Ehad 195

European Heart Journal (2023) 44, 3627–3639 ESC GUIDELINES
https://doi.org/10.1093/eurheartj/ehad195
2023 Focused Update of the 2021 ESC

Guidelines for the diagnosis and treatment
of acute and chronic heart failure
Downloaded from https://academic.oup.com/eurheartj/article/44/37/3627/7246292 by guest on 01 November 2023

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: theresa.mcdonagh@kcl.ac.uk; 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: marco.metra@unibs.it
†
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 docu
ment 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 (journals.permissions@oup.com).
3628 ESC Guidelines
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)

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
6. Data availability statement ........................................................................... 3637

Table of contents 7. Author information ......................................................................................... 3637
1. Preamble .............................................................................................................. 3629 8. Appendix ............................................................................................................. 3638
2. Introduction ....................................................................................................... 3631 9. References .......................................................................................................... 3638
3. Chronic heart failure ...................................................................................... 3631
4. Acute heart failure ........................................................................................... 3634
4.1. Medical therapy ....................................................................................... 3634
4.1.1. Diuretics ............................................................................................. 3634 Tables of Recommendations
4.1.2. Sodium–glucose co-transporter 2 inhibitors ...................... 3634 Recommendation Table 1 — Recommendation for the treatment of
4.2. Management strategies ........................................................................ 3634 patients with symptomatic heart failure with mildly reduced ejection
4.2.1. Admission phase ............................................................................. 3634 fraction ...................................................................................................................... 3633
4.2.2. Pre-discharge and early post-discharge phases .................. 3634 Recommendation Table 2 — Recommendation for the treatment of
5. Comorbidities .................................................................................................... 3635 patients with symptomatic heart failure with preserved ejection
5.1. Chronic kidney disease and type 2 diabetes mellitus ............. 3635 fraction ...................................................................................................................... 3633
5.1.1. Sodium–glucose co-transporter 2 inhibitors ...................... 3635 Recommendation Table 3 — Recommendation for pre-discharge
5.1.2. Finerenone ......................................................................................... 3636 and early post-discharge follow-up of patients hospitalized for acute
5.2. Iron deficiency ......................................................................................... 3636 heart failure ............................................................................................................. 3635
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 evi
dence 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 pro
fessionals 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 recommenda
tions 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:
journals.permissions@oup.com
ESC Guidelines 3629
Recommendation Table 4 — Recommendations for the prevention EMPULSE Empagliflozin in Patients Hospitalized with Acute
of heart failure in patients with type 2 diabetes mellitus and chronic Heart Failure Who Have Been Stabilized (trial)
kidney disease ......................................................................................................... 3636 ESC European Society of Cardiology
Recommendation Table 5 — Recommendations for the FIDELIO-DKD Finerenone in Reducing Kidney Failure and
management of iron deficiency in patients with heart failure ........... 3637 Disease Progression in Diabetic Kidney
Disease (trial)
List of tables FIGARO-DKD Finerenone in Reducing Cardiovascular
Mortality and Morbidity in Diabetic Kidney
Table 1 Classes of recommendations .......................................................... 3630 Disease (trial)
Table 2 Levels of evidence ................................................................................ 3630 HF Heart failure
Table 3 Definition of heart failure with reduced ejection fraction, HFmrEF Heart failure with mildly reduced ejection
mildly reduced ejection fraction, and preserved ejection fraction .. 3632 fraction

HFnEF Heart failure with normal ejection fraction
List of figures HFpEF Heart failure with preserved ejection fraction
HFrEF Heart failure with reduced ejection fraction
Figure 1 Management of patients with heart failure with mildly HR Hazard ratio
reduced ejection fraction .................................................................................. 3633 IRONMAN Effectiveness of Intravenous Iron Treatment
Figure 2 Management of patients with heart failure with preserved versus Standard Care in Patients with Heart
ejection fraction ..................................................................................................... 3633 Failure and Iron Deficiency (trial)
i.v. Intravenous
Abbreviations and acronyms KDIGO Kidney Disease: Improving Global Outcomes
LOE Level of evidence
ACE-I Angiotensin-converting enzyme inhibitor LVEF Left ventricular ejection fraction
ADVOR Acetazolamide in Decompensated Heart MRA Mineralocorticoid receptor antagonist
Failure with Volume Overload (trial) NT-proBNP N-terminal pro-B-type natriuretic peptide
AFFIRM-AHF A Randomized Double-blind Placebo NYHA New York Heart Association
Controlled Trial Comparing the Effects of OR Odds ratio
Intravenous Ferric Carboxymaltose on PIVOTAL Proactive IV Iron Therapy in Haemodialysis
Hospitalizations and Mortality in Iron Deficient Patients (trial)
Subjects Admitted for Acute Heart Failure (trial) REVIVED-BCIS2 Revascularization for Ischemic Ventricular
ARB Angiotensin receptor blocker Dysfunction (trial)
ARNI Angiotensin receptor–neprilysin inhibitor RR Risk ratio
aRR Adjusted risk ratio SCORED Effect of Sotagliflozin on Cardiovascular and
CI Confidence interval Renal Events in Patients with Type 2
CKD Chronic kidney disease Diabetes and Moderate Renal Impairment
CLOROTIC Combination of Loop Diuretics with Who Are at Cardiovascular Risk (trial)
Hydrochlorothiazide in Acute Heart Failure SGLT2 Sodium–glucose co-transporter 2
(trial) STRONG-HF Safety, Tolerability and Efficacy of Rapid
COACH Comparison of Outcomes and Access to Care Optimization, Helped by NT-proBNP Testing, of
for Heart Failure (trial) Heart Failure Therapies (trial)
COR Class of recommendation T2DM Type 2 diabetes mellitus
CPG Clinical Practice Guidelines TRANSFORM-HF Torsemide Comparison with Furosemide for
CREDENCE Canagliflozin and Renal Events in Diabetes Management of Heart Failure (trial)
With Established Nephropathy Clinical TRILUMINATE Clinical Trial to Evaluate Cardiovascular
Evaluation (trial) Pivotal Outcomes in Patients Treated With the
CV Cardiovascular Tricuspid Valve Repair System Pivotal (trial)
DAPA-CKD Dapagliflozin And Prevention of Adverse
outcomes in Chronic Kidney Disease (trial)
DAPA-HF Dapagliflozin And Prevention of Adverse
outcomes in Heart Failure (trial) 1. Preamble
DELIVER Dapagliflozin Evaluation to Improve the LIVEs Guidelines evaluate and summarize available evidence with the aim of as
of Patients with PReserved Ejection Fraction sisting health professionals in proposing the best diagnostic or therapeutic
Heart Failure (trial) approach for an individual patient with a given condition. Guidelines are in
eGFR Estimated glomerular filtration rate tended for use by health professionals and the European Society of
EMPA-KIDNEY EMPAgliflozin once daily to assess cardio-renal Cardiology (ESC) makes its Guidelines freely available.
outcomes in patients with chronic KIDNEY ESC Guidelines do not override the individual responsibility of health
disease (trial) professionals to make appropriate and accurate decisions in consider
EMPEROR- Empagliflozin Outcome Trial in Patients with ation of each patient’s health condition and in consultation with that pa
Preserved Chronic Heart Failure with Preserved tient or the patient’s caregiver where appropriate and/or necessary. It
Ejection (trial) is also the health professional’s responsibility to verify the rules and
3630 ESC Guidelines
regulations applicable in each country to drugs and devices at the time Guidelines here: https://www.escardio.org/Guidelines/Clinical-Practice-
of prescription and, where appropriate, to respect the ethical rules of Guidelines/Acute-and-Chronic-Heart-Failure.
their profession. The members of the Task Force were selected by the ESC to re
ESC Guidelines represent the official position of the ESC on a given present professionals involved with the medical care of patients with
topic and are regularly updated. ESC Policies and Procedures for for this pathology. The Task Force performed a critical evaluation of diag
mulating and issuing ESC Guidelines can be found on the ESC website nostic and therapeutic approaches, including assessment of the risk–
(https://www.escardio.org/Guidelines). benefit ratio. The strength of every new or updated recommendation
Interim Focused Updates are created when the publication of new and the level of evidence supporting them were weighed and scored ac
evidence could influence clinical practice before the next full update cording to predefined scales as outlined below. The Task Force followed
of a guideline is published. This Focused Update provides new and re ESC voting procedures and all approved recommendations were sub
vised recommendations for the 2021 ESC Guidelines for the diagnosis ject to a vote and achieved at least 75% agreement among voting
and treatment of acute and chronic heart failure. View the full 2021 ESC members.

