ESC 2023 Guidelines for the Diagnosis and Treatment of Acute and Chronic Heart Failure PDF

European Heart Journal (2023) 00, 1–13 https://doi.org/10.1093/eurheartj/ehad195 ESC GUIDELINES Developed by the task force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC) With the special contribution of the Heart Failure Association (HFA) of the ESC Authors/Task Force Members: Theresa A. McDonagh *†, (Chairperson) (United Kingdom), Marco Metra *†, (Chairperson) (Italy), Marianna Adamo ‡, (Task Force Co-ordinator) (Italy), Roy S. Gardner ‡, (Task Force Co-ordinator) (United Kingdom), Andreas Baumbach (United Kingdom), Michael Böhm (Germany), Haran Burri (Switzerland), Javed Butler (United States of America), Jelena Čelutkienė (Lithuania), Ovidiu Chioncel (Romania), John G.F. Cleland (United Kingdom), Maria Generosa Crespo-Leiro (Spain), Dimitrios Farmakis (Greece), Martine Gilard (France), Stephane Heymans (Netherlands), Arno W. Hoes (Netherlands), Tiny Jaarsma (Sweden), Ewa A. Jankowska (Poland), Mitja Lainscak (Slovenia), Carolyn S.P. Lam (Singapore), Alexander R. Lyon (United Kingdom), John J.V. McMurray (United Kingdom), Alexandre Mebazaa (France), Richard Mindham (United Kingdom), Claudio Muneretto (Italy), Massimo Francesco Piepoli (Italy), Susanna Price (United Kingdom), Giuseppe M. C. Rosano (United Kingdom), Frank Ruschitzka (Switzerland), Anne Kathrine Skibelund (Denmark), and ESC Scientific Document Group * Corresponding authors: Theresa A. McDonagh, Cardiology Department, King’s College Hospital, Denmark Hill, London, SE5 9RS, United Kingdom. Tel: +44 203 299 325, E-mail: [email protected]; Marco Metra, Institute of Cardiology, ASST Spedali Civili di Brescia and Department of Medical and Surgical Specialties, Radiological Sciences and Public Health, University of Brescia, Brescia, Italy. Tel: +39 303 07221, E-mail: [email protected] † The two Chairpersons contributed equally to the document and are joint corresponding authors. ‡ The two Task Force Co-ordinators contributed equally to the document. Author/Task Force Member affiliations are listed in the Author information. ESC Clinical Practice Guidelines (CPG) Committee: listed in the Appendix. ESC subspecialty communities having participated in the development of this document: Associations: Association of Cardiovascular Nursing & Allied Professions (ACNAP), Association for Acute CardioVascular Care (ACVC), European Association of Cardiovascular Imaging (EACVI), European Association of Preventive Cardiology (EAPC), European Association of Percutaneous Cardiovascular Interventions (EAPCI), European Heart Rhythm Association (EHRA), Heart Failure Association (HFA). Councils: Council of Cardio-Oncology. Working Groups: Cardiovascular Pharmacotherapy, Cardiovascular Surgery, Myocardial and Pericardial Diseases. Patient Forum The content of this European Society of Cardiology (ESC) Focused Update has been published for personal and educational use only. No commercial use is authorized. No part of this document may be translated or reproduced in any form without written permission from the ESC. Permission can be obtained upon submission of a written request to Oxford University Press, the publisher of the European Heart Journal and the party authorized to handle such permissions on behalf of the ESC ([email protected]). Downloaded from https://academic.oup.com/eurheartj/advance-article/doi/10.1093/eurheartj/ehad195/7246292 by ECCO'16 user on 25 August 2023 2023 Focused Update of the 2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure 2 ESC Guidelines All experts involved in the development of this Focused Update have submitted declarations of interest. These have been compiled in a report and simultaneously published in a supplementary document to the Focused Update. The report is also available on the ESC website www.escardio.org/guidelines See the European Heart Journal online for supplementary documents that include evidence tables. Keywords Guidelines Acute heart failure Comorbidities Chronic kidney disease hospitalization Diagnosis Ejection fraction Heart failure Multidisciplinary management Natriuretic peptides Neurohormonal antagonists Pharmacotherapy Prevention Table of contents 1. Preamble...................................................................................................................... 3 2. Introduction............................................................................................................... 5 3. Chronic heart failure.............................................................................................. 5 4. Acute heart failure................................................................................................... 8 4.1. Medical therapy............................................................................................... 8 4.1.1. Diuretics..................................................................................................... 8 4.1.2. Sodium–glucose co-transporter 2 inhibitors.............................. 8 4.2. Management strategies................................................................................ 8 4.2.1. Admission phase..................................................................................... 8 4.2.2. Pre-discharge and early post-discharge phases.......................... 8 5. Comorbidities............................................................................................................ 9 5.1. Chronic kidney disease and type 2 diabetes mellitus..................... 9 5.1.1. Sodium–glucose co-transporter 2 inhibitors.............................. 9 5.1.2. Finerenone.............................................................................................. 10 5.2. Iron deficiency............................................................................................... 10 6. Data availability statement................................................................................ 7. Author information.............................................................................................. 8. Appendix.................................................................................................................. 9. References............................................................................................................... 