the was to analyze the frequency with which HFpEF patients discharged electrocardiogram [ECG] and creatinine). after an AHF episode receive treatment with ANHD. We also analyzed the variables related to this prescription and their relationship with the principal prognostic indicators, including readmission to the ED due to 2.3. Outcomes AHF, need for hospitalization and death following the index event. We defined two co-primary endpoints: the 1-year all-cause mortality 2. Methods and the 90-day post-discharge combined adverse event, which was constituted by all-cause death, hospitalization due to AHF or ED revisit 2.1. Setting due to AHF, whichever happened first. Additionally, each of these three 90-day adverse events was individually considered as a secondary The present study is a subanalysis of the EAHFE Registry. The EAHFE outcome. The revisit and hospitalization event adjudication was based Registry was initiated in 2007 and every 2-3 years it carries out a 1-2- on the clinical judgment of the attending physicians stated in the ED month recruitment period of all consecutive patients diagnosed with report of the revisit or in the discharge report after hospitalization, AHF in Spanish EDs participating in the project. To date, 6 recruitment which were reviewed by the researchers at a local level. The starting phases (in 2007, 2009, 2011, 2014, 2016 and 2018) have been per­ point was the day of patient discharge after the AHF index event, irre­ formed with the participation of 45 EDs from community and university spective of whether discharge was made directly from the ED or after hospitals across Spain (representing about 15% of the Spanish public hospitalization. The vital status of the patients and hospitalization and health care system hospitals), enrolling a total of 18,370 AHF patients. ED revisits were ascertained by consultation of medical records, which Details of patient inclusion have been extensively reported elsewhere [3, are electronically accessible in nearly all Spanish communities. More­ 10, 11]. The EAHFE Registry does not include any planned intervention, over, we contacted patients or relatives through phone call when no and the management of patients is entirely based on the attending ED clear data was present in the clinical history or access was not possible. physician decisions. The only exclusion criteria for inclusion is the Death was also verified through the Spanish public health insurance database that covers >99% of the Spanish population, as every patient 74 J. Tost et al. European Journal of Internal Medicine 94 (2021) 73–84 Fig. 1. Flow chart for patient inclusion. ANHD: antineurohormonal drugs; ED: emergency department; AHF: acute heart failure; LVEF: left ventricle ejection fraction; BB: beta-blockers; RAAS: renin- angiotensin-aldosterone system; inh.: inhibitors; MRA: mineralcorticosteroid-receptor antagonists. death is immediately retired from this database at the exact time point were explored using survival tables and Kaplan-Meier curves, and that death occurs. Every event adjudication was performed at a local comparison between curves was made using the log-rank test. level by the principal investigator of each hospital. Unadjusted and adjusted associations of treatment with ANHD with outcomes were calculated using Cox regression models and expressed as 2.4. Statistical analysis hazard ratios (HR) with 95% confidence interval (CI). Adjustment was performed for age and sex and for any variable regarding baseline status, Continuous variables are expressed as mean and standard deviation clinical characteristic of decompensation and management in the ED (SD) or median and interquartile range (IQR) if not normally distributed, that were found to be statistically different between patients with and and categorical variables as absolute values and percentages. Compar­ without ANHD in the univariable analysis. Missing values in the vari­ ison between groups was carried out using one-way ANOVA for ables included in the adjusted models were replaced using the multiple continuous variables (or by Mann-Whitney non-parametrical test if not imputation technique, generating 10 datasets in which there were no normally distributed) and the chi square test (or Fisher exact test, if missing values among all the variables included in the adjustment. In the needed) for categorical variables. Co-primary and secondary outcomes adjusted model for 1-year mortality, we analyzed the HR for each 75 J. Tost et al. European Journal of Internal Medicine 94 (2021) 73–84 Table 1 Table 1 (continued ) Characteristics of patients with heart failure with preserved ejection fraction Acute coronary (HFpEF) included in the study and comparison according to whether they were syndrome (either discharged with or without antineurohormonal drugs. angina or non- Total Missing With Without p STEMI) N=3,305 data ANHD ANHD Vital signs at ED n (%) n (%) N=2,312 N=993 arrival n (%) n (%) SBP (mmHg) 139 (123- 28 (0.8) 140 (124- 138 (122- 0.01 Demographic data (median (IQR)) 156) 158) 154) Age (years) (median 83.4 0 83 (77- 84.5 0.00 Heart rate (bpm) 83 (70- 70 (2.1) 82 (70- 83 (70- 0.39 (IQR) (77.5- 87.3) (78.8- (median (IQR)) 100) 100) 100) 87.7) 88.5) Oxygen saturation 94 (90- 84 (2.5) 94 (90- 94 (90- 0.02 Female sex 1993 15 (0.5) 1404 589 0.50 (%) (median 97) 97) 96) (60.5) (60.9) (59.6) (IQR)) Basal status of the Analyses patient Hemoglobin (g/L) 11.9 10 (0.3) 12 (10.6- 11.8 0.09 Comorbidities (median (IQR)) (10.6- 13.3) (10.6- Arterial 2823 5 (0.2) 2021 802 0.00 13.3) 13.2) hypertension (87.4) (87.4) (80.8) Creatinine (mg/dL) 1.12 20 (0.6) 1.1 (0.85- 1.18 0.00 Diabetes mellitus 1350 5 (0.2) 973 377 (38) 0.03 (median (IQR)) (0.86- 1.5) (0.89- (40.8) (42.1) 1.5) 1.58) Dyslipidemia 1607 5 (0.2) 1150 457 (46) 0.05 Hyponatremia 436 93 (2.8) 316 120 0.21 (48.6) (49.7) (<135 mmol/L) (13.6) (14.1) (12.4) Ischemic 839 5 (0.2) 622 217 0.00 Hyperpotassemia 410 216 (6.5) 291 119 (13) 0.77 cardiomyopathy (25.4) (26.9) (21.9) (>5 mmol/L) (13.3) (13.4) Chronic renal disease 932 5 (0.2) 650 282 0.87 Raise troponin 997 1324 696 301 0.04 (28.2) (28.1) (28.4) (>99th percentile) (50.2) (40) (48.7) (53.9) Cerebrovascular 407 6 (0.2) 301 (13) 106 0.06 NT-proBNP (pg/mL) 3298 176 (5.3) 3279 3347 0.21 disease (12.3) (10.7) (median (IQR)) (1800- (1800- (1809- Atrial fibrillation 2069 5 (0.2) 1453 616 (62) 0.66 6693) 6514) 7129) (62.6) (62.8) Global severity of 1345 0.78 Valve disease 1095 5 (0.2) 774 321 0.52 decompensation (40.6) (33.1) (33.5) (32.3) episode* Peripheral artery 329 (10) 5 (0.2) 239 90 (9.1) 0.26 - Low risk 837 611 226 (42) disease (10.3) (42.6) (42.8) Chronic obstructive 806 6 (0.2) 523 283 0.00 - Intermediate risk 831 604 227 pulmonary disease (24.4) (22.6) (28.5) (42.3) (42.3) (42.2) Dementia 302 (9.1) 6 (0.2) 213 (9.2) 89 (9) 0.82 - High risk alto 200 146 54 (10) Neoplasia 477 5 (0.2) 320 157 0.14 (10.2) (10.2) (14.4) (13.8) (15.8) - Very high risk 97 (4.9) 