Table 1 Classes of recommendations
Definition Wording to use

Classes of recommendations
Class I Evidence and/or general agreement Is recommended or is indicated

that a given treatment or procedure is
beneficial, useful, effective.
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 Should be considered

favour of usefulness/efficacy.
Class IIb Usefulness/efficacy is less well May be considered

established by evidence/opinion.
Class III Evidence or general agreement that the Is not recommended

given treatment or procedure is not
©ESC 2023
© ESC 2023
useful/effective, and in some cases
may be harmful.
Table 2 Levels of evidence
Level of Data derived from multiple randomized clinical trials

evidence A or meta-analyses.
Level of Data derived from a single randomized clinical trial

evidence B or large non-randomized studies.
Level of Consensus of opinion of the experts and/or small studies,

evidence C retrospective studies, registries.
©ESC 2023
© ESC 2023
ESC Guidelines 3631
The experts of the writing and reviewing panels provided declaration Care for Heart Failure),4 DAPA-CKD (Dapagliflozin And Prevention
of interest forms for all relationships that might be perceived as real or of Adverse outcomes in Chronic Kidney Disease),5 DELIVER
potential sources of conflicts of interest. Their declarations of interest (Dapagliflozin Evaluation to Improve the LIVEs of Patients with
were reviewed according to the ESC declaration of interest rules and PReserved Ejection Fraction Heart Failure),6 EMPA-KIDNEY
can be found on the ESC website (http://www.escardio.org/ (EMPAgliflozin once daily to assess cardio-renal outcomes in patients
guidelines) and have been compiled in a report published in a supple with chronic KIDNEY disease),7 EMPEROR-Preserved (Empagliflozin
mentary document with the guidelines. The Task Force received its en Outcome Trial in Patients with Chronic Heart Failure with Preserved
tire financial support from the ESC without any involvement from the Ejection Fraction),8 EMPULSE (Empagliflozin in Patients Hospitalized
healthcare industry. with Acute Heart Failure Who Have Been Stabilized),9
The ESC Clinical Practice Guidelines (CPG) Committee supervises FIDELIO-DKD (Finerenone in Reducing Kidney Failure and Disease
and coordinates the preparation of new Guidelines and Focused Progression in Diabetic Kidney Disease),10 FIGARO-DKD
Updates and is responsible for the approval process. ESC Guidelines (Finerenone in Reducing Cardiovascular Mortality and Morbidity in

and Focused Updates undergo extensive review by the CPG Diabetic Kidney Disease),11 IRONMAN (Effectiveness of Intravenous
Committee and external experts, including members from across the Iron Treatment versus Standard Care in Patients with Heart Failure
whole of the ESC region and from relevant ESC Subspecialty and Iron Deficiency),12 PIVOTAL (Proactive IV Iron Therapy
Communities and National Cardiac Societies. After appropriate revi in Haemodialysis Patients),13,14 REVIVED-BCIS2 (Revascularization
sions, Guidelines and Focused Updates are signed off by all the experts for Ischemic Ventricular Dysfunction),15 STRONG-HF (Safety,
involved in the Task Force. Finalized documents are signed off by the Tolerability and Efficacy of Rapid Optimization, Helped by
CPG Committee for publication in the European Heart Journal. This NT-proBNP Testing, of Heart Failure Therapies),16
Focused Update was developed after careful consideration of the scien TRANSFORM-HF (Torsemide Comparison with Furosemide for
tific and medical knowledge and the evidence available at the time of Management of Heart Failure),17 and TRILUMINATE Pivotal (Clinical
writing. Tables of evidence summarizing the findings of studies Trial to Evaluate Cardiovascular Outcomes in Patients Treated With
informing development of the Focused Update are included. The ESC the Tricuspid Valve Repair System Pivotal).18
warns readers that the technical language may be misinterpreted and Only results that would lead to new or changed class I/IIa recommen
declines any responsibility in this respect. dations were selected for inclusion in Recommendation Tables. Trials
Off-label use of medication may be presented in this Focused Update that would have an impact upon recommendations in other ESC
if a sufficient level of evidence shows that it can be considered medically Guidelines under preparation have not been included to avoid discord
appropriate for a given condition. However, the final decisions con ance. This is the case for REVIVED-BCIS2, which will be considered in
cerning an individual patient must be made by the responsible health the upcoming chronic coronary syndrome Guidelines.
professional giving special consideration to: In addition to selecting the trials to be included, the Task Force also
discussed changing the description of HF with preserved ejection frac
• The specific situation of the patient. Unless otherwise provided for
tion (HFpEF) to HF with normal ejection fraction (HFnEF) and the left
by national regulations, off-label use of medication should be limited
ventricular ejection fraction (LVEF) threshold for HFnEF. The Task
to situations where it is in the patient’s interest with regard to the
Force ultimately decided to keep the term HFpEF and left any further
quality, safety, and efficacy of care, and only after the patient has
changes in terminology to be considered in the next ESC HF Guidelines.
been informed and has provided consent.
In assigning recommendations, as in the 2021 ESC HF Guidelines, the
• Country-specific health regulations, indications by governmental
Task Force focused on the primary endpoints of trials. This means that,
drug regulatory agencies, and the ethical rules to which health profes
for most HF trials, effective treatments reduce the risk of the time to
sionals are subject, where applicable.
first occurrence of the composite of either HF hospitalization or cardio
vascular (CV) death (the correct convention for describing such a com
posite). Of course, that does not mean each component is reduced
2. Introduction individually. For total-event trials, where the primary composite out
Since the publication of the 2021 ESC Guidelines for the diagnosis and come included total (first and repeat) HF hospitalizations and all CV
treatment of acute and chronic heart failure (HF),1 there have been sev deaths, the convention for describing this composite, i.e. and not or,
eral randomized controlled trials that should change patient manage was used. Once again that does not mean that both components
ment ahead of the next scheduled full guidelines. This 2023 Focused were reduced. All the new recommendations are additive to the re
Update addresses changes in recommendations for the treatment of commendations of the 2021 ESC HF Guidelines and changed recom
HF because of this new evidence. New evidence was considered until mendations substitute those of the 2021 ESC HF Guidelines.
31 March 2023. All major randomized controlled clinical trials and After due deliberation, the Task Force decided to update recom
meta-analyses were presented, discussed, and then voted upon for in mendations for the following sections of the 2021 ESC HF Guidelines:
clusion. Members with declared interests in specific topics were asked
• Chronic HF: HF with mildly reduced ejection fraction (HFmrEF) and
to abstain from voting on those topics. The trials were presented and
HFpEF
discussed in detail before a consensus was reached about any possible
• Acute HF
classes of recommendations (COR) (Table 1) and levels of evidence
• Comorbidities and prevention of HF.
(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
3. Chronic heart failure
(Combination of Loop Diuretics with Hydrochlorothiazide in Acute The original 2021 ESC HF Guidelines adopted the classification of
Heart Failure),3 COACH (Comparison of Outcomes and Access to chronic HF according to LVEF (Table 3).
3632 ESC Guidelines
Table 3 Definition of heart failure with reduced ejection fraction, mildly reduced ejection fraction, and preserved
ejection fraction
Type of HF HFrEF HFmrEF HFpEF
Criteria 1 Symptoms ± signsa Symptoms ± signsa Symptoms ± signsa