11 11 12 12 Tables of Recommendations Recommendation Table 1 — Recommendation for the treatment of patients with symptomatic heart failure with mildly reduced ejection fraction.............................................................................................................................. 7 Recommendation Table 2 — Recommendation for the treatment of patients with symptomatic heart failure with preserved ejection fraction.............................................................................................................................. 7 Recommendation Table 3 — Recommendation for pre-discharge and early post-discharge follow-up of patients hospitalized for acute heart failure..................................................................................................................... 9 Disclaimer. The ESC Guidelines and Focused Updates represent the views of the ESC and were produced after careful consideration of the scientific and medical knowledge and the evidence available at the time of their publication. The ESC is not responsible in the event of any contradiction, discrepancy and/or ambiguity between the ESC Guidelines and Focused Updates and any other official recommendations or guidelines issued by the relevant public health authorities, in particular in relation to good use of healthcare or therapeutic strategies. Health professionals are encouraged to take the ESC Guidelines and Focused Updates fully into account when exercising their clinical judgment, as well as in the determination and the implementation of preventive, diagnostic or therapeutic medical strategies; however, the ESC Guidelines and Focused Updates do not override, in any way whatsoever, the individual responsibility of health professionals to make appropriate and accurate decisions in consideration of each patient’s health condition and in consultation with that patient and, where appropriate and/or necessary, the patient’s caregiver. Nor do the ESC Guidelines and Focused Updates exempt health professionals from taking into full and careful consideration the relevant official updated recommendations or guidelines issued by the competent public health authorities, in order to manage each patient’s case in light of the scientifically accepted data pursuant to their respective ethical and professional obligations. It is also the health professional’s responsibility to verify the applicable rules and regulations relating to drugs and medical devices at the time of prescription. This article is co-published with permission in the European Heart Journal and the European Journal of Heart Failure. All rights reserved. © The European Society of Cardiology 2023. The articles are identical except for stylistic differences in keeping with each journal’s style. Either citation can be used when citing this article. For permissions, please e-mail: [email protected] Downloaded from https://academic.oup.com/eurheartj/advance-article/doi/10.1093/eurheartj/ehad195/7246292 by ECCO'16 user on 25 August 2023 Document Reviewers: Rudolf A. de Boer, (CPG Review Co-ordinator) (Netherlands), P. Christian Schulze, (CPG Review Co-ordinator) (Germany), Elena Arbelo (Spain), Jozef Bartunek (Belgium), Johann Bauersachs (Germany), Michael A. Borger (Germany), Sergio Buccheri (Sweden), Elisabetta Cerbai (Italy), Erwan Donal (France), Frank Edelmann (Germany), Gloria Färber (Germany), Bettina Heidecker (Germany), Borja Ibanez (Spain), Stefan James (Sweden), Lars Køber (Denmark), Konstantinos C. Koskinas (Switzerland), Josep Masip (Spain), John William McEvoy (Ireland), Robert Mentz (United States of America), Borislava Mihaylova (United Kingdom), Jacob Eifer Møller (Denmark), Wilfried Mullens (Belgium), Lis Neubeck (United Kingdom), Jens Cosedis Nielsen (Denmark), Agnes A. Pasquet (Belgium), Piotr Ponikowski (Poland), Eva Prescott (Denmark), Amina Rakisheva (Kazakhstan), Bianca Rocca (Italy), Xavier Rossello (Spain), Leyla Elif Sade (United States of America/Türkiye), Hannah Schaubroeck (Belgium), Elena Tessitore (Switzerland), Mariya Tokmakova (Bulgaria), Peter van der Meer (Netherlands), Isabelle C. Van Gelder (Netherlands), Mattias Van Heetvelde (Belgium), Christiaan Vrints (Belgium), Matthias Wilhelm (Switzerland), Adam Witkowski (Poland), and Katja Zeppenfeld (Netherlands) 3 ESC Guidelines EMPULSE List of tables FIGARO-DKD Table 1 Classes of recommendations.................................................................. 4 Table 2 Levels of evidence........................................................................................ 4 Table 3 Definition of heart failure with reduced ejection fraction, mildly reduced ejection fraction, and preserved ejection fraction.......... 6 HF HFmrEF List of figures Figure 1 Management of patients with heart failure with mildly reduced ejection fraction.......................................................................................... 7 Figure 2 Management of patients with heart failure with preserved ejection fraction............................................................................................................. 7 Abbreviations and acronyms ACE-I ADVOR AFFIRM-AHF ARB ARNI aRR CI CKD CLOROTIC COACH COR CPG CREDENCE CV DAPA-CKD DAPA-HF DELIVER eGFR EMPA-KIDNEY EMPERORPreserved Angiotensin-converting enzyme inhibitor Acetazolamide in Decompensated Heart Failure with Volume Overload (trial) A Randomized Double-blind Placebo Controlled Trial Comparing the Effects of Intravenous Ferric Carboxymaltose on Hospitalizations and Mortality in Iron Deficient Subjects Admitted for Acute Heart Failure (trial) Angiotensin receptor blocker Angiotensin receptor–neprilysin inhibitor Adjusted risk ratio Confidence interval Chronic kidney disease Combination of Loop Diuretics with Hydrochlorothiazide in Acute Heart Failure (trial) Comparison of Outcomes and Access to Care for Heart Failure (trial) Class of recommendation Clinical Practice Guidelines Canagliflozin and Renal Events in Diabetes With Established Nephropathy Clinical Evaluation (trial) Cardiovascular Dapagliflozin And Prevention of Adverse outcomes in Chronic Kidney Disease (trial) Dapagliflozin And Prevention of Adverse outcomes in Heart Failure (trial) Dapagliflozin Evaluation to Improve the LIVEs of Patients with PReserved Ejection Fraction Heart Failure (trial) Estimated glomerular filtration rate EMPAgliflozin once daily to assess cardio-renal outcomes in patients with chronic KIDNEY disease (trial) Empagliflozin Outcome Trial in Patients with Chronic Heart Failure with Preserved Ejection (trial) ESC