66 (4.6) 31 (5.8) Hepatic cirrhosis 48 (1.5) 8 (0.2) 39 (1.7) 9 (0.9) 0.09 Management in the Previous heart 2352 174 (5.3) 1627 725 0.32 ED failure (75) (74.5) (76.2) Treatment in the Functional capacity ED Barthel index 90 (70- 110 (3.3) 90 (75- 90 (70- 0.01 Endovenous diuretic 2710 75 (2.3) 1924 786 0.00 (points) (median 100) 100) 100) (83.8) (85.2) (80.4) (IQR)) Endovenous 256 (7.9) 76 (2.3) 191 (8.5) 65 (6.7) 0.08 NYHA Class III-IV 788 78 (2.4) 541 247 0.29 nitroglycerine (24.4) (23.9) (25.6) Morphine 155 (4.8) 75 (2.3) 99 (4.4) 56 (5.7) 0.10 LVEF (%) (median 60 (55- 211 (6.4) 60 (55- 57 (55- 0.01 Digoxin 363 75 (2.3) 274 89 (9.1) 0.01 (IQR)) 65) 65) 65) (11.2) (12.1) Chronic treatment Amiodarone 76 (2.3) 75 (2.3) 50 (2.2) 26 (2.7) 0.45 Diuretics 2297 5 (0.2) 1579 718 0.02 Inotrops/ 13 (0.4) 76 (2.3) 10 (0.4) 3 (0.3) 0.57 (69.5) (68.3) (72.3) vasopressors ACEIs or ARA-II 1823 5 (0.2) 1461 362 0.00 Non-invasive 217 (6.7) 75 (2.3) 147 (6.5) 70 (7.2) 0.50 (55.2) (63.2) (36.5) ventilation Betablockers 1720 6 (0.2) 1377 343 0.00 Patient destination (52.1) (59.6) (34.5) Hospitalization 2642 5 (0.2) 1834 808 0.18 Aldosterone receptor 500 5 (0.2) 387 113 0.00 (79.9) (79.3) (81.4) antagonists (15.1) (16.7) (11.4) Length of hospital 6 (2-10) 17 (0.5) 6 (2-10) 6 (3-11) 0.01 Digoxin 455 5 (0.2) 301 (13) 154 0.06 stay (days) (13.8) (15.5) (median (IQR)) Characteristics of ANHD antineurohormonal drugs; NYHA: New York Heart Association; LVEF: left the ventricular ejection fraction; ACEI: angiotensin- converting enzyme decompensation Inhibitors; ARAII: Angiotensin receptor antagonists-II. STEMI: ST-elevation episode Precipitating factor myocardial infarction. SBP: systolic blood pressure; ED: emergency department; Infection 1359 60 (1.8) 894 465 0.00 IQR: interquartile range. (41.8) (39.4) (47.5) The p values in bold highlight the differences considered statistically significant. * Rapid atrial 480 62 (1.9) 361 119 0.01 The severity of the episode was estimated with the MEESSI scale which fibrillation (14.8) (15.9) (12.2) classifies the risk of death of a patient with left cardiac insufficiency in the 30 Anemia 238 (7.3) 60 (1.8) 176 (7.7) 62 (6.3) 0.16 days following presentation to the emergency department based on 13 variables Hypertensive crisis 165 (5.1) 60 (1.8) 135 (5.9) 30 (3.1) 0.00 obtained at arrival to the emergency department: age, Barthel index, NYHA Non-adherence to 76 (2.3) 60 (1.8) 62 (2.7) 14 (1.4) 0.02 respiratory class, systolic blood pressure, respiratory frequency, oxygen satu­ pharmacological or dietetic ration, signs of low cardiac output, episode triggered by an acute coronary treatment syndrome, left ventricular hypertrophy in the ECG and NT-proBNP, troponin, 53 (1.6) 36 (1.1) 43 (1.9) 10 (1) 0.07 creatinine and potassium values. 76 J. Tost et al. European Journal of Internal Medicine 94 (2021) 73–84 Fig. 2. Kaplan-Meier analysis of the co-primary and secondary outcomes in patients with heart failure with preserved ejection fraction (HFpEF) according to whether they were discharged with or without antineurohormonal drugs. ED: emergency department; ANHD: antineurohormonal drugs; AHF: acute heart failure. individual year quarter by replacing all patients surviving at the end of USA). the 90-day quarter period at the starting point (day 0) of the next quarter and then calculating the HR for the 90-day mortality of the next year 2.5. Ethics quarter. In addition, we also compared outcomes in a propensity score (PS) matched cohort of paired patients. The PS was calculated by logistic The EAHFE Registry protocol was approved by a central Ethics regression (including age, sex, and the independent variables that Committee at the Hospital Universitario Central de Asturias (Oviedo, significantly differed between groups, defined as a p <0.05) and deter­ Spain) with the reference numbers 49/2010, 69/2011, 166/13, 160/15 mined the probability that participants would receive ANHD based on and 205/17. Due to the non-interventional design of the registry, these individual characteristics. Patients were then paired (1:1) based on Spanish legislation allows central Ethical Committee approval, accom­ the nearest neighbor matching with a caliper of 0.1. panied by notification to the local Ethical Committees. All participating We carried out multiple subgroup analyses in the adjusted models patients gave informed consent to be included in the registry and to be comparing patients receiving any combination of ANHD (BB, RAAS in­ contacted for follow-up. The present study was carried out in strict hibitors and MRA) with patients without ANHD in order to uncover compliance with the principles of the Declaration of Helsinki. individual medications (or specific combinations) achieving statistical differences in any co-primary or secondary outcomes. For the primary 3. Results outcomes, we also explored the presence of interaction for four variables (age, sex, ischemic cardiomyopathy as comorbidity, and de novo versus Of the 12,525 patients diagnosed with AHF in the participating EDs worsening HF), in order to uncover whether ANHD could exert a dif­ during phases 4, 5 and 6 of the EAHFE Registry, 3,305 patients with ferential effect on a particular subgroup of patients. We also performed HFpEF fulfilled the inclusion criteria and were finally included. The some sensitivity analyses in the adjusted models by including only those mean age was 83 years (IQR 77-88), and 60% were women. Of these, patients that initiate treatment with ANHD after AHF decompensation 2,312 patients were receiving ANHD (70.3%), and the 993 remaining (i.e., excluding patients receiving chronic ANHD before decompensa­ patients made up the group without ANHD (29.7%). The ANHD most tion) and compared them with those that were maintained without any frequently prescribed was BB (45.8%), and the most frequent combi­ ANHD after discharge from the AHF episode. nation was BB plus RAAS inhibitors (19.9%) (Fig. 1). Statistical significance was accepted if the p value was less than 0.05 The univariable analysis between patients with and without ANHD or if the 95%CI of the HR excluded the value 1. Since this was an showed significant differences in 23 of the 49 variables analyzed exploratory study, a pre-hoc sample size calculation was not made. All (Table 1). The group receiving ANHD was younger, had a higher pres­ calculations were made using SPSS v24.0 software (IBM, Armonk, NY, ence of hypertension, diabetes mellitus and ischemic cardiomyopathy, 77 J. Tost et al. European Journal of Internal Medicine 94 (2021) 73–84 Fig. 3. Unadjusted and adjusted hazard ratios for patients with heart failure with preserved ejection fraction (HFpEF) receiving antineurohormonal drugs for the co- primary and secondary outcomes. *Propensity score matching provided 711 pairs of patients matched by demographic, basal status, characteristics of the decompensation and management in the emergency department. ANHD: