Novel Recommendations for the Treatment of Patients With Heart Failure: 2023 Focused Update of the 2021 ESC Heart Failure Guidelines

Abstract

The Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC) generally updates their guidelines every 4 years. However, since the presentation of the latest guidelines in 2021, a remarkable number of studies that could potentially change the guidelines have been published. Therefore, the task force decided to provide a focused update of the 2021 guidelines, which includes a few important novel recommendations that are outlined below (Figure).1McDonagh TA Metra M Adamo M Gardner RS Baumbach A Böhm M Burri H Butler J Čelutkienė J Chioncel O Cleland JGF Crespo-Leiro MG Farmakis D Gilard M Heymans S Hoes AW Jaarsma T Jankowska EA Lainscak M Lam CSP Lyon AR McMurray JJV Mebazaa A Mindham R Muneretto C Francesco Piepoli M Price S Rosano GMC Ruschitzka F Skibelund AK ESC Scientific Document Group2023 Focused Update of the 2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure.Eur Heart J. 2023 Aug 25; : ehad195https://doi.org/10.1093/eurheartj/ehad195Crossref Google Scholar SGLT2-inhibitors have now received a class I (level of evidence A) recommendation for the treatment of patients with heart failure and a mildly reduced (HFmrEF) and preserved ejection fraction (HFpEF).1McDonagh TA Metra M Adamo M Gardner RS Baumbach A Böhm M Burri H Butler J Čelutkienė J Chioncel O Cleland JGF Crespo-Leiro MG Farmakis D Gilard M Heymans S Hoes AW Jaarsma T Jankowska EA Lainscak M Lam CSP Lyon AR McMurray JJV Mebazaa A Mindham R Muneretto C Francesco Piepoli M Price S Rosano GMC Ruschitzka F Skibelund AK ESC Scientific Document Group2023 Focused Update of the 2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure.Eur Heart J. 2023 Aug 25; : ehad195https://doi.org/10.1093/eurheartj/ehad195Crossref Google Scholar This recommendation was based on two large randomized placebo controlled trials with respectively empagliflozin (EMPEROR-Preserved) and dapagliflozin (DELIVER).2Solomon SD McMurray JJV Claggett B de Boer RA DeMets D Hernandez AF et al.Dapagliflozin in heart failure with mildly reduced or preserved ejection fraction.N Engl J Med. 2022; 387: 1089-1098https://doi.org/10.1056/NEJMoa2206286Crossref PubMed Scopus (417) Google Scholar,3Anker SD Butler J Filippatos G Ferreira JP Bocchi E Bohm M et al.Empagliflozin in heart failure with a preserved ejection fraction.N Engl J Med. 2021; 385: 1451-1461https://doi.org/10.1056/NEJMoa2107038Crossref PubMed Scopus (1475) Google Scholar The Task Force did not specify NT-proBNP thresholds for treatment, even though both EMPEROR-Preserved and DELIVER only included patients with a NT-proBNP above 300 pg/ml. Secondly, patients in DELIVER and EMPEROR-Preserved needed to be on (loop) diuretic treatment. Thirdly, patients needed to have either left ventricular hypertrophy or left atrial enlargement. Whether the beneficial effects of empagliflozin and dapagliflozin can be extended to less symptomatic patients with lower natriuretic peptide levels without left ventricular hypertrophy or left atrial enlargement is unknown. Nevertheless, the taskforce decided to provide a broad recommendation for all patients with HFpEF and HFmrEF. The current recommendation in the 2022 AHA/ACC/HFSA Guideline for the Management of Heart Failure provide a IIa (level of evidence B) recommendation since only the data of EMPEROR-Preserved were available at that time, while the data of DELIVER were still pending.4Heidenreich PA, Bozkurt B, Aguilar D, Allen LA, Byun JJ, Colvin MM, Deswal A, Drazner MH, Dunlay SM, Evers LR, Fang JC, Fedson SE, Fonarow GC, Hayek SS, Hernandez AF, Khazanie P, Kittleson MM, Lee CS, Link MS, Milano CA, Nnacheta LC, Sandhu AT, Stevenson LW, Vardeny O, Vest AR, Yancy CW. 2022 AHA/ACC/HFSA Guideline for the Management of Heart Failure: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. J