FIDELIO-DKD HFnEF HFpEF HFrEF HR IRONMAN i.v. KDIGO LOE LVEF MRA NT-proBNP NYHA OR PIVOTAL REVIVED-BCIS2 RR SCORED SGLT2 STRONG-HF T2DM TRANSFORM-HF TRILUMINATE Pivotal Empagliflozin in Patients Hospitalized with Acute Heart Failure Who Have Been Stabilized (trial) European Society of Cardiology Finerenone in Reducing Kidney Failure and Disease Progression in Diabetic Kidney Disease (trial) Finerenone in Reducing Cardiovascular Mortality and Morbidity in Diabetic Kidney Disease (trial) Heart failure Heart failure with mildly reduced ejection fraction Heart failure with normal ejection fraction Heart failure with preserved ejection fraction Heart failure with reduced ejection fraction Hazard ratio Effectiveness of Intravenous Iron Treatment versus Standard Care in Patients with Heart Failure and Iron Deficiency (trial) Intravenous Kidney Disease: Improving Global Outcomes Level of evidence Left ventricular ejection fraction Mineralocorticoid receptor antagonist N-terminal pro-B-type natriuretic peptide New York Heart Association Odds ratio Proactive IV Iron Therapy in Haemodialysis Patients (trial) Revascularization for Ischemic Ventricular Dysfunction (trial) Risk ratio Effect of Sotagliflozin on Cardiovascular and Renal Events in Patients with Type 2 Diabetes and Moderate Renal Impairment Who Are at Cardiovascular Risk (trial) Sodium–glucose co-transporter 2 Safety, Tolerability and Efficacy of Rapid Optimization, Helped by NT-proBNP Testing, of Heart Failure Therapies (trial) Type 2 diabetes mellitus Torsemide Comparison with Furosemide for Management of Heart Failure (trial) Clinical Trial to Evaluate Cardiovascular Outcomes in Patients Treated With the Tricuspid Valve Repair System Pivotal (trial) 1. Preamble Guidelines evaluate and summarize available evidence with the aim of assisting health professionals in proposing the best diagnostic or therapeutic approach for an individual patient with a given condition. Guidelines are intended for use by health professionals and the European Society of Cardiology (ESC) makes its Guidelines freely available. ESC Guidelines do not override the individual responsibility of health professionals to make appropriate and accurate decisions in consideration of each patient’s health condition and in consultation with that patient or the patient’s caregiver where appropriate and/or necessary. It is also the health professional’s responsibility to verify the rules and Downloaded from https://academic.oup.com/eurheartj/advance-article/doi/10.1093/eurheartj/ehad195/7246292 by ECCO'16 user on 25 August 2023 Recommendation Table 4 — Recommendations for the prevention of heart failure in patients with type 2 diabetes mellitus and chronic kidney disease.............................................................................................................. 10 Recommendation Table 5 — Recommendations for the management of iron deficiency in patients with heart failure................ 11 4 ESC Guidelines Guidelines here: https://www.escardio.org/Guidelines/Clinical-PracticeGuidelines/Acute-and-Chronic-Heart-Failure. The members of the Task Force were selected by the ESC to represent professionals involved with the medical care of patients with this pathology. The Task Force performed a critical evaluation of diagnostic and therapeutic approaches, including assessment of the risk– benefit ratio. The strength of every new or updated recommendation and the level of evidence supporting them were weighed and scored according to predefined scales as outlined below. The Task Force followed ESC voting procedures and all approved recommendations were subject to a vote and achieved at least 75% agreement among voting members. Deﬁnition Wording to use Class I Evidence and/or general agreement that a given treatment or procedure is beneﬁcial, useful, eﬀective. Is recommended or is indicated Class II Conﬂicting evidence and/or a divergence of opinion about the usefulness/ eﬃcacy of the given treatment or procedure. Class IIa Weight of evidence/opinion is in favour of usefulness/eﬃcacy. Should be considered Class IIb Usefulness/eﬃcacy is less well established by evidence/opinion. May be considered Evidence or general agreement that the given treatment or procedure is not useful/eﬀective, and in some cases may be harmful. Is not recommended © ESC 2023 Class III ©ESC 2023 Classes of recommendations Table 1 Classes of recommendations Data derived from multiple randomized clinical trials or meta-analyses. Level of evidence B Data derived from a single randomized clinical trial or large non-randomized studies. Level of evidence C Consensus of opinion of the experts and/or small studies, retrospective studies, registries. © ESC 2023 Level of evidence A ©ESC 2023 Table 2 Levels of evidence Downloaded from https://academic.oup.com/eurheartj/advance-article/doi/10.1093/eurheartj/ehad195/7246292 by ECCO'16 user on 25 August 2023 regulations applicable in each country to drugs and devices at the time of prescription and, where appropriate, to respect the ethical rules of their profession. ESC Guidelines represent the official position of the ESC on a given topic and are regularly updated. ESC Policies and Procedures for formulating and issuing ESC Guidelines can be found on the ESC website (https://www.escardio.org/Guidelines). Interim Focused Updates are created when the publication of new evidence could influence clinical practice before the next full update of a guideline is published. This Focused Update provides new and revised recommendations for the 2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure. View the full 2021 ESC 5 ESC Guidelines The specific situation of the patient. Unless otherwise provided for by national regulations, off-label use of medication should be limited to situations where it is in the patient’s interest with regard to the quality, safety, and efficacy of care, and only after the patient has been informed and has provided consent. Country-specific health regulations, indications by governmental drug regulatory agencies, and the ethical rules to which health professionals are subject, where applicable. 