b
2 LVEF ≤40% LVEF 41–49% LVEF ≥50%
© ESC 2023
3 – – 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 peptides were also a mandatory inclusion criterion (≥300 pg/mL in
Force made weak recommendations (COR IIb, LOE C) in the 2021 ESC sinus rhythm or ≥600 pg/mL in atrial fibrillation).6,20,21
HF Guidelines for the use of disease-modifying therapies that have class I Dapagliflozin reduced the primary endpoint of CV death or worsen
evidence for use in HF with reduced ejection fraction (HFrEF). These ing HF (HF hospitalization or urgent HF visit) (HR 0.82, 95% CI 0.73–
were based on subgroup analyses of trials that were not specifically de 0.92; P < .001). Once again, the principal effect was due to a reduction
signed to focus on HFmrEF, including trials where the overall endpoints in worsening HF and there was no reduction in CV death. Dapagliflozin
were statistically neutral. The Task Force made no recommendations also improved symptom burden. The effects were independent of
for the use of sodium–glucose co-transporter 2 (SGLT2) inhibitors.1 T2DM status.6 The efficacy of dapagliflozin was consistent in those
For those with HFpEF, the Task Force made no recommendations who remained symptomatic, despite improved LVEF, suggesting that
for the use of disease-modifying HFrEF therapies as clinical trials with these patients may also benefit from SGLT2 inhibition.6,22 The benefit
angiotensin-converting enzyme inhibitors (ACE-I), angiotensin recep of dapagliflozin was also consistent across the range of LVEF studied.6,23
tor blockers (ARB), mineralocorticoid receptor antagonists (MRA), The background use of therapies for concomitant CV disease was high:
and angiotensin receptor–neprilysin inhibitors (ARNI) failed to meet 77% were on a loop diuretic, 77% were on an ACE-I/ARB/ARNI, 83%
their primary endpoints. There were no published trials with SGLT2 in were on a beta-blocker, and 43% were on an MRA.6
hibitors to consider at the time.1 A subsequent aggregate data meta-analysis of the two trials con
Since then, two trials have become available with the SGLT2 inhibi firmed a 20% reduction in the composite endpoint of CV death or first
tors empagliflozin and dapagliflozin, in patients with HF and LVEF hospitalization for HF (HR 0.80, 95% CI 0.73–0.87; P < .001). CV death
>40%, that justify an update in the recommendations for both was not reduced significantly (HR 0.88, 95% CI 0.77–1.00; P = .052). HF
HFmrEF and HFpEF.6,8 hospitalization was reduced by 26% (HR 0.74, 95% CI 0.67–0.83;
The first trial to report was the EMPEROR-Preserved trial.8 It re P < .001). There were consistent reductions in the primary endpoint
cruited 5988 patients with HF (New York Heart Association [NYHA] across the LVEF range studied.24 Another individual patient data
class II–IV) whose LVEF was >40% and who had raised plasma concen meta-analysis that incorporated data from DAPA-HF (Dapagliflozin
trations of N-terminal pro-B-type natriuretic peptide (NT-proBNP) And Prevention of Adverse outcomes in Heart Failure) in HFrEF with
(>300 pg/mL for those in sinus rhythm or >900 pg/mL for those in at DELIVER confirmed that there was no evidence that the effect of
rial fibrillation). They were randomized to empagliflozin (10 mg once dapagliflozin differed by ejection fraction.22 This also showed that dapa
daily) or placebo. The primary outcome was a composite of CV death gliflozin reduced the risk of death from CV causes (HR 0.86, 95% CI
or hospitalization for HF. At a median follow-up of 26.2 months, empa 0.76–0.97; P = .01).22
gliflozin reduced the primary endpoint (hazard ratio [HR] 0.79, 95% The Task Force discussed the results of these trials in depth, focusing
confidence interval [CI] 0.69–0.90; P < .001). The effect was mainly dri particularly on the fact that they both met their primary endpoints, but
ven by a reduction in HF hospitalizations with empagliflozin and there they did so by a reduction in HF hospitalizations and not CV death. The
was no reduction in CV death. The effects were seen in patients with Task Force decided to make recommendations on the primary end
and without type 2 diabetes mellitus (T2DM).8 The majority of patients points. That is consistent with all the recommendations made in the
were on an ACE-I/ARB/ARNI (80%) and beta-blocker (86%) and 37% 2021 ESC HF Guidelines. The Task Force did not specify
were on an MRA.19 NT-proBNP thresholds for treatment, consistent with recommenda
A year later, the DELIVER trial reported on the effects of dapagliflo tions for other therapies in the original 2021 ESC HF Guidelines.
zin (10 mg once daily) compared with placebo in 6263 patients with HF However, it should be noted that, in the diagnostic algorithm for HF
(NYHA class II–IV).6 Patients had to have an LVEF >40% at the time of in the 2021 ESC HF Guidelines, raised concentrations of natriuretic
recruitment, but those who previously had an LVEF ≤40% that had im peptides are usually implicit to that diagnosis. Taking these two trials
proved to >40% were also enrolled. Outpatients and inpatients hospi into account, the following recommendations have been made for
talized for HF were eligible. An elevated concentrations of natriuretic HFmrEF and HFpEF (see Figs 1 and 2, respectively).
ESC Guidelines 3633
Recommendation Table 1 — Recommendation for the Recommendation Table 2 — Recommendation for the
treatment of patients with symptomatic heart failure treatment of patients with symptomatic heart failure
with mildly reduced ejection fraction with preserved ejection fraction
Recommendation Classa Levelb Recommendation Classa Levelb
© ESC 2023
© ESC 2023
An SGLT2 inhibitor (dapagliflozin or empagliflozin) is An SGLT2 inhibitor (dapagliflozin or empagliflozin) is
recommended in patients with HFmrEF to reduce I A recommended in patients with HFpEF to reduce the I A
the risk of HF hospitalization or CV death.c 6,8 risk of HF hospitalization or CV death.c 6,8
CV, cardiovascular; HF, heart failure; HFmrEF, heart failure with mildly reduced ejection CV, cardiovascular; HF, heart failure; HFpEF, heart failure with preserved ejection fraction;
fraction; SGLT2, sodium–glucose co-transporter 2. SGLT2, sodium–glucose co-transporter 2.
a a
Class of recommendation. Class of recommendation.
b b
Level of evidence. Level of evidence.