antineurohormonal drugs; AHF: acute heart failure; ED: emergency department. P values in bold highlight differences considered statistically significant. less functional capacity, and decompensation was more frequent due to patients with balanced possibilities of receiving ANHD, rendered very tachyarrhythmia, hypertensive crisis or incompliance with pharmaco­ similar results (Fig. 3). logical or dietetic treatments. There were no significant differences be­ When the ANHD were analyzed individually in relation to their as­ tween the two groups with respect to the severity of the AHF episode sociation with outcomes (Table 2), we observed that MRA alone and BB, estimated using the MEESSI scale or by the need for hospitalization. In alone or combined with other ANHD, were associated with worse results the case of hospitalization, the median hospital stay was longer in the in some co-primary and secondary endpoints. When assessing the as­ group without ANHD. sociation of ANHD with 1-year mortality for every individual year The risk of death at 1 year was 26.9%, and the risk of experiencing a quarter, we observed that a negative impact becomes more evident after combined adverse event at 90 days was 54.4%, while the risk of 90-day the second quarter for ANHD considered altogether as well as for the BB death, hospitalization and ED-revisit individually considered was 9.8%, and MRA considered individually (Fig. 4). On the other hand, the only 35.1% and 52.6%, respectively. Survival curves for patients with and ANHD positive impact for HFpEF patients was observed in those who without ANHD were not statistically different for any of these co- exclusively received RAAS inhibitors, showing a significant reduction in primary or secondary outcomes (Fig. 2). After adjustment, there was the risk of hospitalization for a new AHF episode at 90 days (HR=0.735, also no statistically significant association between treatment with 98%CI=0.564-0.957). We did not find interaction for the co-primary ANHD and 1-year mortality (HR=1.167 for patients with ANHD, 95% outcomes for any subgroup of patients based on age, sex, ischemic car­ CI=0.984-1.384) or the 90-day combined adverse event (HR=1.143, diomyopathy as a comorbidity or de novo versus worsening HF (Fig. 5). 95%CI=0.999-1.306). With respect to secondary outcomes, only ED revisit was statistically greater in the adjusted model in patients with 4. Discussion ANHD (HR=1.154, 95%CI=1.007-1.323), while there were no differ­ ences in the risk of death or rehospitalization (Fig. 3). The analysis of This study has three main findings. The first was that there were no outcomes in the PS matched cohort, which provided 711 pairs of significant changes in 1-year mortality or 90-day combined adverse 78 J. Tost et al. European Journal of Internal Medicine 94 (2021) 73–84 Table 2 Adjusted hazard ratios for patients with heart failure with preserved ejection fraction (HFpEF) receiving antineurohormonal drugs for the co-primary and secondary outcomes considered in the present study. Co-primary endpoints Secondary endpoints 90-day combined 1-year all-cause 90-day all-cause 90-day hospitalization due 90-day ED revisit due adverse event death death to AHF to AHF HR (95% CI)* HR (95% CI)* HR (95% CI)* HR (95% CI)* HR (95% CI)* Receiving any antineurohormonal drug 1.136 (0.993-1.298) 1.181 (0.997- 1.087 (0.833- 1.058 (0.895-1.251) 1.154 (1.007-1.323) 1.400) 1.417) Receiving BB (either alone or in combination) 1.407 (1.157-1.711) 1.247 (0.963- 1.119 (0.755- 1.489 (1.168-1.898) 1.398 (1.145-1.707) 1.616) 1.658) Receiving RAAS inhibitor (either alone or in 0.989 (0.807-1.211) 1.004 (0.767- 0.989 (0.629- 0.817 (0.627-1.065) 1.018 (0.828-1.251) combination) 1.314) 1.553) Receiving MRA (either alone or in 1.089 (0.804-1.475) 1.398 (0.971- 1.057 (0.578- 1.067 (0.731-1.557) 1.130 (0.830-1.540) combination) 2.105) 1.934) Receiving only BB 1.421 (1.172-1.723) 1.222 (0.948- 1.174 (0.800- 1.503 (1.182-1.911) 1.415 (1.162-1.722) 1.575) 1.725) Receiving only RAAS inhibitor 0.945 (0.773-1.154) 1.059 (0.815- 0.958 (0.620- 0.735 (0.564-0.957) 0.974 (0.794-1.194) 1.376) 1.480) Receiving only MRA 1.074 (0.780-1.477) 1.579 (1.096- 1.280 (0.703- 0.980 (0.655-1.466) 1.069 (0.769-1.484) 2.274) 2.329) Receiving the combination of BB + RAAS 1.236 (1.013-1.507) 1.148 (0.872- 1.224 (0.798- 1.187 (0.920-1.532) 1.226 (1.001-1.502) inhibitor 1.510) 1.878) Receiving the combination of BB + MRA 1.008 (0.724-1.403) 1.271 (0.836- 0.895 (0.457- 1.056 (0.696-1.601) 1.074 (0.769-1.499) 1.933) 1.752) Receiving the combination of RAAS inhibitor 0.966 (0.675-1.381) 0.795 (0.468- 0.506 (0.179- 0.903 (0.575-1.420) 1.067 (0.747-1.524) + MRA 1.379) 1.432) Receiving the combination of BB + RAAS 0.949 (0.689-1.307) 1.304 (0.870- 1.309 (0.696- 0.758 (0.484-1.189) 0.975 (0.703-1.353) inhibitor + MRA 1.953) 2.460) AHF: acute heart failure; ANHD: antineurohormonal drugs; BB: beta-blocker; RAAS: renin-angiotensin system inhibitors; MRA: mineralcorticosteroid-receptor antagonist * Hazard ratios were performed for age and sex, hypertension, diabetes mellitus, ischemic cardiomyopathy and chronic obstructive pulmonary disease as comor­ bidities, Barthel index at baseline, left ventricular ejection fraction, chronic treatment with loop-diuretic, renin-angiotensin system inhibitors and beta-blockers and mineralcorticosteroid-receptor antagonists, infection, rapid atrial fibrillation, hypertensive crisis and dietetic/pharmacologic transgression as precipitants of the index episode of acute heart failure, systolic blood pressure, pulsioxymetry, creatinine and raised troponin at emergency department arrival, and treatment with intravenous diuretics and digoxin in the emergency department, and length of hospitalization. events among patients with HFpEF treated with ANHD, although a In addition, the contribution of each ANHD to outcomes is difficult to significant 15% increase in ED revisit due to AHF was noted. Second, determine. However, of note was the increase of almost 30% in ED re­ treatment with BB (alone or in combination) was associated with sig­ visits, hospitalizations and combined adverse events in association with nificant increases of between 25% and 50% in mortality, combined the use of BB, that could be of up to 50% when BB are used alone, with adverse events, hospitalizations and ED revisits for AHF. Additionally, no other ANHD in combination. Treatment with BB in HFpEF is espe­ when MRA were used alone, a 58% of increase in 1-year mortality was cially controversial because of the limited number of studies available observed. And third, treatment with RAAS inhibitors showed a neutral and the contradictory results (14-21), and also because most studies and effect in relation to most of the endpoint variables, and even when these reviews also include patients with LVEF between 40-49% (currently drugs were received alone (in the absence of BB or MRA cotreatment), classified as HF with