Card Fail 202;28(5):810-830.Google Scholar Two important randomized controlled trials on diuretics in patients who were hospitalized for acute heart failure have recently been published. First, the CLOROTIC trial showed that the addition of 25-100 mg hydrochlorothiazide resulted in 1.4 kg additional body weight loss, but there was no difference in the change in dyspnea and no reduction in the risk of heart failure rehospitalization and all-cause death or the length of hospital stay.5Trullàs JC Morales-Rull JL Casado J Carrera-Izquierdo M Sánchez-Marteles M Conde-Martel A et al.Combining loop with thiazide diuretics for decompensated heart failure: the CLOROTIC trial.Eur Heart J. 2023; 44: 411-421https://doi.org/10.1093/eurheartj/ehac689Crossref PubMed Scopus (29) Google Scholar However, worsening of renal function and hypokalemia were more frequently observed in the hydrochlorothiazide group. Second, the ADVOR trial showed that the addition of acetazolamide on top off standard of care resulted more often in successful decongestion in 519 patients with acute decompensated heart failure, clinical signs of volume overload and elevated natriuretic peptides.6Mullens W Dauw J Martens P Verbrugge FH Nijst P Meekers E et al.Acetazolamide in acute decompensated heart failure with volume overload.N Engl J Med. 2022; 387: 1185-1195https://doi.org/10.1056/NEJMoa2203094Crossref PubMed Scopus (93) Google Scholar In addition, length of hospital stay was reduced by one day. However, similar to CLOROTIC, the enhanced decongestion was not accompanied by an improvement in symptoms or a reduction of the risk of heart failure hospital readmission or death. In addition, median eGFR increased in the placebo group from 38 ml/min at baseline to 39 ml/min at 72 hours, while median eGFR dropped from 40 ml/min at baseline to 35 ml/min at 72 hours in the acetazolamide group.6Mullens W Dauw J Martens P Verbrugge FH Nijst P Meekers E et al.Acetazolamide in acute decompensated heart failure with volume overload.N Engl J Med. 2022; 387: 1185-1195https://doi.org/10.1056/NEJMoa2203094Crossref PubMed Scopus (93) Google Scholar It should be noted that the reduction in eGFR in combination with enhanced diuresis is a physiological response of the kidney, and is not associated with worse outcomes.7Emmens JE Ter Maaten JM Matsue Y Figarska SM Sama IE Cotter G Cleland JGF Davison BA Felker GM Givertz MM Greenberg B Pang PS Severin T Gimpelewicz C Metra M Voors AA Teerlink JR. Worsening renal function in acute heart failure in the context of diuretic response.Eur J Heart Fail. 2022 Feb; 24: 365-374Crossref Scopus (18) Google Scholar However, lower eGFR might theoretically lead to less uptake of chronic heart failure therapies, such as ACEi/ARB/ARNI and MRA. The taskforce recognized the enhanced decongestion by both therapies, but the lack of an impact on clinical outcomes precluded any recommendation in the current guideline update. Around the same time, the results of STRONG-HF were presented and published.8Mebazaa A Davison B Chioncel O Cohen-Solal A Diaz R Filippatos G et al.Safety, tolerability and efficacy of up-titration of guideline-directed medical therapies for acute heart failure (STRONG-HF): a multinational, open-label, randomised, trial.Lancet. 2022; 400: 1938-1952https://doi.org/10.1016/S0140-6736(22)02076-1Abstract Full Text Full Text PDF PubMed Scopus (86) Google Scholar STRONG-HF was designed to study the effects of rapid uptitration of guideline directed medical therapies for chronic heart failure in combination with intensified follow-up in 1078 patients who were hospitalized for acute heart failure and not already on full doses of evidence-based HF therapies. The patients that were randomly assigned, before discharge, to high-intensity care received early and rapid intensification of oral HF treatment with ACE-I (or