c c
This recommendation is based on the reduction of the primary composite endpoint used 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 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 be noted that there was a significant reduction only in HF hospitalizations and no reduction
in CV death. in CV death.
Management of patients with HFmrEF
Diuretics for Dapagliflozin/

ACEI/ARNI/ARB MRA Beta-blocker
fluid retention Empagliflozin
(Class IIb) (Class IIb) (Class IIb)
(Class I) (Class I)
Figure 1 Management of patients with heart failure with mildly reduced ejection fraction. ACE-I, angiotensin-converting enzyme inhibitor; ARB, angio
tensin receptor blocker; ARNI, angiotensin receptor–neprilysin inhibitor; HFmrEF, heart failure with mildly reduced ejection fraction; MRA, mineralo
corticoid receptor antagonist.
Management of patients with HFpEF
Diuretics for Dapagliflozin/ Treatment for aetiology,

fluid retention Empagliflozin CV and non-CV comorbodities
(Class I) (Class I) (Class I)
Figure 2 Management of patients with heart failure with preserved ejection fraction. CV, cardiovascular; HFpEF, heart failure with preserved ejection
fraction.
3634 ESC Guidelines
4. Acute heart failure agent, or starting a mechanical or surgical intervention) was performed.9
Patients were randomized in hospital when clinically stable, with a median
Treatment of acute HF was outlined in the recent 2021 ESC HF time from hospital admission to randomization of 3 days, and were treated
Guidelines and a Heart Failure Association scientific statement on for up to 90 days. The primary endpoint was achieved in more patients
HF.1,25 Since these publications, trials have been conducted with diure treated with empagliflozin compared with placebo (stratified win ratio
tics, as well as on management strategies for patients with acute HF. 1.36, 95% CI 1.09–1.68; P = .0054). Efficacy was independent of LVEF
The results are summarized here. and diabetes status. From a safety perspective, the rate of adverse events
was similar between the two treatment groups.9
4.1. Medical therapy These results are consistent with those shown for SGLT2 inhibitors
in patients with chronic HF, regardless of LVEF, and also in those re
4.1.1. Diuretics
cently hospitalized for HF, once clinically stable.9,26–28 Caution is, how
ADVOR was a multicentre, randomized, parallel-group, double-blind,
ever, needed in patients with T2DM at risk of diabetic ketoacidosis,
placebo-controlled trial that enrolled 519 patients with acute decom

particularly those treated with insulin when carbohydrate intake is re
pensated HF, clinical signs of volume overload (i.e. oedema, pleural
duced or dose of insulin changed.29 SGLT2 inhibitors are not indicated
effusion, or ascites), and an NT-proBNP level of >1000 pg/mL or a
in patients with type 1 diabetes.
B-type natriuretic peptide level of >250 pg/mL. They were randomized
to receive intravenous (i.v.) acetazolamide (500 mg once daily) or pla
cebo added to standardized i.v. loop diuretic treatment.2 The primary 4.2. Management strategies
endpoint of successful decongestion, defined as the absence of signs Two large trials have been published since the last guidelines: COACH
of volume overload, within 3 days after randomization and without and STRONG-HF.
an indication for escalation of decongestive therapy, was achieved in
108 of 256 patients (42.2%) in the acetazolamide group and in 79 of 4.2.1. Admission phase
259 patients (30.5%) in the placebo group (risk ratio [RR] 1.46, 95% The COACH trial was a cross-sectional, stepped-wedge, cluster-
CI 1.17–1.82; P < .001). Rehospitalization for HF or all-cause death oc randomized trial including 5452 patients (2972 during the control phase
curred in 76 patients (29.7%) in the acetazolamide group and in 72 pa and 2480 during the intervention phase) enrolled at 10 centres in
tients (27.8%) in the placebo group (HR 1.07, 95% CI 0.78–1.48). Ontario, Canada.4 During the intervention phase, hospital staff used the
Length of hospital stay was 1 day shorter with acetazolamide compared Emergency Heart Failure Mortality Risk Grade 30 Day Mortality-ST
with placebo (8.8 [95% CI 8.0–9.5] vs. 9.9 [95% CI 9.1–10.8] days). No Depression (‘EHMRG30-ST’) score to ascertain whether patients had a
difference between the acetazolamide and placebo groups was found low, intermediate, or high risk of death within 7 days or within 30 days.
for other outcomes and adverse events.2 Although these results may The study protocol recommended that low-risk patients be discharged
support the addition of acetazolamide to a standard diuretic regimen early (in ≤3 days) and be treated with standardized outpatient care up
to aid decongestion, further data on outcomes and safety are needed. to 30-day follow-up, whereas it was advised that intermediate- and high-
The CLOROTIC trial enrolled 230 patients with acute HF and ran risk patients be admitted to the hospital. Although early discharge oc
domized them to oral hydrochlorothiazide (25–100 mg daily, depend curred at a similar rate in the intervention and control groups (57% vs.
ing on estimated glomerular filtration rate [eGFR]) or placebo, in 58%), the trial was successful in showing a 12% reduction in the primary
addition to i.v. furosemide.3 The trial had two co-primary endpoints, outcome of all-cause death or CV hospitalization in the interventional arm
change in body weight and change in patient-reported dyspnoea compared with the control arm (HR 0.88, 95% CI 0.78–0.99), consistent
from baseline to 72 h after randomization. Patients on hydrochlor with a favourable effect of post-discharge care.4 The trial may need fur
othiazide had a greater decrease in body weight at 72 h compared ther confirmation multinationally before any recommendation on its ap
with those on placebo (−2.3 vs. −1.5 kg; adjusted estimated difference proach can be offered in a guideline.
−1.14 kg, 95% CI −1.84 to −0.42 kg; P = .002). Changes in patient-
reported dyspnoea were similar between the two groups.3 An increase 4.2.2. Pre-discharge and early post-discharge phases
in serum creatinine occurred more frequently in patients on hydro
The importance of pre-discharge and early post-discharge assessment in
chlorothiazide (46.5%) compared with those on placebo (17.2%)
patients admitted to hospital for an episode of acute HF was already
(P < .001). The rates of HF rehospitalization and all-cause death were
stressed in the original 2021 ESC HF Guidelines.1 The STRONG-HF trial
similar between groups, as was length of stay.3 The lack of an impact
recently showed the safety and efficacy of an approach based on starting
on clinical outcomes precludes any recommendation in the current
and titrating oral medical therapy for HF within 2 days before anticipated
guideline update. Further data on outcomes and safety are needed.
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
4.1.2. Sodium–glucose co-transporter 2 inhibitors doses of evidence-based HF therapies, who were haemodynamically
EMPULSE tested the efficacy of the early initiation of empagliflozin in pa stable, with elevated NT-proBNP concentrations at screening
tients hospitalized for acute HF.9 The primary endpoint was ‘clinical bene (>2500 pg/mL), and a >10% decrease in concentration between screen
fit’, defined using a hierarchical composite of death from any cause, number ing and randomization, were randomly assigned, before discharge, to
of HF events, and time to first HF event, or a ≥5 point difference in change usual care or high-intensity care. Patients in the high-intensity care group
from baseline in the Kansas City Cardiomyopathy Questionnaire total received early and rapid intensification of oral HF treatment with ACE-I
symptom score at 90 days, assessed using the win-ratio method. HF events (or ARB) or ARNI, beta-blockers, and MRA.16
were defined as HF hospitalizations, urgent HF visits, and unplanned out The goal of the first titration visit, which occurred within 48 h before
patient HF visits. An event was considered HF-related only if worsening hospital discharge, was to reach at least half of the target doses of re
signs and symptoms of HF were present and an intensification of therapy commended medications. Titration to full target doses of oral therapies
(defined as an increase in oral or i.v. diuretics, augmentation of a vasoactive was attempted within 2 weeks after discharge, with appropriate safety
ESC Guidelines 3635
monitoring. Follow-up visits, including physical examination and labora