mid-range ejection fraction, HFmrEF). In these this was related to a significant reduction of 27% in hospitalization due latter studies, treatment with ANHD tends to improve the clinical to AHF. manifestations (mainly dyspnea), echocardiographic results and mor­ In the ANHD group (formed by patients receiving BB, RAAS inhibitor tality, especially when the patient profile is similar to that of patients or MRA, alone or in combination), the elevated percentage of hyper­ with HFrEF in whom treatment with BB is mandatory (20). Thus, in the tension (87%) and cases in which decompensation of hypertension study by Zheng et al., which included patients with a LVEF greater than became a precipitating factor for the hypertension episode were of note. 40%, the use of BB significantly reduced the mortality by 22% compared This suggests that hypertension in these patients was not adequately to placebo (17). In the meta-analysis by Liu et al., which also included controlled. In addition, this could justify why almost 20% of patients patients with an LVEF greater than 40%, there was a significant reduc­ with HFpEF that were not on chronic medication with ANHD initiated tion in all-cause mortality of 9%, but hospitalization did not decrease treatment with ANHD at discharge with the aim of achieving better (18). Very recently, Kimmoun et al. analyzed outcomes of more than 15 control of hypertension, since BB and RAAS inhibitors make up an million of AHF episodes from 285 studies and found positive correla­ essential part of the treatment of hypertension. Likewise, it was of note tions between treatment with BB (alone or, ideally, combined with that although the greater risk of ED revisit due to a new AHF episode RAAS inhibitors) and AHF survival (but not rehospitalization), and this among the patients with HFpEF with ANHD could have been related to relationship was similarly obtained in patients with LVEF ≥40% and the greater percentage of comorbidities, this group was actually with LVEF <40% (21). Conversely, studies in patients with a LVEF younger, had better LVEF and renal function and lower troponin levels. greater than 50% did not find benefits with the use of BB, and some In addition, these patients presented less physical fragility (since they studies even reported increases in hospitalization of greater than 70% had a better Barthel index), and fragility is related to worse prognosis (15,16), in line with our findings. The use of BB is not advised by other (13). Moreover, this increase in risk of ED revisit in the ANHD group was authors due to the risk of adverse cardiovascular events in relation to an observed in the adjusted model in which these differences were taken increase in central venous pressure and prolonged diastolic filling. These into account. Therefore, we have no clear explanation for this finding events increase ventricle load, plasma natriuretic peptide concentrations and were unable to find any bibliographic references with respect to the and bradyarrhythmias due to impairment of the conduction system effect of treatment with ANHD (considered globally) in patients with related to older age (19). HFpEF on the results in the setting of real clinical practice. In contrast to BB, patients with HFpEF treated only with RAAS 79 J. Tost et al. European Journal of Internal Medicine 94 (2021) 73–84 Supplemental Table 1 Supplemental Table 1 (continued ) Glossary of the variables included in the present study. Indicate if the patient is diagnosed with DEMOGRAPHICS cirrhosis independently of the etiology Age Age calculated as the difference in or stage or is if receiving specific decimal years between the date of treatment. inclusion in the study and the date of Prior episode of heart failure Indicate if the patient has heart failure, is birth. receiving specific treatment or the Sex Male/Female clinical history reports previous episodes MEDICAL HISTORY of AHF. Hypertension Indicate if the patient has arterial BASELINE STATUS hypertension because this is shown Cardiorespiratory class Indicate the functional grade of basal under previous clinical history or the dyspnea (within the 15 days prior to the patient is receiving specific treatment. exacerbation episode) of the patient Diabetes Mellitus Indicate if the patient has diabetes according to the New York Heart mellitus because this is shown under Association (NYHA) scale. Class I: No previous clinical history or the patient is limitation in physical activity. Routine receiving specific treatment. activity does not cause fatigue, Dyslipemia Indicate if the patient has been palpitations, dyspnea or angina-like diagnosed with dyslipemia because this pain. Class II: Slight limitation in is shown under previous clinical history physical activity. Comfortable when or the patient is receiving specific resting. Routine activity causes fatigue, treatment. palpitations, dyspnea or angina-like Ischemic cardiomyopathy Indicate if the patient has any form of pain, Class III: Marked limitation in ischaemic heart disease (acute coronary physical activity. Comfortable while syndrome without an elevation of the ST resting. Less than normal physical segment, acute coronary syndrome with activity causes fatigue, palpitations, an elevation of the ST segment unstable dyspnea or angina-like pain. Class IV: angina, stable angina, etc.) because this Incapacity to perform any physical is shown under previous clinical history activity without discomfort. The or the patient is receiving specific symptoms of cardiac insufficiency or treatment. angina-like syndrome may be present Chronic kidney disease Indicate if the patient has chronic renal even when resting. Any physical activity insufficiency or chronic kidney disease increases the discomfort. or if analyses over the previous year Baseline Barthel index Barthel index value of the patient at least show creatinine values >2 mg/dL. 15 days prior to the date seen in the ED. Cerebrovascular disease Indicate if the patient has had a previous Left ventricular ejection fraction Refers to the last value obtained within cerebrovascular accident or (LVEF) (%) the previous 6 months. cerebrovascular disease because this is CHRONIC TREATMENT AT HOME described in the clinical history or shown Any diuretic Receiving chronic treatment with in CT or MR imaging studies within the diuretics, either loop-diuretics or previous year and reported as thiazide diuretics or mineralocorticoid cerebrovascular disease. receptor antagonist Atrial fibrillation Indicate if the previous history describes Mineralcorticoid receptor antagonist Receiving chronic treatment with permanent or chronic atrial fibrillation aldosterone-receptor antagonists or an electrocardiogram performed Beta-blocker Receiving chronic treatment with beta- within the previous year shows atrial blocker fibrillation and this continues to be Angiotensin-converter enzyme (ACE) Receiving chronic treatment with ACE present. inhibitors or