2. Introduction Since the publication of the 2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure (HF),1 there have been several randomized controlled trials that should change patient management ahead of the next scheduled full guidelines. This 2023 Focused Update addresses changes in recommendations for the treatment of HF because of this new evidence. New evidence was considered until 31 March 2023. All major randomized controlled clinical trials and meta-analyses were presented, discussed, and then voted upon for inclusion. Members with declared interests in specific topics were asked to abstain from voting on those topics. The trials were presented and discussed in detail before a consensus was reached about any possible classes of recommendations (COR) (Table 1) and levels of evidence (LOE) (Table 2) to be assigned. The Task Force considered and discussed the following new trials and any meta-analyses including them: ADVOR (Acetazolamide in Decompensated Heart Failure with Volume Overload),2 CLOROTIC (Combination of Loop Diuretics with Hydrochlorothiazide in Acute Heart Failure),3 COACH (Comparison of Outcomes and Access to Care for Heart Failure),4 DAPA-CKD (Dapagliflozin And Prevention of Adverse outcomes in Chronic Kidney Disease),5 DELIVER (Dapagliflozin Evaluation to Improve the LIVEs of Patients with PReserved Ejection Fraction Heart Failure),6 EMPA-KIDNEY (EMPAgliflozin once daily to assess cardio-renal outcomes in patients with chronic KIDNEY disease),7 EMPEROR-Preserved (Empagliflozin Outcome Trial in Patients with Chronic Heart Failure with Preserved Ejection Fraction),8 EMPULSE (Empagliflozin in Patients Hospitalized with Acute Heart Failure Who Have Been Stabilized),9 FIDELIO-DKD (Finerenone in Reducing Kidney Failure and Disease Progression in Diabetic Kidney Disease),10 FIGARO-DKD (Finerenone in Reducing Cardiovascular Mortality and Morbidity in Diabetic Kidney Disease),11 IRONMAN (Effectiveness of Intravenous Iron Treatment versus Standard Care in Patients with Heart Failure and Iron Deficiency),12 PIVOTAL (Proactive IV Iron Therapy in Haemodialysis Patients),13,14 REVIVED-BCIS2 (Revascularization for Ischemic Ventricular Dysfunction),15 STRONG-HF (Safety, Tolerability and Efficacy of Rapid Optimization, Helped by NT-proBNP Testing, of Heart Failure Therapies),16 TRANSFORM-HF (Torsemide Comparison with Furosemide for Management of Heart Failure),17 and TRILUMINATE Pivotal (Clinical Trial to Evaluate Cardiovascular Outcomes in Patients Treated With the Tricuspid Valve Repair System Pivotal).18 Only results that would lead to new or changed class I/IIa recommendations were selected for inclusion in Recommendation Tables. Trials that would have an impact upon recommendations in other ESC Guidelines under preparation have not been included to avoid discordance. This is the case for REVIVED-BCIS2, which will be considered in the upcoming chronic coronary syndrome Guidelines. In addition to selecting the trials to be included, the Task Force also discussed changing the description of HF with preserved ejection fraction (HFpEF) to HF with normal ejection fraction (HFnEF) and the left ventricular ejection fraction (LVEF) threshold for HFnEF. The Task Force ultimately decided to keep the term HFpEF and left any further changes in terminology to be considered in the next ESC HF Guidelines. In assigning recommendations, as in the 2021 ESC HF Guidelines, the Task Force focused on the primary endpoints of trials. This means that, for most HF trials, effective treatments reduce the risk of the time to first occurrence of the composite of either HF hospitalization or cardiovascular (CV) death (the correct convention for describing such a composite). Of course, that does not mean each component is reduced individually. For total-event trials, where the primary composite outcome included total (first and repeat) HF hospitalizations and all CV deaths, the convention for describing this composite, i.e. and not or, was used. Once again that does not mean that both components were reduced. All the new recommendations are additive to the recommendations of the 2021 ESC HF Guidelines and changed recommendations substitute those of the 2021 ESC HF Guidelines. After due deliberation, the Task Force decided to update recommendations for the following sections of the 2021 ESC HF Guidelines: Chronic HF: HF with mildly reduced ejection fraction (HFmrEF) and HFpEF Acute HF Comorbidities and prevention of HF. 3. Chronic heart failure The original 2021 ESC HF Guidelines adopted the classification of chronic HF according to LVEF (Table 3). Downloaded from https://academic.oup.com/eurheartj/advance-article/doi/10.1093/eurheartj/ehad195/7246292 by ECCO'16 user on 25 August 2023 The experts of the writing and reviewing panels provided declaration of interest forms for all relationships that might be perceived as real or potential sources of conflicts of interest. Their declarations of interest were reviewed according to the ESC declaration of interest rules and can be found on the ESC website (http://www.escardio.org/ guidelines) and have been compiled in a report published in a supplementary document with the guidelines. The Task Force received its entire financial support from the ESC without any involvement from the healthcare industry. The ESC Clinical Practice Guidelines (CPG) Committee supervises and coordinates the preparation of new Guidelines and Focused Updates and is responsible for the approval process. ESC Guidelines and Focused Updates undergo extensive review by the CPG Committee and external experts, including members from across the whole of the ESC region and from relevant ESC Subspecialty Communities and National Cardiac Societies. After appropriate revisions, Guidelines and Focused Updates are signed off by all the experts involved in the Task Force. Finalized documents are signed off by the CPG Committee for publication in the European Heart Journal. This Focused Update was developed after careful consideration of the scientific and medical knowledge and the evidence available at the time of writing. Tables of evidence summarizing the findings of studies informing development of the Focused Update are included. The ESC warns readers that the technical language may be misinterpreted and declines any responsibility in this respect. Off-label use of medication may be presented in this Focused Update if a sufficient level of evidence shows that it can be considered medically appropriate for a given condition. However, the final decisions concerning an individual patient must be made by the responsible health professional giving special consideration to: 6 ESC Guidelines Table 3 Definition of heart failure with reduced ejection fraction, mildly reduced ejection fraction, and