tory evaluation, including NT-proBNP measurement, were performed
5. Comorbidities
at 1, 2, 3, and 6 weeks after randomization to assess the safety and tol 5.1. Chronic kidney disease and type 2
erability of medical therapy. Patients assigned to high-intensity care
diabetes mellitus
were more likely to receive full doses of oral therapies than those in
The 2021 ESC HF Guidelines gave recommendations for the preven
the usual care group (renin–angiotensin system inhibitors 55% vs. 2%,
tion of HF in patients with diabetes. This update provides new recom
beta-blockers 49% vs. 4%, and MRA 84% vs. 46%). The trial was
mendations for prevention of HF in patients with chronic kidney
stopped early for benefit. The primary outcome of HF readmission
disease (CKD) and T2DM.5,7,10,11,34,35
or all-cause death at 180 days occurred in 15.2% of patients in the high-
Previous trials have shown the effects of ARB in preventing HF events
intensity care group and in 23.3% of patients in the usual care group (ad
in patients with diabetic nephropathy.36,37 Both the Kidney Disease:
justed RR [aRR] 0.66, 95% CI 0.50–0.86; P = .0021). Readmissions for
Improving Global Outcomes (KDIGO) and the 2022 American
HF were reduced (aRR 0.56, 95% CI 0.38–0.81; P = .0011), whereas all-
Diabetes Association Standards of Medical Care in Diabetes and

cause death by day 180 was not (aRR 0.84, 95% CI 0.56–1.26; P = .42).
KDIGO recommendations indicate treatment with an ACE-I or ARB
Similar rates of serious adverse events (16% vs. 17%) and fatal adverse
for patients with CKD, diabetes, and hypertension or albuminuria.38,39
events (5% vs. 6%) were reported in each group.16
Based upon the results of STRONG-HF, high-intensity care for initi
ation and rapid up-titration of oral HF therapies and close follow-up in 5.1.1. Sodium–glucose co-transporter 2 inhibitors
the first 6 weeks after discharge for an acute HF hospitalization is re Two randomized controlled trials, which were stopped early for effi
commended to reduce HF readmission or all-cause death. During the cacy, and a meta-analysis were recently published. DAPA-CKD was a
follow-up visits, particular attention should be paid to symptoms and multicentre, double-blind, placebo-controlled, randomized trial includ
signs of congestion, blood pressure, heart rate, NT-proBNP values, po ing both diabetic and non-diabetic patients with a urinary
tassium concentrations, and eGFR. albumin-to-creatinine ratio ≥200 mg/g and an eGFR of 25–75 mL/
STRONG-HF has several limitations. First, the population was care min/1.73 m2, who were randomly assigned 1:1 to dapagliflozin 10 mg
fully selected, based on baseline NT-proBNP concentrations and their once daily or placebo.5 Overall, 468 of the 4304 patients enrolled
decline during hospitalization. Second, the majority of patients in the (11%) had a history of HF. During a median follow-up of 2.4 years, a re
control group received less than half of full optimal doses of ACE-I/ duction in the primary outcome, a composite of sustained decline in
ARB/ARNI and beta-blockers, and, although similar to many real-world eGFR of ≥50%, end-stage kidney disease, or kidney-related or CV
clinical settings,30–33 their relative undertreatment may have favoured death, was reduced by 39% by dapagliflozin compared with placebo
the high-intensity care arm. Third, the trial was initiated prior to current (HR 0.61, 95% CI 0.51–0.72; P < .001). Also, the risk of the secondary
evidence and recommendations for SGLT2 inhibitors, which were not outcome of HF hospitalization or CV death was decreased by dapagli
mandated in the protocol. flozin 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.
Recommendation Table 3 — Recommendation for 6.4% with dapagliflozin vs. placebo).5
pre-discharge and early post-discharge follow-up of EMPA-KIDNEY enrolled a broader group of patients with CKD,
patients hospitalized for acute heart failure 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
Recommendation Classa Levelb 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
An intensive strategy of initiation and rapid
daily or placebo.7 Overall, 658 of the 6609 patients enrolled (10%) had a
up-titration of evidence-based treatment before
history of HF. During a median follow-up of 2.0 years, a reduction in the
discharge and during frequent and careful follow-up
I B primary composite endpoint of progression of kidney disease or CV death
© ESC 2023
visits in the first 6 weeks following a HF

was observed.7 The risk of HF hospitalization or death for CV causes was
hospitalization is recommended to reduce the risk of
not reduced significantly (HR 0.84, 95% CI 0.67–1.07; P = .15).7
HF rehospitalization or death.c,d,e 16 DAPA-CKD, EMPA-KIDNEY, CREDENCE39a (Canagliflozin and Renal
ACE-I, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; ARNI, Events in Diabetes With Established Nephropathy Clinical Evaluation),
angiotensin receptor–neprilysin inhibitor; CV, cardiovascular; HF, heart failure; HFmrEF, and SCORED39b (Effect of Sotagliflozin on Cardiovascular and
heart failure with mildly reduced ejection fraction; HFpEF, heart failure with preserved
Renal Events in Patients with Type 2 Diabetes and Moderate Renal
ejection fraction; HFrEF, heart failure with reduced ejection fraction; MRA,
mineralocorticoid receptor antagonist; NT-proBNP, N-terminal pro-B-type natriuretic Impairment Who Are at Cardiovascular Risk) were included with
peptide. HF trials in a recent meta-analysis.35 The reduction in HF hospitaliza
a
Class of recommendation. tions and CV death was similar irrespective of a history of diabetes
b
Level of evidence.
c when both HF and CKD trials were included (HR 0.77, 95% CI
In STRONG-HF, the use of ACE-I/ARB/ARNI, beta-blockers, and MRA was evaluated in
patients with HFrEF, HFmrEF, and HFpEF. 0.73–0.81 in patients with T2DM, and HR 0.79, 95% CI 0.72–0.87 in those
d
This recommendation is based on the reduction of the primary endpoint used in the without T2DM). However, results were not significant in patients without
STRONG-HF trial. However, it should be noted that there was a significant reduction diabetes when only CKD trials were included (HR for HF hospitalizations
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 and CV death of 0.74, 95% CI 0.66–0.82 in patients with T2DM, and HR of
evidence-based HF therapies, who were haemodynamically stable, with elevated 0.95, 95% CI 0.65–1.40 in patients without T2DM).35 Based on these re
NT-proBNP concentrations at screening (>2500 pg/mL), and a >10% decrease in sults, SGLT2 inhibitors are recommended in patients with CKD and
concentration between screening and randomization, according to the enrolment criteria.
e T2DM, and with the additional characteristics of the participants in these
Although STRONG-HF was based only on triple therapy with neurohormonal modulators,
this recommendation also includes empagliflozin or dapagliflozin based on recent trials, including an eGFR >20–25 mL/min/1.73 m2, to reduce the risk of
evidence.6,8,9 HF hospitalization or CV death.
3636 ESC Guidelines
5.1.2. Finerenone Recommendation Table 4 — Recommendations for the