angiotensin-II receptor inhibitors or angiotensin-II receptor Heart valve disease Indicate if the patient has any type of blocker blocker clinically significant heart valve disease Digoxin Receiving chronic treatment with according to an ultrasound or digoxin hemodynamic study reported in the VITAL SIGNS AT EMERGENCY DEPARTMENT ARRIVAL previous clinical history. Systolic blood pressure Systolic blood pressure (SBP) measured Peripheral vascular disease Indicate if the patient has peripheral in mmHg of the patient on arrival to the artery disease in either the lower ED. This value can be that obtained extremities or carotid artery, and if the during triage or the first taken on patient is receiving specific treatment, initiating care. has undergone specific surgery (by-pass Heart rate Central heart rate measured as beats per of lower extremities, endarterectomy, minute of the patient on arrival to the etc.) or there is a previous history of an ED. This value can be that obtained ankle brachial index <0.90. during triage or the first taken on Chronic obstructive pulmonary Indicate if the patient is diagnosed with initiating care. disease chronic obstructive pulmonary disease Room air pulsioxymetry Oxygen saturation expressed as because this is shown under previous percentage obtained by capillary clinical history, has undergone a pulsioxymetry on arrival to the ED. This spirometry test which was not normal or value can be that obtained during triage the patient is receiving specific or the first taken on initiating care. treatment BLOOD TESTS AT EMERGENCY DEPARTMENT ARRIVAL Dementia Indicate if the patient has dementia or Hemoglobin In g/dL cognitive deterioration or is receiving Creatinine In mg/dL specific treatment. Sodium In mmol/L Neoplasia Indicate if the clinical history describes Potassium In mmol/L the presence of any type of cancer of any Natriuretic peptides: NT-proBNP In pmol/L grade at present or in the past Increased troponin Yes / No (according to the upper limit for independently of the current status normality provided by the (active, cured, in complete remission, manufacturer) with or without treatment, etc.). INTENSIVE TREATMENT AT EMERGENCY DEPARTMENT Liver Cirrhosis Morphine (continued on next page) 80 J. Tost et al. European Journal of Internal Medicine 94 (2021) 73–84 Supplemental Table 1 (continued ) different, particularly with increased adverse events in decompensated Receiving treatment with subcutaneous patients. Finally, TOPCAT included patients with an ejection fraction or intravenous morphine in the ED from 45% on upwards, and we only included patients with an ejection Intravenous diuretic Receiving treatment with intravenous fraction from 50%. Therefore, MRA should be used with caution in diuretic in the ED. Notes whether the elderly populations with HFpEF, such as that in the present study. intravenous diuretic is administered in continuous intravenous perfusion. It was of note that our results were obtained in a sample of consec­ Intravenous nitroglycerine Receiving treatment with intravenous utive patients with AHF, and 60% were women. As women are sys­ nitrates during the first care given in the tematically underrepresented in clinical trials, we believe that our data ED of a real world scenario complement findings reported in ideal clinical Inotropic or vasopressor treatment Receiving treatment with inotropic or trial scenarios. In these latter scenarios, most of the studies on ANHD in vasoactive drugs (dopamine, dobutamine, levosimendan, HFpEF have shown neutral or non-conclusive results (14,25,26). With noradrenalin) during the first care given this lack of evidence, treatment of HFpEF is limited to depletive and in the ED symptomatic treatment and to the control of associated risk factors. For Digoxin Receiving treatment with intravenous this reason, the current recommendations of ANHD in HFpEF are weak digoxin and some guidelines only suggest treatment with angiotensin receptor Amiodarone Receiving treatment with intravenous amiodarone antagonists and MRA to reduce hospitalizations for AHF, while always Severity of the decompensation episode maintaining strict control of potassium levels and renal function (8). The severity of the episode was estimated with the MEESSI scale which classifies the Nonetheless, the prescription of ANHD in patients with HFpEF is very risk of death of a patient with left cardiac insufficiency frequent and, in general, greater than 60%. There are differences be­ in the 30 days following presentation to the emergency department based on 13 variables obtained at arrival to the emergency department: tween the most prevalent types of ANHD according to different coun­ age, Barthel index, NYHA respiratory class, systolic blood pressure, respiratory tries. Thus, while in Spain RAAS inhibitors are more commonly used, in frequency, oxygen saturation, signs of low cardiac output, Japan and the USA BB predominate, with the prescription of BB in the episode triggered by an acute coronary syndrome, left ventricular hypertrophy in USA reaching 80% of HFpEF cases (9,27,28). Some authors believe that the ECG and NT-proBNP, troponin, creatinine and potassium this elevated prescription of ANHD in HFpEF is not justified and could values. Low risk Predicted risk of death at 30 days potentially generate iatrogenesis, especially in older aged patients who between 0 and 3.9% make up most of the patients with HFpEF (29). The results of our study Intermediate risk Predicted risk of death at 30 days are in line with this hypothesis since, with the exception of the use of between 3.9% to 14.5% RAAS inhibitors alone, we found no benefits with the use of ANHD in High risk Predicted risk of death at 30 days between 14,7% and 25.7% general, and, in the specific case of BB, their use could even be delete­ Very high risk Predicted risk of death at 30 days higher rious. In fact, differences in 1-year mortality after the AHF episode be­ than 25.7% tween treated and untreated patients became more evident after the DISPOSITION second year quarter for ANHD taking altogether and for BB and MRA Discharged home without Patient is discharged directly home from when considered individually. hospitalization the ED without hospital admission. Hospital admission Patient was transferred to an in-hospital Along the same line as the studies mentioned previously, our results ward after ED management, whatever show that treatment with ANHD is very frequent (70%), especially with the type (regular, semi-intensive, BB and RAAS inhibitors, alone or in combination. We do not know the intensive or coronary care unit) or the reason why these treatments were prescribed to our patients. It is likely specialty (internal medicine, cardiology, short stay unit, geriatric unit) or other that in part of the patients the treatment was not clearly indicated since (including subacute units). the ANHD in patients receiving them as chronic treatment