ARB) or ARNI, beta-blockers, and MRA with the aim to be on 50% of recommended doses of these therapies before discharge and to 100% of the recommended dose within 2 weeks after discharge. The study was prematurely discontinued due to a large benefit in the patients of the high-intensive care group, with a 34% reduction in the risk of cardiovascular death or heart failure hospitalization. It should be noted that the trial was initiated before the beneficial effects of SGLT2 inhibitors in patients with heart failure became apparent, and they were therefore not mandated in the protocol. However, beneficial effects of initiation of the SGLT2-inhibitor empagliflozin during hospital admission for acute heart failure on clinical outcomes were provided from the EMPULSE trial.9Voors AA Angermann CE Teerlink JR Collins SP Kosiborod M Biegus J et al.The SGLT2 inhibitor empagliflozin in patients hospitalized for acute heart failure: a multinational randomized trial.Nat Med. 2022; 28: 568-574https://doi.org/10.1038/s41591-021-01659-1Crossref PubMed Scopus (212) Google Scholar A total of 530 patients were randomized in hospital, when clinically stable, to empagliflozin 10 mg/day or placebo and were treated for up to 90 days. The primary endpoint was a hierarchical composite of mortality, heart failure rehospitalizations or quality of life. Patients treated with empagliflozin had a 36% higher likelihood to obtain a clinical benefit, independent of LVEF, and diabetes status or whether they were de novo patients or those with decompensated chronic heart failure. In addition, post-hoc analyses showed that the use of empagliflozin resulted in a marked reduction of signs and symptoms of congestion.10Biegus J Voors AA Collins SP Kosiborod MN Teerlink JR Angermann CE Tromp J Ferreira JP Nassif ME Psotka MA Brueckmann M Salsali A Blatchford JP Ponikowski P Impact of empagliflozin on decongestion in acute heart failure: the EMPULSE trial.Eur Heart J. 2023 Jan 1; 44: 41-50Crossref Scopus (23) Google Scholar Taken together, these studies in patients who were hospitalized for acute heart failure taught us that enhanced decongestion with thiazides or acetazolamide did not provide additional benefit, while treatment with the “foundational four” (ACEi/ARB/ARNI, beta blockers, MRA and SGLT2-inhibitor) improve clinical outcomes in combination with an improvement in signs and symptoms of congestion. Based on these observations, the Taskforce of the 2023 focused update provided a class I (level of evidence B) recommendation for hospitalized heart failure patients to rapidly uptitrate evidence-based treatment before discharge and during frequent and careful follow-up visits in the first 6 weeks following a HF hospitalization to reduce the risk of HF rehospitalization or death. Even though the data from STRONG-HF were not yet available, the 2022 AHA/ACC/HFSA Guideline for the Management of Heart Failure provides a class I (level of evidence B) recommendation for the initiation or uptitration of guideline-directed medical therapies during hospitalization after clinical stability is achieved.4Heidenreich PA, Bozkurt B, Aguilar D, Allen LA, Byun JJ, Colvin MM, Deswal A, Drazner MH, Dunlay SM, Evers LR, Fang JC, Fedson SE, Fonarow GC, Hayek SS, Hernandez AF, Khazanie P, Kittleson MM, Lee CS, Link MS, Milano CA, Nnacheta LC, Sandhu AT, Stevenson LW, Vardeny O, Vest AR, Yancy CW. 2022 AHA/ACC/HFSA Guideline for the Management of Heart Failure: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. J Card Fail 202;28(5):810-830.Google Scholar Intravenous iron supplementation in symptomatic patients with HFrEF and HFmrEF, and iron deficiency, to alleviate HF symptoms and improve quality of life is upgraded from a class II (level of evidence A) to class I (level of evidence A) recommendation. In addition, the recommendation to provide intravenous iron supplementation with