preserved ejection fraction Criteria 1 HFrEF HFmrEF Symptoms ± signsa Symptoms ± signsa LVEF ≤40% LVEF 41–49% 3 – – Symptoms ± signsa b LVEF ≥50% Objective evidence of cardiac structural and/or functional abnormalities consistent with the presence of LV diastolic dysfunction/raised LV filling pressures, including raised natriuretic peptidesc HF, heart failure; HFmrEF, heart failure with mildly reduced ejection fraction; HFpEF, heart failure with preserved ejection fraction; HFrEF, heart failure with reduced ejection fraction; LV, left ventricle; LVEF, left ventricular ejection fraction. a Signs may not be present in the early stages of HF (especially in HFpEF) and in optimally treated patients. b For the diagnosis of HFmrEF, the presence of other evidence of structural heart disease (e.g. increased left atrial size, LV hypertrophy, or echocardiographic measures of impaired LV filling) makes the diagnosis more likely. c For the diagnosis of HFpEF, the greater the number of abnormalities present, the higher the likelihood of HFpEF. For those with HFmrEF, with LVEF between 41% and 49%, the Task Force made weak recommendations (COR IIb, LOE C) in the 2021 ESC HF Guidelines for the use of disease-modifying therapies that have class I evidence for use in HF with reduced ejection fraction (HFrEF). These were based on subgroup analyses of trials that were not specifically designed to focus on HFmrEF, including trials where the overall endpoints were statistically neutral. The Task Force made no recommendations for the use of sodium–glucose co-transporter 2 (SGLT2) inhibitors.1 For those with HFpEF, the Task Force made no recommendations for the use of disease-modifying HFrEF therapies as clinical trials with angiotensin-converting enzyme inhibitors (ACE-I), angiotensin receptor blockers (ARB), mineralocorticoid receptor antagonists (MRA), and angiotensin receptor–neprilysin inhibitors (ARNI) failed to meet their primary endpoints. There were no published trials with SGLT2 inhibitors to consider at the time.1 Since then, two trials have become available with the SGLT2 inhibitors empagliflozin and dapagliflozin, in patients with HF and LVEF >40%, that justify an update in the recommendations for both HFmrEF and HFpEF.6,8 The first trial to report was the EMPEROR-Preserved trial.8 It recruited 5988 patients with HF (New York Heart Association [NYHA] class II–IV) whose LVEF was >40% and who had raised plasma concentrations of N-terminal pro-B-type natriuretic peptide (NT-proBNP) (>300 pg/mL for those in sinus rhythm or >900 pg/mL for those in atrial fibrillation). They were randomized to empagliflozin (10 mg once daily) or placebo. The primary outcome was a composite of CV death or hospitalization for HF. At a median follow-up of 26.2 months, empagliflozin reduced the primary endpoint (hazard ratio [HR] 0.79, 95% confidence interval [CI] 0.69–0.90; P <.001). The effect was mainly driven by a reduction in HF hospitalizations with empagliflozin and there was no reduction in CV death. The effects were seen in patients with and without type 2 diabetes mellitus (T2DM).8 The majority of patients were on an ACE-I/ARB/ARNI (80%) and beta-blocker (86%) and 37% were on an MRA.19 A year later, the DELIVER trial reported on the effects of dapagliflozin (10 mg once daily) compared with placebo in 6263 patients with HF (NYHA class II–IV).6 Patients had to have an LVEF >40% at the time of recruitment, but those who previously had an LVEF ≤40% that had improved to >40% were also enrolled. Outpatients and inpatients hospitalized for HF were eligible. An elevated concentrations of natriuretic peptides were also a mandatory inclusion criterion (≥300 pg/mL in sinus rhythm or ≥600 pg/mL in atrial fibrillation).6,20,21 Dapagliflozin reduced the primary endpoint of CV death or worsening HF (HF hospitalization or urgent HF visit) (HR 0.82, 95% CI 0.73– 0.92; P <.001). Once again, the principal effect was due to a reduction in worsening HF and there was no reduction in CV death. Dapagliflozin also improved symptom burden. The effects were independent of T2DM status.6 The efficacy of dapagliflozin was consistent in those who remained symptomatic, despite improved LVEF, suggesting that these patients may also benefit from SGLT2 inhibition.6,22 The benefit of dapagliflozin was also consistent across the range of LVEF studied.6,23 The background use of therapies for concomitant CV disease was high: 77% were on a loop diuretic, 77% were on an ACE-I/ARB/ARNI, 83% were on a beta-blocker, and 43% were on an MRA.6 A subsequent aggregate data meta-analysis of the two trials confirmed a 20% reduction in the composite endpoint of CV death or first hospitalization for HF (HR 0.80, 95% CI 0.73–0.87; P <.001). CV death was not reduced significantly (HR 0.88, 95% CI 0.77–1.00; P =.052). HF hospitalization was reduced by 26% (HR 0.74, 95% CI 0.67–0.83; P <.001). There were consistent reductions in the primary endpoint across the LVEF range studied.24 Another individual patient data meta-analysis that incorporated data from DAPA-HF (Dapagliflozin And Prevention of Adverse outcomes in Heart Failure) in HFrEF with DELIVER confirmed that there was no evidence that the effect of dapagliflozin differed by ejection fraction.22 This also showed that dapagliflozin reduced the risk of death from CV causes (HR 0.86, 95% CI 0.76–0.97; P =.01).22 The Task Force discussed the results of these trials in depth, focusing particularly on the fact that they both met their primary endpoints, but they did so by a reduction in HF hospitalizations and not CV death. The Task Force decided to make recommendations on the primary endpoints. That is consistent with all the recommendations made in the 2021 ESC HF Guidelines. The Task Force did not specify NT-proBNP thresholds for treatment, consistent with recommendations for other therapies in the original 2021 ESC HF Guidelines. However, it should be noted that, in the diagnostic algorithm for HF in the 2021 ESC HF Guidelines, raised concentrations of natriuretic peptides are usually implicit to that diagnosis. Taking these two trials into account, the following recommendations have been made for HFmrEF and HFpEF (see Figs 1 and 2, respectively). Downloaded from https://academic.oup.com/eurheartj/advance-article/doi/10.1093/eurheartj/ehad195/7246292 by ECCO'16 user on 25 August 2023 2 HFpEF © ESC 2023 Type of HF 7 ESC Guidelines Levelb I A the risk of HF hospitalization or CV death.c 6,8 