were with­ Length of hospital stay Length of time from admission to a drawn after discharge for the episode of AHF in 20% of the cases. hospitalization ward until discharge However, in many cases their prescription would have been indicated to home, in days control associated risk factors, especially hypertension and ischemic cardiomyopathy, which were present in 87.4% and 26.9% of the pa­ inhibitors present a 30% reduction in the risk of hospitalization for AHF. tients with ANHD, respectively. Treatment of chronic hypertension is There are only a few studies reporting a beneficial effect of RAAS in­ the principal preventive factor for the development of HFpEF, and hibitors in HFpEF, although, as previously commented, many of these therefore aggressive treatment to maintain the control of blood pressure studies include patients with a LVEF greater than 40 or 45%, making is strongly recommended (30). Among ANHD, both RAAS inhibitors and comparison with our results, which included patients with a LVEF of BB are therapeutic options for the control of hypertension in HFpEF 50% or greater, difficult. In the PEP-CHF study, perindopril in patients (with level of evidence: C, class IIb), although the latter are less effective over the age of 70 improved the symptoms and exercise capacity and in the control of hypertension and, in view of our results, have a po­ reduced hospitalizations in the first year, although this was not main­ tential deleterious effect on HFpEF itself. Therefore, although ANHD in tained later (20). Likewise, the CHARM-Preserved study reported that general are not indicated in the treatment of HFpEF, if it is necessary to candesartan reduced hospitalizations by 26% (22). control hypertension, treatment with RAAS inhibitors rather than BB Finally, the increased 1-year mortality of 58% with MRA is of note should be prioritized. Nonetheless, studies are needed that are specif­ and contrasts with randomized data such as that from the TOPCAT trial ically designed to demonstrate this choice in patients with HFpEF as in which there certainly was no increase in mortality (and in fact a defined in the current guidelines; that is, those with a LVEF greater than reduction in HF hospitalization was observed) (23). However, we or equal to 50%. believe that three relevant differences between the two cohorts could have remarkably influenced the differences. Patients included in the 4.1. Limitations TOPCAT trial had a median age of 69 years, while in our study it was of 83. Elderly populations are more sensitive to drug-related adverse The main limitation of this study is we do not know the reasons for events, and MRA are particularly poorly tolerated in patients with the prescription of ANHD when these are prescribed as chronic medi­ advanced ages (24). Second, in most cases, TOPCAT recruited HF pa­ cation (pre-decompensation) and at discharge (post-decompensation). tients with a stable condition. In our study, patient inclusion (time zero) This makes it difficult to know whether ANHD are indicated with the was at the time of decompensation, and the impact of drugs can be aim of controlling a risk factor such as hypertension or if, to the con­ trary, ANHD are not indicated. Along the same line, we do not know why 81 J. Tost et al. European Journal of Internal Medicine 94 (2021) 73–84 Fig. 4. Analysis of adjusted associations between antineurohormonal drugs (whichever or by individual drug class) and 1-year all-cause mortality, during the whole time period (up) and by year quarter (down). ANHD: antineurohormonal drugs; ED: emergency department; BB: bet-blockers; RAAS: renin-angiotensin-aldosterone; MRA: mineralcorticosteroid- receptor antagonist. ANHD withdrawn or introduced at discharge, and as mentioned previ­ without hospitalization, and their prognosis (32). Seventh, our study ously, this occurred in an elevated percentage of cases (20% in both included a high percentage of elderly AHF patients in whom frailty and groups). Secondly, we do not know if the ANHD doses were correct or dependence are frequent, and are two factors strongly related to mor­ were up-titrated to the maximum dose tolerated, although doses lower tality (13,33). Eighth, this was real life cohort without any planned than maximum titration may also be beneficial for patients (31). intervention, and there could have been differences in physician stra­ Thirdly, we did not perform a follow-up of the potential modifications in tegies of ANHD use, not only in terms of indication, but also in terms of treatment during the 90 days after discharge and, in turn, do not know the initial doses and up-titration strategies. the degree of patient compliance. Fourth, as in every observational study, causal relationships cannot be inferred. Therefore, the results of 5. Conclusion the current analysis are limited by the retrospective design, potentially including bias by treatment indication, and should be considered as An elevated percentage of patients with HFpEF are treated with hypothesis generating. In this sense, it was of note that we only recorded ANHD at discharge (70%) with no clear indication, although this could one ejection fraction per patient (the most recent in the 6 months pre­ be related to the control of associated factors such as AHT or ischemic vious to decompensation). Therefore, we cannot rule out that some cardiomyopathy. Alternatively, some cases could represent incorrect patients may have transitioned from HFpEF to HFrEF, or from HFrEF to interpretation of the current clinical practice guidelines. Whatever the HFpEF. In this latter scenario, patients with previous recording of HFrEF cause leading to ANHD use, it does not have an impact on mortality or should have been considered as HFrEF (or excluded from the present hospitalization, but these drugs are related to an increase in ED revisit study) even with current normal EF, but we were not able to discrimi­ for AHF. Among ANHD, RAAS inhibitors could introduce some benefits nate this situation and this imposes an additional limitation. Fifth, there in the short-term, especially for reducing the risk of hospitalization due was no sample size calculation, and this could have influenced the lack to a new AHF episode. However, as our data come from a retrospective of statistical significance in some comparisons (beta-error). Sixth, the analysis of a real world registry, the presence of limited adjustment, patients came from a nationwide cohort with a universal public health residual confounders, lack of information of alternative indications to care system, and external validation might be needed to confirm their treatment or no verification of the actual compliance (among others) generalizability. For example, Spanish EDs are able to provide obser­ preclude making firm conclusions until further large international vation, which is not the rule in other countries, and this can influence studies verify or refute them. the