The selective, non-steroidal, MRA finerenone was tested in two trials in prevention of heart failure in patients with type 2
diabetes mellitus and chronic kidney disease
patients with diabetic kidney disease. The FIDELIO-DKD trial enrolled
5734 patients with a urinary albumin-to-creatinine ratio 30–300 mg/g,
Recommendations Classa Levelb
an eGFR 25–60 mL/min/1.73 m2, and diabetic retinopathy, or a urinary
albumin-to-creatinine ratio 300–5000 mg/g and an eGFR 25–75 mL/ In patients with T2DM and CKD,c SGLT2 inhibitors
min/1.73 m2.10 The primary outcome of the trial, assessed in a are recommended to reduce the risk of HF I A
time-to-event analysis, was a composite of kidney failure, a sustained hospitalization or CV death.35
© ESC 2023
decrease of ≥40% in the eGFR from baseline over a period of ≥4 In patients with T2DM and CKD,c finerenone is
weeks, or death from renal causes. Kidney failure was defined as end- recommended to reduce the risk of HF I A
stage kidney disease or an eGFR <15 mL/min/1.73 m2; end-stage kidney hospitalization.10,11,34,40
disease was defined as the initiation of long-term dialysis (for ≥90 days)

or kidney transplantation. The primary endpoint of the trial was re CKD, chronic kidney disease; CV, cardiovascular; eGFR, estimated glomerular filtration
rate; HF, heart failure; SGLT2, sodium–glucose co-transporter 2; T2DM, type 2 diabetes
duced by finerenone compared with placebo by 18% (HR 0.82, 95% mellitus.
CI 0.73–0.93; P = .001), during a median follow-up of 2.6 years.10 a
Class of recommendation.
b
There was no evidence of a reduction in HF hospitalizations with finer Level of evidence.
c
CKD was defined as follows: an eGFR 25–75 mL/min/1.73 m2 and a urinary
enone vs. placebo (HR 0.86, 95% CI 0.68–1.08), although finerenone
albumin-to-creatinine ratio ≥200–5000 mg/g in DAPA-CKD;5 an eGFR 20–45 mL/min/
was associated with a lower occurrence of the key secondary endpoint, 1.73 m2 or an eGFR 45–90 mL/min/1.73 m2 with a urinary albumin-to-creatinine ratio
a composite of CV death, non-fatal myocardial infarction, non-fatal ≥200 mg/g in EMPA-KIDNEY;7 an eGFR 25–60 mL/min/1.73 m2, a urinary
stroke, and hospitalization for HF (HR 0.86, 95% CI 0.75–0.99; P 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,
= .03).10 Patients with HFrEF and NYHA class II–IV were excluded in FIDELIO-DKD;10 and an eGFR 25–90 mL/min/1.73 m2 and a urinary
from the trial. However, patients with asymptomatic or NYHA class I albumin-to-creatinine ratio 30 to <300 mg/g, or an eGFR >60 mL/min/1.73 m2 and a
HFrEF, or with HFmrEF or HFpEF, could be enrolled, so that 7.7% of urinary albumin-to-creatinine ratio 300–5000 mg/g, in FIGARO-DKD.11
the patients included had a history of HF. The effects of finerenone
on the composite of CV and renal outcomes, including HF hospitaliza
tions, were independent of a previous history of HF.34
In the more recent FIGARO-DKD trial, the primary outcome, as
sessed in a time-to-event analysis, was a composite of death from CV 5.2. Iron deficiency
causes, non-fatal myocardial infarction, non-fatal stroke, or hospitaliza Recommendations for the diagnosis and treatment of iron deficiency
tion for HF.11 The trial enrolled adult patients with T2DM and CKD were given in the 2021 ESC HF Guidelines: COR I, LOE C for the diag
treated with a renin–angiotensin system inhibitor at the maximum tol nosis of iron deficiency, COR IIa, LOE A to improve HF symptoms, ex
erated dose. CKD was defined according to one of two sets of criteria: ercise capacity, and quality of life, and COR IIa, LOE B to reduce HF
persistent, moderately elevated albuminuria (urinary albumin-to-cre hospitalizations, for treatment with ferric carboxymaltose.1
atinine ratio 30 to <300 mg/g) and an eGFR 25–90 mL/min/1.73 m2 A new trial, IRONMAN, has now been published.12 This was a pro
(i.e. stage 2 to 4 CKD); or persistent, severely elevated albuminuria spective, randomized, open-label, blinded-endpoint trial including pa
(urinary albumin-to-creatinine ratio 300–5000 mg/g) and an eGFR tients with HF, LVEF ≤45%, and transferrin saturation <20% or
>60 mL/min/1.73 m2 (i.e. stage 1 or 2 CKD). Patients were required serum ferritin <100 μg/L who were randomly allocated 1:1 to i.v. ferric
to have a serum potassium level of ≤4.8 mmol/L at the time of screen derisomaltose or usual care. The patients included were mainly ambu
ing.11 The trial included 7437 patients randomly assigned to finerenone latory, although 14% were enrolled during an HF hospitalization and
or placebo.11 At a median follow-up of 3.4 years, the rate of the primary 18% had an HF hospitalization in the previous 6 months. After a median
outcome, CV death, non-fatal myocardial infarction, non-fatal stroke, follow-up of 2.7 years, the rate ratio for the primary endpoint, a com
or HF hospitalization, was lower in the treatment arm compared posite of total (first and recurrent) HF hospitalizations and CV death,
with placebo (HR 0.87, 95% CI 0.76–0.98; P = .03). The benefit was dri was 0.82 (95% CI 0.66–1.02; P = .070). Total hospital admissions for
ven by a numerically small, but statistically significant, lower incidence of HF were not reduced significantly with ferric derisomaltose vs. usual
HF hospitalization with finerenone vs. placebo (3.2% vs. 4.4%; HR 0.71, care (16.7 vs. 20.9 per 100 patient-years; RR 0.80, 95% CI 0.62–1.03;
95% CI 0.56–0.90), with no differences in CV death.11 In both P = .085). As in AFFIRM-AHF (A Randomized Double-blind Placebo
FIDELIO-DKD and FIGARO-DKD the occurrence of hyperkalaemia Controlled Trial Comparing the Effects of Intravenous Ferric
was higher in the finerenone group compared with the placebo group. Carboxymaltose on Hospitalizations and Mortality in Iron Deficient
However, the rate of adverse events was similar between the two arms. Subjects Admitted for Acute Heart Failure),41 a pre-specified
A pre-specified individual patient-level, pooled analysis, including COVID-19 analysis, censoring follow-up on September 2020, showed
13 026 patients with diabetic kidney disease followed for a median a reduction in the risk of the primary endpoint with ferric derisomal
of 3.0 years from both the FIDELIO-DKD and FIGARO-DKD trials, tose vs. control (HR 0.76, 95% CI 0.58–1.00; P = .047). There was a
showed a reduction in the composite CV outcome, including CV statistically borderline improvement in the Minnesota Living with
death, non-fatal stroke, non-fatal myocardial infarction, and HF hospi Heart Failure Questionnaire score with ferric derisomaltose (between
talizations, as well as in HF hospitalizations alone with finerenone vs. treatment difference −3.33, 95% CI −6.67 to 0.00; P = .050), but no dif
placebo (HR 0.86, 95% CI 0.78–0.95; P = .0018; and HR 0.78, 95% CI ference in EQ-5D visual analogue scale or EQ-5D index.12 Some of
0.66–0.92; P = .0030, respectively).40 Thus, finerenone is recom these findings in secondary outcomes might be explained by the lack
mended for the prevention of HF hospitalization in patients with of adjustment for multiple testing.42 Safety endpoints, i.e. death and
CKD and T2DM. hospitalization due to infection, did not differ between the two arms.12
ESC Guidelines 3637
These results have been included in meta-analyses of the randomized Internal Medicine Clinic III, Saarland University, Saarbrücken,
controlled trials comparing the effects of i.v. iron therapy with standard Germany; Haran Burri, Cardiology Department, University Hospital
of care or placebo in patients with HF and iron deficiency.43–46 In the ana of Geneva, Geneva, Switzerland; Javed Butler, Baylor Scott and
lysis by Graham et al.44 including 10 trials with 3373 patients, i.v. iron re White Research Institute, Baylor Scott and White Health, Dallas, TX,
duced the composite of total HF hospitalizations and CV death (RR United States of America, Department of Medicine, University of
0.75, 95% CI 0.61–0.93; P < .01) and first HF hospitalization or CV death Mississippi, Jackson, MS, United States of America; Jelena
(odds ratio [OR] 0.72, 95% CI 0.53–0.99; P = .04). There was no effect on Čelutkienė, Clinic of Cardiac and Vascular Diseases, Vilnius
CV (OR 0.86, 95% CI 0.70–1.05; P = .14) or all-cause mortality (OR 0.93, University, Vilnius, Lithuania; Ovidiu Chioncel, ICCU, Emergency
95% CI 0.78–1.12; P = .47). Similar results were found in the other Institute for Cardiovascular Diseases ‘Prof. Dr.C.C.Iliescu’, Bucuresti,
meta-analyses.43,45,46 In the PIVOTAL trial, a high-dose i.v. iron regimen, Romania, Department of Cardiology, University of Medicine Carol
compared with a low-dose regimen, reduced the occurrence of first and Davila, Bucuresti, Romania; John G.F. Cleland, British Heart
recurrent HF events in patients undergoing dialysis for end-stage CKD.13,14 Foundation Centre of Research Excellence, School of Cardiovascular