CV, cardiovascular; HF, heart failure; HFmrEF, heart failure with mildly reduced ejection fraction; SGLT2, sodium–glucose co-transporter 2. a Class of recommendation. b Level of evidence. c This recommendation is based on the reduction of the primary composite endpoint used in the EMPEROR-Preserved and DELIVER trials and in a meta-analysis. However, it should be noted that there was a significant reduction only in HF hospitalizations and no reduction in CV death. Recommendation An SGLT2 inhibitor (dapagliflozin or empagliflozin) is recommended in patients with HFpEF to reduce the Classa Levelb I A risk of HF hospitalization or CV death.c 6,8 CV, cardiovascular; HF, heart failure; HFpEF, heart failure with preserved ejection fraction; SGLT2, sodium–glucose co-transporter 2. a Class of recommendation. b Level of evidence. c This recommendation is based on the reduction of the primary composite endpoint used in the EMPEROR-Preserved and DELIVER trials and in a meta-analysis. However, it should be noted that there was a significant reduction only in HF hospitalizations and no reduction in CV death. Management of patients with HFmrEF Diuretics for fluid retention (Class I) Dapagliflozin/ Empagliflozin (Class I) ACEI/ARNI/ARB (Class IIb) MRA (Class IIb) Beta-blocker (Class IIb) Figure 1 Management of patients with heart failure with mildly reduced ejection fraction. ACE-I, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; ARNI, angiotensin receptor–neprilysin inhibitor; HFmrEF, heart failure with mildly reduced ejection fraction; MRA, mineralocorticoid receptor antagonist. Management of patients with HFpEF Diuretics for fluid retention (Class I) Dapagliflozin/ Empagliflozin (Class I) Treatment for aetiology, CV and non-CV comorbodities (Class I) Figure 2 Management of patients with heart failure with preserved ejection fraction. CV, cardiovascular; HFpEF, heart failure with preserved ejection fraction. Downloaded from https://academic.oup.com/eurheartj/advance-article/doi/10.1093/eurheartj/ehad195/7246292 by ECCO'16 user on 25 August 2023 An SGLT2 inhibitor (dapagliflozin or empagliflozin) is recommended in patients with HFmrEF to reduce Classa © ESC 2023 Recommendation Recommendation Table 2 — Recommendation for the treatment of patients with symptomatic heart failure with preserved ejection fraction © ESC 2023 Recommendation Table 1 — Recommendation for the treatment of patients with symptomatic heart failure with mildly reduced ejection fraction 8 4. Acute heart failure 4.1. Medical therapy 4.1.1. Diuretics ADVOR was a multicentre, randomized, parallel-group, double-blind, placebo-controlled trial that enrolled 519 patients with acute decompensated HF, clinical signs of volume overload (i.e. oedema, pleural effusion, or ascites), and an NT-proBNP level of >1000 pg/mL or a B-type natriuretic peptide level of >250 pg/mL. They were randomized to receive intravenous (i.v.) acetazolamide (500 mg once daily) or placebo added to standardized i.v. loop diuretic treatment.2 The primary endpoint of successful decongestion, defined as the absence of signs of volume overload, within 3 days after randomization and without an indication for escalation of decongestive therapy, was achieved in 108 of 256 patients (42.2%) in the acetazolamide group and in 79 of 259 patients (30.5%) in the placebo group (risk ratio [RR] 1.46, 95% CI 1.17–1.82; P <.001). Rehospitalization for HF or all-cause death occurred in 76 patients (29.7%) in the acetazolamide group and in 72 patients (27.8%) in the placebo group (HR 1.07, 95% CI 0.78–1.48). Length of hospital stay was 1 day shorter with acetazolamide compared with placebo (8.8 [95% CI 8.0–9.5] vs. 9.9 [95% CI 9.1–10.8] days). No difference between the acetazolamide and placebo groups was found for other outcomes and adverse events.2 Although these results may support the addition of acetazolamide to a standard diuretic regimen to aid decongestion, further data on outcomes and safety are needed. The CLOROTIC trial enrolled 230 patients with acute HF and randomized them to oral hydrochlorothiazide (25–100 mg daily, depending on estimated glomerular filtration rate [eGFR]) or placebo, in addition to i.v. furosemide.3 The trial had two co-primary endpoints, change in body weight and change in patient-reported dyspnoea from baseline to 72 h after randomization. Patients on hydrochlorothiazide had a greater decrease in body weight at 72 h compared with those on placebo (−2.3 vs. −1.5 kg; adjusted estimated difference −1.14 kg, 95% CI −1.84 to −0.42 kg; P =.002). Changes in patientreported dyspnoea were similar between the two groups.3 An increase in serum creatinine occurred more frequently in patients on hydrochlorothiazide (46.5%) compared with those on placebo (17.2%) (P <.001). The rates of HF rehospitalization and all-cause death were similar between groups, as was length of stay.3 The lack of an impact on clinical outcomes precludes any recommendation in the current guideline update. Further data on outcomes and safety are needed. 4.1.2. Sodium–glucose co-transporter 2 inhibitors EMPULSE tested the efficacy of the early initiation of empagliflozin in patients hospitalized for acute HF.9 The primary endpoint was ‘clinical benefit’, defined using a hierarchical composite of death from any cause, number of HF events, and time to first HF event, or a ≥5 point difference in change from baseline in the Kansas City Cardiomyopathy Questionnaire total symptom score at 90 days, assessed using the win-ratio method. HF events were defined as HF hospitalizations, urgent HF visits, and unplanned outpatient HF visits. An event was considered HF-related only if worsening signs and symptoms of HF were present and an intensification of therapy (defined as an increase in oral or i.v. diuretics, augmentation of a vasoactive agent, or starting a mechanical or surgical intervention) was performed.9 Patients were randomized in hospital when clinically stable, with a median time from hospital admission to randomization of 3 days, and were treated for up to 90 days. The primary endpoint was achieved in more patients treated with empagliflozin compared with placebo (stratified win ratio 1.36, 95% CI 1.09–1.68; P =.0054). Efficacy was independent of LVEF and diabetes status. From a safety perspective, the rate of adverse events was similar between the two treatment groups.9 These results are consistent with those shown for SGLT2 inhibitors in patients with chronic HF, regardless of LVEF, and also in those recently hospitalized for HF, once clinically stable.9,26–28 Caution is, however, needed in patients with T2DM at risk of diabetic ketoacidosis, particularly those treated with insulin when carbohydrate intake is reduced or dose of insulin changed.29 SGLT2 inhibitors are not indicated in patients with type 1 diabetes. 