percentage of patients who are directly sent home from the ED, 82 J. Tost et al. European Journal of Internal Medicine 94 (2021) 73–84 Fig. 5. Results of subgroup analyses (according age, sex, ischemic cardiomyopathy and de novo heart failure) for the co-primary endpoints ANHD: antineurohormonal drugs; Acknowledgments (Hospital Miguel Servet de Zaragoza), Ana Belén Mecina (Hospital de Alcorcón de Madrid), Josep Tost, Marta Berenguer, Ruxandra Donea This study was partially supported by competitive grants from the (Consorci Sanitari de Terrassa), Susana Sánchez Ramón, Virginia Car­ Instituto de Salud Carlos III supported with funds from the Spanish bajosa Rodríguez (Hospital Universitario Rio Hortega de Valladolid), Ministry of Health and FEDER (PI15/01019, PI15/00773, PI18/00393, Pascual Piñera, José Andrés Sánchez Nicolás (Hospital Reina Sofía de PI18/00456), Catalonia Government (SGR 2009/1385, 2014/0313, Murcia), Raquel Torres Garate (Hospital Severo Ochoa de Madrid), Aitor 2017/1424), and the Fundació La Marató. de TV3 (2015/2510). The Alquézar-Arbé, Miguel Alberto Rizzi, Sergio Herrera (Hospital de la ICA-Research Group has received unrestricted funding from Novartis Santa Creu y Sant Pau de Barcelona), Javier Jacob, Alex Roset, Irene and Orion Pharma. The design of the study, patient inclusion, data Cabello, Antonio Haro (Hospital Universitari de Bellvitge de Barcelona), analysis, discussion and final conclusions were exclusively carried out Fernando Richard, José María Álvarez Pérez, María Pilar López Diez by the authors with no participation of the granters. The authors thank (Hospital Universitario de Burgos), Pablo Herrero Puente, Joaquín Alícia Díaz for her professionalism in data management. Vázquez Álvarez, Belén Prieto García, María García García, Marta Sánchez González (Hospital Universitario Central de Asturias de Appendix 1 Oviedo), Pere Llorens, Patricia Javaloyes, Inmaculada Jiménez, Néstor Hernández, Begoña Espinosa, Adriana Gil, Francisca Molina, Tamara Marta Fuentes, Cristina Gil (Hospital Universitario de Salamanca), García (Hospital General de Alicante), Juan Antonio Andueza (Hospital Héctor Alonso, Enrique Pérez-Llantada (Hospital Marqués de Valdecilla General Universitario Gregorio Marañón de Madrid), Rodolfo Romero de Santander), Francisco Javier Martín-Sánchez, Guillermo Llopis Gar­ (Hospital Universitario de Getafe de Madrid), Martín Ruíz, Roberto cía, Mar Suárez Cadenas (Hospital Clínico San Carlos de Madrid), Òscar Calvache (Hospital de Henares de Madrid), María Teresa Lorca Serralta, Miró, Víctor Gil, Rosa Escoda, Sira Aguiló, Carolina Sánchez (Hospital Luis Ernesto Calderón Jave (Hospital del Tajo de Madrid), Beatriz Clínic de Barcelona), Javier Millán (Hospital Politénic La Fe de Valen­ Amores Arriaga, Beatriz Sierra Bergua (Hospital Clínico Lozano Blesa de cia), José Pavón (Hospital Dr. Negrín de Las Palmas de Gran Canaria), Zaragoza), Enrique Martín Mojarro, Brigitte Silvana Alarcón Jiménez Antonio Noval (Hospital Insular de Las Palmas de Gran Canaria), María (Hospital Sant Pau i Santa Tecla de Tarragona), Lisette Travería Bécquer, Luisa López-Grima, Amparo Valero, María Ángeles Juan (Hospital Dr. Guillermo Burillo (Hospital Universitario de Canarias de Tenerife), Lluís Peset de Valencia), Alfons Aguirre, Maria Angels Pedragosa, Silvia Llauger García, Gerard Corominas LaSalle. (Hospital Universitari de Vic Mínguez Masó (Hospital del Mar de Barcelona), María Isabel Alonso, de Barcelona), Carmen Agüera Urbano, Ana Belén García Soto, Elisa Francisco Ruiz (Hospital de Valme de Sevilla), José Miguel Franco Delgado Padial (Hospital Costa del Sol de Marbella de Málaga), Ester Soy 83 J. Tost et al. European Journal of Internal Medicine 94 (2021) 73–84 Ferrer, María Adroher Múñoz (Hospital Josep Trueta de Girona). José Böhm M, Andersson B, Kjekshus J, Packer M, Rigby AS, Rosano G, Wedel H, Å Hjalmarson, Wikstrand J, D; Kotecha. Beta-blockers in Heart Failure Manuel Garrido (Hospital Virgen Macarena de Sevilla), Francisco Javier Collaborative Group. Beta-blockers for heart failure with reduced, mid-range, and Lucas-Imbernón (Hospital General Universitario de Albacete), Rut Gaya preserved ejection fraction: an individual patient-level analysis of double-blind (Hospital Juan XXIII de Tarragona), Carlos Bibiano, María Mir, Beatriz randomized trials. Eur Heart J 2018;39(1):26–35. Rodríguez (Hospital Infanta Leonor de Madrid), José Luis Carballo [17] Zheng SL, Chan FT, Nabeebaccus AA, Shah AM, McDonagh T, Okonko DO, Ayis S. Drug treatment effects on outcomes in heart failure with preserved ejection (Complejo Hospitalario Universitario de Ourense), Esther Rodríguez- fraction: a systematic review and meta-analysis. Heart. 2018 Mar;104(5):407-415. Adrada, Belén Rodríguez Miranda, Monika Vicente Martín (Hospital Rey doi: 10.1136/heartjnl-2017-311652. Epub 2017 Aug 5. PMID: 28780577; PMCID: Juan Carlos de Móstoles de Madrid). Pere Coma Casanova, Joan Espi­ PMC5861385. [18] Liu F, Chen Y, Feng X, Teng Z, Yuan Y, Bin J. Effects of beta-blockers on heart nach Alvarós (Hospital San Joan de Deu de Martorell, Barcelona). failure with preserved ejection fraction: a meta-analysis. PLoS One 2014;9(3): e90555. https://doi.org/10.1371/journal.pone.0090555. PMID: 24599093; References PMCID: PMC3944014. [19] Goyal P, Rich MW. Electrophysiology and heart rhythm disorders in older adults. J Geriatr Cardiol 2016;13(8):645–51. [1] Llorens P, Escoda R, Miró O, Mueller C, Mebazaa A, Herrero-Puente P, et al. EAHFE [20] Cleland JG, Tendera M, Adamus J, Freemantle N, Polonski L, Taylor J, Registry (Epidemiology of Acute Heart Failure in Spanish Emergency Investigators PEP-CHF. The perindopril in elderly people with chronic heart failure Departments): clinical characteristics, therapeutic approach and outcomes of (PEP-CHF) study. Eur Heart J 2006;27(19):2338–45. https://doi.org/10.1093/ patients diagnosed of acute heart failure at Spanish emergency departments. eurheartj/ehl250. Epub 2006 Sep 8. PMID: 16963472. Emergencias 2015;27:11–22. [21] Kimmoun A, Takagi K, Gall E, Ishihara S, Hammoum P, El Bèze N, Bourgeois A, [2] Fonarow GC, Corday E, ADHERE Scientific Advisory Committee. Overview of Chassard G, Pegorer-Sfes H, Gayat E, Solal AC, Hollinger A, Merkling T, acutely decompensated congestive heart failure (ADHF): a report from the Mebazaa A, METAHF team. Temporal trends in mortality and readmission after ADHERE registry. Heart Fail Rev. 2004;9:179–85. acute heart failure: a systematic review and meta-regression in the past four [3] Miró Ò, Gil V, Rosselló X, Martín-Sánchez FJ, Llorens P, Jacob J, et al. Patients with decades. Eur J Heart Fail 2021. https://doi.org/10.1002/ejhf.2103 (in press). acute heart failure discharged from the emergency department and classified as [22] Yusuf S, Pfeffer MA, Swedberg K, et al. Effects of candesartan in patients with low risk by the MEESSI score (multiple risk estimate based on the Spanish chronic heart failure