Based on trials and recent meta-analyses,13,14,41,43,45–49 i.v. iron supple and Metabolic Health, University of Glasgow, Glasgow, United
mentation is now recommended in patients with HFrEF or HFmrEF, and Kingdom; Maria Generosa Crespo-Leiro, Cardiology, Complexo
iron deficiency, to improve symptoms and quality of life, and should be Hospitalario Universitario A Coruña (CHUAC), A Coruña, Spain,
considered to reduce the risk of HF hospitalization. Iron deficiency was Physiotherapy, Medicine and Medical Sciences, University of A
diagnosed by a low transferrin saturation (<20%) or a low serum ferritin Coruña (UDC), A Coruña, Spain, Centro Investigación Biomédica en
concentration (<100 μg/L).12,41 Notably, in IRONMAN, patients were Red Cardiovascular (CIBERCV), Instituto de Salud Carlos III, Madrid,
excluded if they had haemoglobin >13 g/dL (for women) and >14 g/dL Spain; Dimitrios Farmakis, Second Department of Cardiology,
(for men).12 The new recommendations are shown below. Athens University Hospital Attikon, National and Kapodistrian
University of Athens Medical School, Athens, Greece; Martine
Recommendation Table 5 — Recommendations for the Gilard, Cardiology, INSERM UMR 1304 GETBO, Brest University,
management of iron deficiency in patients with heart Brest, France; Stephane Heymans, Department of Cardiology,
failure Cardiovascular Research Institute Maastricht, University of Maastricht,
Maastricht, Netherlands, Department of Cardiovascular Sciences,
Recommendations Classa Levelb Leuven University, Leuven, Belgium; Arno W. Hoes, Julius Center
for Health Sciences and Primary Care, University Medical Center
Intravenous iron supplementation is recommended
Utrecht, Utrecht University, Utrecht, Netherlands; Tiny Jaarsma,
in symptomatic patients with HFrEF and HFmrEF,
I A Department of Health Medicine, Caring Science, Linköping University,
and iron deficiency, to alleviate HF symptoms and
Linköping, Sweden, Department of Nursing Science, Julius Center,
improve quality of life.c 12,41,47–49
University Medical Center, Utrecht, Netherlands; Ewa
Intravenous iron supplementation with ferric A. Jankowska, Institute of Heart Diseases, Wroclaw Medical
carboxymaltose or ferric derisomaltose should be University, Poland, Institute of Heart Diseases, University Hospital in
© ESC 2023
considered in symptomatic patients with HFrEF and IIa A Wroclaw, Poland; Mitja Lainscak, Faculty of Medicine, University of
HFmrEF, and iron deficiency, to reduce the risk of HF Ljubljana, Ljubljana, Slovenia, Division of Cardiology, General Hospital
hospitalization.c 12,41,43–46 Murska Sobota, Murska Sobota, Slovenia; Carolyn S.P. Lam,
Cardiology, National Heart Centre of Singapore, Singapore,
HF, heart failure; HFmrEF, heart failure with mildly reduced ejection fraction; HFrEF, heart
failure with reduced ejection fraction. Singapore, Cardiovascular Academic Clinical Programme,
a
Class of recommendation. Duke-National University of Singapore, Singapore, Singapore;
b
Level of evidence. Alexander R. Lyon, Cardio-Oncology Service, Royal Brompton
c
Most of the evidence refers to patients with left ventricular ejection fraction ≤45%.
Hospital, London, United Kingdom; John J.V. McMurray, BHF
Cardiovascular Research Centre, University of Glasgow, Glasgow,
United Kingdom; Alexandre Mebazaa, Faculté Santé, Université
6. Data availability statement Paris Cité, Paris, France, Anesthesia and Critical care, Assistance
No new data were generated or analysed in support of this research. Publique-Hôpitaux de Paris, Paris, France, MASCOT INSERM, Paris,
France; Richard Mindham (United Kingdom), ESC Patient Forum,
Sophia Antipolis, France, Claudio Muneretto, Cardiac Surgery,
University of Brescia, ASST Spedali Civili, Brescia, Italy; Massimo
7. Author information Francesco Piepoli, Cardiology, IRCCS Policlinico San Donato, San
Author/Task Force Member Affiliations: Marianna Adamo, Donato Milanese, Italy, Dipartimento di Scienze Biomediche per la
ASST Spedali Civili di Brescia and Department of Medical and Surgical Salute, University of Milan, Milan, Italy; Susanna Price, Cardiology
Specialties, Radiological Sciences and Public Health, University of and critical care, Royal Brompton and Harefield Hospitals, London,
Brescia, Institute of Cardiology, Brescia, Italy; Roy S. Gardner, United Kingdom, National Heart and Lung Institute, Imperial College,
Scottish National Advanced Heart Failure Service, Golden Jubilee London, United Kingdom; Giuseppe M.C. Rosano, Basic and
National Hospital, Clydebank, Glasgow, United Kingdom; Andreas Clinical Research, IRCCS San Raffaele Roma, Rome, Italy; Frank
Baumbach, Queen Mary University of London, Barts Heart Center, Ruschitzka, Department of Cardiology, University Hospital Zurich
London, United Kingdom; Michael Böhm, Internal Medicine Clinic and University of Zurich, Zurich, Switzerland; and Anne Kathrine
III, Universitätsklinikum des Saarlandes, Homburg, Saar, Germany, Skibelund (Denmark), ESC Patient Forum, Sophia Antipolis, France.
3638 ESC Guidelines
8. Appendix Cardiology, Olivier Manintveld; North Macedonia:The National