4.2. Management strategies Two large trials have been published since the last guidelines: COACH and STRONG-HF. 4.2.1. Admission phase The COACH trial was a cross-sectional, stepped-wedge, clusterrandomized trial including 5452 patients (2972 during the control phase and 2480 during the intervention phase) enrolled at 10 centres in Ontario, Canada.4 During the intervention phase, hospital staff used the Emergency Heart Failure Mortality Risk Grade 30 Day Mortality-ST Depression (‘EHMRG30-ST’) score to ascertain whether patients had a low, intermediate, or high risk of death within 7 days or within 30 days. The study protocol recommended that low-risk patients be discharged early (in ≤3 days) and be treated with standardized outpatient care up to 30-day follow-up, whereas it was advised that intermediate- and highrisk patients be admitted to the hospital. Although early discharge occurred at a similar rate in the intervention and control groups (57% vs. 58%), the trial was successful in showing a 12% reduction in the primary outcome of all-cause death or CV hospitalization in the interventional arm compared with the control arm (HR 0.88, 95% CI 0.78–0.99), consistent with a favourable effect of post-discharge care.4 The trial may need further confirmation multinationally before any recommendation on its approach can be offered in a guideline. 4.2.2. Pre-discharge and early post-discharge phases The importance of pre-discharge and early post-discharge assessment in patients admitted to hospital for an episode of acute HF was already stressed in the original 2021 ESC HF Guidelines.1 The STRONG-HF trial recently showed the safety and efficacy of an approach based on starting and titrating oral medical therapy for HF within 2 days before anticipated hospital discharge and in follow-up visits occurring early after discharge.16 In this trial, 1078 patients hospitalized for acute HF, not already on full doses of evidence-based HF therapies, who were haemodynamically stable, with elevated NT-proBNP concentrations at screening (>2500 pg/mL), and a >10% decrease in concentration between screening and randomization, were randomly assigned, before discharge, to usual care or high-intensity care. Patients in the high-intensity care group received early and rapid intensification of oral HF treatment with ACE-I (or ARB) or ARNI, beta-blockers, and MRA.16 The goal of the first titration visit, which occurred within 48 h before hospital discharge, was to reach at least half of the target doses of recommended medications. Titration to full target doses of oral therapies was attempted within 2 weeks after discharge, with appropriate safety Downloaded from https://academic.oup.com/eurheartj/advance-article/doi/10.1093/eurheartj/ehad195/7246292 by ECCO'16 user on 25 August 2023 Treatment of acute HF was outlined in the recent 2021 ESC HF Guidelines and a Heart Failure Association scientific statement on HF.1,25 Since these publications, trials have been conducted with diuretics, as well as on management strategies for patients with acute HF. The results are summarized here. ESC Guidelines 9 ESC Guidelines 5. Comorbidities monitoring. Follow-up visits, including physical examination and laboratory evaluation, including NT-proBNP measurement, were performed at 1, 2, 3, and 6 weeks after randomization to assess the safety and tolerability of medical therapy. Patients assigned to high-intensity care were more likely to receive full doses of oral therapies than those in the usual care group (renin–angiotensin system inhibitors 55% vs. 2%, beta-blockers 49% vs. 4%, and MRA 84% vs. 46%). The trial was stopped early for benefit. The primary outcome of HF readmission or all-cause death at 180 days occurred in 15.2% of patients in the highintensity care group and in 23.3% of patients in the usual care group (adjusted RR [aRR] 0.66, 95% CI 0.50–0.86; P =.0021). Readmissions for HF were reduced (aRR 0.56, 95% CI 0.38–0.81; P =.0011), whereas allcause death by day 180 was not (aRR 0.84, 95% CI 0.56–1.26; P =.42). Similar rates of serious adverse events (16% vs. 17%) and fatal adverse events (5% vs. 6%) were reported in each group.16 Based upon the results of STRONG-HF, high-intensity care for initiation and rapid up-titration of oral HF therapies and close follow-up in the first 6 weeks after discharge for an acute HF hospitalization is recommended to reduce HF readmission or all-cause death. During the follow-up visits, particular attention should be paid to symptoms and signs of congestion, blood pressure, heart rate, NT-proBNP values, potassium concentrations, and eGFR. STRONG-HF has several limitations. First, the population was carefully selected, based on baseline NT-proBNP concentrations and their decline during hospitalization. Second, the majority of patients in the control group received less than half of full optimal doses of ACE-I/ ARB/ARNI and beta-blockers, and, although similar to many real-world clinical settings,30–33 their relative undertreatment may have favoured the high-intensity care arm. Third, the trial was initiated prior to current evidence and recommendations for SGLT2 inhibitors, which were not mandated in the protocol. 