and preserved left-ventricular ejection fraction: CHARM- emergency department scale): prevalence of adverse events and predictability. Preserved trial. Lancet 2003;362:777–81. Emergencias 2019;31:5–14. [23] Pitt B, Pfeffer MA, Assmann SF, Boineau R, Anand IS, Claggett B, Clausell N, [4] P Ponikowski, Voors AA, Anker SD, Bueno H, Cleland JGF, Coats AJS, et al. ESC Desai AS, Diaz R, Fleg JL, Gordeev I, Harty B, Heitner JF, Kenwood CT, Lewis EF, Guidelines for the diagnosis and treatment of acute and chronic heart failure: The O’Meara E, Probstfield JL, Shaburishvili T, Shah SJ, Solomon SD, Sweitzer NK, Task Force for the diagnosis and treatment of acute and chronic heart failure of the Yang S, McKinlay SM, TOPCAT Investigators. Spironolactone for heart failure with European Society of Cardiology (ESC) developed with the special contribution of preserved ejection fraction. N Engl J Med. 2014;370:1383–92. the Heart Failure Association (HFA) of the ESC. Eur Heart J 2016;37:2129–200. [24] Sztramko R, Chau V, Wong R. Adverse drug events and associated factors in heart [5] Oktay AA, Rich JD, Shah SJ. The emerging epidemic of heart failure with preserved failure therapy among the very elderly. Can Geriatr J 2011;14:79–92. ejection fraction. Curr Heart Fail Rep 2013;10:401–10. [25] Massie BM, Carson PE, McMurray JJ, et al. Irbesartan in patients with heart failure [6] Lam CSP, Voors AA, de Boer RA, Solomon SD, van Veldhuisen DJ. Heart failure and preserved ejection fraction. N Engl J Med 2008;359:2456–67. with preserved ejection fraction: from mechanisms to therapies. Eur Heart J 2018; [26] Solomon SD, McMurray JJV, Anand IS, Ge J, Lam CSP, Maggioni AP, Martinez F, 39(30):2780–92. Packer M, Pfeffer MA, Pieske B, Redfield MM, Rouleau JL, van Veldhuisen DJ, [7] Meta-analysis Global Group in Chronic Heart Failure (MAGGIC). The survival of Zannad F, Zile MR, Desai AS, Claggett B, Jhund PS, Boytsov SA, Comin-Colet J, patients with heart failure with preserved or reduced left ventricular ejection Cleland J, Düngen HD, Goncalvesova E, Katova T, Kerr Saraiva JF, Lelonek M, fraction: an individual patient data meta-analysis. Eur Heart J 2012;33(14): Merkely B, Senni M, Shah SJ, Zhou J, Rizkala AR, Gong J, Shi VC, Lefkowitz MP, 1750–7. PARAGON-HF Investigators and Committees. Angiotensin-Neprilysin Inhibition in [8] JA Ezekowitz, O’Meara E, McDonald MA, Abrams H, Chan M, Ducharme A, Heart Failure with Preserved Ejection Fraction. N Engl J Med. 2019;381(17): Giannetti N, Grzeslo A, Hamilton PG, Heckman GA, Howlett JG, Koshman SL, 1609–20. Lepage S, McKelvie RS, Moe GW, Rajda M, Swiggum E, Virani SA, Zieroth S, Al- [27] Nagai T, Yoshikawa T, Saito Y, Takeishi Y, Yamamoto K, Ogawa H, Anzai T, Hesayen A, Cohen-Solal A, D’Astous M, De S, Estrella-Holder E, Fremes S, Green L, Investigators JASPER. Clinical characteristics, management, and outcomes of Haddad H, Harkness K, Hernandez AF, Kouz S, LeBlanc MH, Masoudi FA, Ross HJ, Japanese patients hospitalized for heart failure with preserved ejection fraction - a Roussin A, 2017 Sussex B. Comprehensive update of the canadian cardiovascular report from the Japanese heart failure syndrome with preserved ejection fraction society guidelines for the management of heart failure. Can J Cardiol 2017;33(11): (JASPER) registry. Circ J 2018;82(6):1534–45. 1342–433. [28] GC Fonarow, Stough WG, Abraham WT, Albert NM, Gheorghiade M, [9] Trullàs JC, Pérez-Calvo JI, Conde-Martel A, Llàcer Iborra P, Suárez Pedreira I, Greenberg BH, O’Connor CM, Sun JL, Yancy CW, JB; Young. OPTIMIZE-HF Ormaechea G, Soler Rangel L, González Franco A, Cepeda JM, Montero-Pérez- Investigators and Hospitals. Characteristics, treatments, and outcomes of patients Barquero M. en representación de los investigadores del registro RICA. with preserved systolic function hospitalized for heart failure: a report from the Epidemiology of heart failure with preserved ejection fraction: results from the OPTIMIZE-HF Registry. J Am Coll Cardiol 2007;50(8):768–77. RICA Registry. Med Clin (Barc) 2020. S0025-7753(20)30566-2. [29] Rudiger A, Harjola VP, Müller A, Mattila E, Säila P, Nieminen M, Follath F. Acute [10] Miró Ò, Rossello X, Gil V, Martín-Sánchez FJ, Llorens P, Herrero-Puente P, et al. heart failure: clinical presentation, one-year mortality and prognostic factors. Eur J Predicting 30-day mortality for patients with acute heart failure in the emergency Heart Fail 2005;7(4):662–70. department: a cohort study. Ann Intern Med 2017;167:698–705. [30] Beckett NS, Peters R, Fletcher AE, Staessen JA, Liu L, Dumitrascu D, [11] Llauger L, Jacob J, Moreno LA, Aguirre A, Martín-Mojarro E, Romero-Carrete JC, Stoyanovsky V, Antikainen RL, Nikitin Y, Anderson C, Belhani A, Forette F, et al. Factores asociados con el empeoramiento de la función renal durante un Rajkumar C, Thijs L, Banya W, Bulpitt CJ. Treatment of hypertension in patients 80 episodio de insuficiencia cardiaca aguda y su relación con la mortalidad a corto y years of age or older. N Engl J Med 2008;358:1887–98. largo plazo: estudio EAHFE - EFRICA. Emergencias 2020;32:332–9. [31] Packer M. Inferential characterization of the dose-response relationships of [13] Aguilar Ginés S. Prognosis in heart failure: importance of physical frailty at the neurohormonal antagonists in chronic heart failure: A novel approach based on time of admission. Emergencias 2020;32:147–8. large-scale trials with active comparators. Int J Cardiol 2018;261:130–3. [14] Martin N, Manoharan K, Thomas J, Davies C, Lumbers RT. Beta-blockers and [32] Miró Ò, Rossello X, Gil V, Martín-Sánchez FJ, Llorens P, Herrero-Puente P, Jacob J, inhibitors of the renin-angiotensin aldosterone system for chronic heart failure Piñera P, Mojarro EM, Lucas-Imbernón FJ, Llauger L, Agüera C, López-Díez MP, with preserved ejection fraction. Cochrane Database Syst Rev 2018;6(6). Valero A, Bueno H, Pocock SJ, Research Group ICA-SEMES. Analysis of how CD012721. emergency physicians’ decisions to hospitalize or discharge patients with acute [15] Silverman DN, Plante TB, Infeld M, Callas PW, Juraschek SP, Dougherty GB, heart failure match the clinical risk categories of the MEESSI-AHF scale. Ann Meyer M. Association of β-blocker use with heart failure hospitalizations and Emerg Med 2019;74:204–15. cardiovascular disease mortality among patients with heart failure with a [33] Martín-Sánchez FJ, Llopis García G, Llorens P, Jacob J, Herrero P, Gil V, et al. preserved ejection fraction: a secondary analysis of the TOPCAT Trial. JAMA Netw Planning to reduce 30-day adverse events after discharge of frail elderly patients Open 2019;2(12):e1916598. https://doi.org/10.1001/ with acute heart failure: design and rationale for the DEED frail-AHF trial. jamanetworkopen.2019.16598. PMID: 31800067; PMCID: PMC6902757. Emergencias 2019;31:27–35. [16] Cleland JGF, Bunting KV, Flather MD, Altman DG, Holmes J, Coats AJS, Manzano L, McMurray JJV, Ruschitzka F, van Veldhuisen DJ, von Lueder TG, 84