Society of Cardiology of North Macedonia, Elizabeta Srbinovska
ESC Scientific Document Group Kostovska; Norway: Norwegian Society of Cardiology, Kaspar
Includes Document Reviewers and ESC National Cardiac Societies. Broch; Poland: Polish Cardiac Society, Jadwiga Nessler; Portugal:
Document Reviewers: Rudolf A. de Boer (CPG Review Portuguese Society of Cardiology, Fatima Franco; Romania:
Co-ordinator) (Netherlands), P. Christian Schulze (CPG Review Romanian Society of Cardiology, Bogdan A. Popescu; San Marino:
Co-ordinator) (Germany), Elena Arbelo (Spain), Jozef Bartunek San Marino Society of Cardiology, Marina Foscoli; Serbia:
(Belgium), Johann Bauersachs (Germany), Michael A. Borger Cardiology Society of Serbia, Anastazija Stojsic Milosavljevic;
(Germany), Sergio Buccheri (Sweden), Elisabetta Cerbai (Italy), Erwan Slovakia: Slovak Society of Cardiology, Eva Goncalvesova;
Donal (France), Frank Edelmann (Germany), Gloria Färber (Germany), Slovenia: Slovenian Society of Cardiology, Zlatko Fras; Spain:
Bettina Heidecker (Germany), Borja Ibanez (Spain), Stefan James Spanish Society of Cardiology, Jose Gonzalez-Costello; Sweden:
(Sweden), Lars Køber (Denmark), Konstantinos C. Koskinas Swedish Society of Cardiology, Krister Lindmark; Switzerland:

(Switzerland), Josep Masip (Spain), John William McEvoy (Ireland), Swiss Society of Cardiology, Matthias Paul; Syrian Arab Republic:
Robert Mentz (United States of America), Borislava Mihaylova (United Syrian Cardiovascular Association, Abdulnasser Oudeh; Tunisia:
Kingdom), Jacob Eifer Møller (Denmark), Wilfried Mullens (Belgium), Lis Tunisian Society of Cardiology and Cardiovascular Surgery, Lilia
Neubeck (United Kingdom), Jens Cosedis Nielsen (Denmark), Agnes Zakhama; Türkiye: Turkish Society of Cardiology, Ahmet Celik;
A. Pasquet (Belgium), Piotr Ponikowski (Poland), Eva Prescott Ukraine: Ukrainian Association of Cardiology, Leonid Voronkov;
(Denmark), Amina Rakisheva (Kazakhstan), Bianca Rocca (Italy), Xavier United Kingdom of Great Britain and Northern Ireland:
Rossello (Spain), Leyla Elif Sade (United States of America / Türkiye), British Cardiovascular Society, Andrew Clark; and Uzbekistan:
Hannah Schaubroeck (Belgium), Elena Tessitore (Switzerland), Mariya Association of Cardiologists of Uzbekistan, Timur Abdullaev.
Tokmakova (Bulgaria), Peter van der Meer (Netherlands), Isabelle ESC Clinical Practice Guidelines (CPG) Committee: Eva
C. Van Gelder (Netherlands), Mattias Van Heetvelde (Belgium), Prescott (Chairperson) (Denmark), Stefan James (Co-Chairperson)
Christiaan Vrints (Belgium), Matthias Wilhelm (Switzerland), Adam (Sweden), Elena Arbelo (Spain), Colin Baigent (United Kingdom),
Witkowski (Poland), and Katja Zeppenfeld (Netherlands). Michael A. Borger (Germany), Sergio Buccheri (Sweden), Borja
ESC National Cardiac Societies actively involved in the review Ibanez (Spain), Lars Køber (Denmark), Konstantinos C. Koskinas
process of the 2023 Focused Update of the 2021 ESC Guidelines for (Switzerland), John William McEvoy (Ireland), Borislava Mihaylova
the diagnosis and treatment of acute and chronic heart failure: (United Kingdom), Richard Mindham (United Kingdom), Lis Neubeck
Albania: Albanian Society of Cardiology, Naltin Shuka; Algeria: (United Kingdom), Jens Cosedis Nielsen (Denmark), Agnes
Algerian Society of Cardiology, Mohammed Chettibi; Armenia: A. Pasquet (Belgium), Amina Rakisheva (Kazakhstan), Bianca Rocca
Armenian Cardiologists Association, Hamlet Hayrapetyan; Austria: (Italy), Xavier Rossello (Spain), Ilonca Vaartjes (Netherlands),
Austrian Society of Cardiology, Noemi Pavo; Azerbaijan: Christiaan Vrints (Belgium), Adam Witkowski (Poland), and Katja
Azerbaijan Society of Cardiology, Aysel Islamli; Belgium: Belgian Zeppenfeld (Netherlands).
Society of Cardiology, Anne-Catherine Pouleur; Bosnia and
Herzegovina: Association of Cardiologists of Bosnia and
Herzegovina, Zumreta Kusljugic; Bulgaria: Bulgarian Society of 9. References
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European Heart Journal (2023) 44, 3627–3639 ESC GUIDELINES

2023 Focused Update of the 2021 ESC

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Authors/Task Force Members: Theresa A. McDonagh *†, (Chairperson) (United

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6. Data availability statement ........................................................................... 3637

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Deﬁnition Wording to use

Class I Evidence and/or general agreement Is recommended or is indicated

Class II Conﬂicting evidence and/or a divergence of opinion about the usefulness/

Class IIa Weight of evidence/opinion is in Should be considered

Class IIb Usefulness/eﬃcacy is less well May be considered

Class III Evidence or general agreement that the Is not recommended

Table 2 Levels of evidence

Level of Data derived from multiple randomized clinical trials

Level of Data derived from a single randomized clinical trial

Level of Consensus of opinion of the experts and/or small studies,

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Type of HF HFrEF HFmrEF HFpEF

Criteria 1 Symptoms ± signsa Symptoms ± signsa Symptoms ± signsa

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Recommendation Classa Levelb Recommendation Classa Levelb

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Management of patients with HFmrEF

Diuretics for Dapagliflozin/

Management of patients with HFpEF

Diuretics for Dapagliflozin/ Treatment for aetiology,

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monitoring. Follow-up visits, including physical examination and labora­

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visits in the first 6 weeks following a HF

5.1.2. Finerenone Recommendation Table 4 — Recommendations for the

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8. Appendix Cardiology, Olivier Manintveld; North Macedonia:The National

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