5.1. Chronic kidney disease and type 2 diabetes mellitus 5.1.1. Sodium–glucose co-transporter 2 inhibitors Recommendation Table 3 — Recommendation for pre-discharge and early post-discharge follow-up of patients hospitalized for acute heart failure Recommendation Classa Levelb I B An intensive strategy of initiation and rapid discharge and during frequent and careful follow-up visits in the first 6 weeks following a HF hospitalization is recommended to reduce the risk of HF rehospitalization or death.c,d,e 16 ACE-I, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; ARNI, angiotensin receptor–neprilysin inhibitor; CV, cardiovascular; HF, heart failure; HFmrEF, heart failure with mildly reduced ejection fraction; HFpEF, heart failure with preserved ejection fraction; HFrEF, heart failure with reduced ejection fraction; MRA, mineralocorticoid receptor antagonist; NT-proBNP, N-terminal pro-B-type natriuretic peptide. a Class of recommendation. b Level of evidence. c In STRONG-HF, the use of ACE-I/ARB/ARNI, beta-blockers, and MRA was evaluated in patients with HFrEF, HFmrEF, and HFpEF. d This recommendation is based on the reduction of the primary endpoint used in the STRONG-HF trial. However, it should be noted that there was a significant reduction only in HF hospitalization and no reduction in CV death or all-cause death alone and that these results were obtained in a specific patient population, not already on full doses of evidence-based HF therapies, who were haemodynamically stable, with elevated NT-proBNP concentrations at screening (>2500 pg/mL), and a >10% decrease in concentration between screening and randomization, according to the enrolment criteria. e Although STRONG-HF was based only on triple therapy with neurohormonal modulators, this recommendation also includes empagliflozin or dapagliflozin based on recent evidence.6,8,9 © ESC 2023 up-titration of evidence-based treatment before Two randomized controlled trials, which were stopped early for efficacy, and a meta-analysis were recently published. DAPA-CKD was a multicentre, double-blind, placebo-controlled, randomized trial including both diabetic and non-diabetic patients with a urinary albumin-to-creatinine ratio ≥200 mg/g and an eGFR of 25–75 mL/ min/1.73 m2, who were randomly assigned 1:1 to dapagliflozin 10 mg once daily or placebo.5 Overall, 468 of the 4304 patients enrolled (11%) had a history of HF. During a median follow-up of 2.4 years, a reduction in the primary outcome, a composite of sustained decline in eGFR of ≥50%, end-stage kidney disease, or kidney-related or CV death, was reduced by 39% by dapagliflozin compared with placebo (HR 0.61, 95% CI 0.51–0.72; P <.001). Also, the risk of the secondary outcome of HF hospitalization or CV death was decreased by dapagliflozin compared with placebo (HR 0.71, 95% CI 0.55–0.92; P =.009) with, however, a relatively small absolute risk reduction (4.6% vs. 6.4% with dapagliflozin vs. placebo).5 EMPA-KIDNEY enrolled a broader group of patients with CKD, compared with DAPA-CKD, including patients with eGFR 20–45 mL/ min/1.73 m2, even in the absence of albuminuria, or with an eGFR of 45–90 mL/min/1.73 m2 and a urinary albumin-to-creatinine ratio ≥200 mg/g. Patients were randomized 1:1 to empagliflozin 10 mg once daily or placebo.7 Overall, 658 of the 6609 patients enrolled (10%) had a history of HF. During a median follow-up of 2.0 years, a reduction in the primary composite endpoint of progression of kidney disease or CV death was observed.7 The risk of HF hospitalization or death for CV causes was not reduced significantly (HR 0.84, 95% CI 0.67–1.07; P =.15).7 DAPA-CKD, EMPA-KIDNEY, CREDENCE (Canagliflozin and Renal Events in Diabetes With Established Nephropathy Clinical Evaluation), and SCORED (Effect of Sotagliflozin on Cardiovascular and Renal Events in Patients with Type 2 Diabetes and Moderate Renal Impairment Who Are at Cardiovascular Risk) were included with HF trials in a recent meta-analysis.35 The reduction in HF hospitalizations and CV death was similar irrespective of a history of diabetes when both HF and CKD trials were included (HR 0.77, 95% CI 0.73–0.81 in patients with T2DM, and HR 0.79, 95% CI 0.72–0.87 in those without T2DM). However, results were not significant in patients without diabetes when only CKD trials were included (HR for HF hospitalizations and CV death of 0.74, 95% CI 0.66–0.82 in patients with T2DM, and HR of 0.95, 95% CI 0.65–1.40 in patients without T2DM).35 Based on these results, SGLT2 inhibitors are recommended in patients with CKD and T2DM, and with the additional characteristics of the participants in these trials, including an eGFR >20–25 mL/min/1.73 m2, to reduce the risk of HF hospitalization or CV death. Downloaded from https://academic.oup.com/eurheartj/advance-article/doi/10.1093/eurheartj/ehad195/7246292 by ECCO'16 user on 25 August 2023 The 2021 ESC HF Guidelines gave recommendations for the prevention of HF in patients with diabetes. This update provides new recommendations for prevention of HF in patients with chronic kidney disease (CKD) and T2DM.5,7,10,11,34,35 Previous trials have shown the effects of ARB in preventing HF events in patients with diabetic nephropathy.36,37 Both the Kidney Disease: Improving Global Outcomes (KDIGO) and the 2022 American Diabetes Association Standards of Medical Care in Diabetes and KDIGO recommendations indicate treatment with an ACE-I or ARB for patients with CKD, diabetes, and hypertension or albuminuria.38,39 10 Recommendations In patients with T2DM and CKD,c SGLT2 inhibitors (dapagliflozin or empagliflozin) are recommended to reduce the risk of HF hospitalization or CV Classa Levelb I A I A death.5,7,35 In patients with T2DM and CKD,c finerenone is recommended to reduce the risk of HF hospitalization.10,11,34,40 CKD, chronic kidney disease; CV, cardiovascular; eGFR, estimated glomerular filtration rate; HF, heart failure; SGLT2, sodium–glucose co-transporter 2; T2DM, type 2 diabetes mellitus. a Class of recommendation. b Level of evidence. c CKD was defined as follows: an eGFR 25–75 mL/min/1.73 m2 and a urinary albumin-to-creatinine ratio ≥200–5000 mg/g in DAPA-CKD;5 an eGFR 20–45 mL/min/ 1.73 m2 or an eGFR 45–90 mL/min/1.73 m2 with a urinary albumin-to-creatinine ratio ≥200 mg/g in EMPA-KIDNEY;7 an eGFR 25–60 mL/min/1.73 m2, a urinary albumin-to-creatinine ratio 30–300 mg/g, and diabetic retinopathy, or an eGFR 25–75 mL/min/1.73 m2 and a urinary albumin-to-creatinine ratio 300–5000 mg/g, in FIDELIO-DKD;10 and an eGFR 25–90 mL/min/1.73 m2 and a urinary albumin-to-creatinine ratio 30 to 60 mL/min/1.73 m2 and a urinary albumin-to-creatinine ratio 300–5000 mg/g, in FIGARO-DKD.11 5.2. Iron deficiency Recommendations for the diagnosis and treatment of iron deficiency were given in the 2021 ESC HF Guidelines: COR I, LOE C for the diagnosis of iron deficiency, COR IIa, LOE A to improve HF symptoms, exercise capacity, and quality of life, and COR IIa, LOE B to reduce HF hospitalizations, for treatment with ferric carboxymaltose.1 A new trial, IRONMAN, has now been published.12 This was a prospective, randomized, open-label, blinded-endpoint trial including patients with HF, LVEF ≤45%, and transferrin saturation

ESC 2023 Guidelines for the Diagnosis and Treatment of Acute and Chronic Heart Failure PDF

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