ferric carboxymaltose or ferric derisomaltose in symptomatic patients with HFrEF and HFmrEF, and iron deficiency, to reduce the risk of a heart failure hospitalization is upgraded from class IIa (level of evidence B) to class IIa (level of evidence A). These upgrades are related to the recent publications of IRONMAN and AFFIRM-AHF.11Kalra PR Cleland JGF Petrie MC Thomson EA Kalra PA Squire IB et al.Intravenous ferric derisomaltose in patients with heart failure and iron deficiency in the UK (IRONMAN): an investigator-initiated, prospective, randomised, open-label, blinded-endpoint trial.Lancet. 2022; 400: 2199-2209https://doi.org/10.1016/S0140-6736(22)02083-9Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar,12Ponikowski P Kirwan BA Anker SD McDonagh T Dorobantu M Drozdz J et al.Ferric carboxymaltose for iron deficiency at discharge after acute heart failure: a multicentre, double-blind, randomised, controlled trial.Lancet. 2020; 396: 1895-1904https://doi.org/10.1016/S0140-6736(20)32339-4Abstract Full Text Full Text PDF PubMed Scopus (336) Google Scholar IRONMAN showed a non-significant reduction of the composite of total (first and recurrent) HF hospitalizations and CV death in 1137 patients with mainly chronic HFrEF (LVEF<45%) who were treated for a mean of 2.7 years with i.v. ferric derisomaltose.11Kalra PR Cleland JGF Petrie MC Thomson EA Kalra PA Squire IB et al.Intravenous ferric derisomaltose in patients with heart failure and iron deficiency in the UK (IRONMAN): an investigator-initiated, prospective, randomised, open-label, blinded-endpoint trial.Lancet. 2022; 400: 2199-2209https://doi.org/10.1016/S0140-6736(22)02083-9Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar The results of AFFIRM-AHF were already available at the time of the 2021 ESC Guidelines.12Ponikowski P Kirwan BA Anker SD McDonagh T Dorobantu M Drozdz J et al.Ferric carboxymaltose for iron deficiency at discharge after acute heart failure: a multicentre, double-blind, randomised, controlled trial.Lancet. 2020; 396: 1895-1904https://doi.org/10.1016/S0140-6736(20)32339-4Abstract Full Text Full Text PDF PubMed Scopus (336) Google Scholar In addition, it was shown that a pre-specified COVID-19 analysis, censoring follow-up on September 2020, resulted in a borderline significant reduction in the risk of the primary endpoint with ferric derisomaltose. Yet, immediately after the presentation and publication of the 2023 focused update of the ESC guidelines, the results of HEART-FID were presented and published.13Mentz RJ Garg J Rockhold FW Butler J De Pasquale CG Ezekowitz JA Lewis GD O'Meara E Ponikowski P Troughton RW Wong YW She L Harrington J Adamczyk R Blackman N Hernandez AF Ferric Carboxymaltose in Heart Failure with Iron Deficiency.; HEART-FID Investigators.N Engl J Med. 2023 Aug 26; https://doi.org/10.1056/NEJMoa2304968Crossref Google Scholar This large randomized placebo controlled trial randomized 3065 patients with HFrEF and iron deficiency to ferric carboxymaltose or placebo. The composite primary hierarchical outcome of death or heart failure hospitalization at 1 year or change in 6-minutes walking distance at 6 months narrowly missed statistical significance. Fourteen years after the publication of FAIR-HF in 2009, a large number of randomized controlled trials on i.v. iron in patients with heart failure (mainly HFrEF) have been published. These trials show a consistent modest effect on hard clinical endpoints, but a clear effect on symptoms, exercise capacity and quality of life. These findings are well reflected by the current recommendations in the 2023 focused update of the ESC heart failure guidelines. However, there is a remarkable difference with the 2022 AHA/ACC/HFSA Guideline for the Management of Heart Failure. They provide a class 2a (level of evidence B) for using i.v. iron in patients with HFrEF to improve functional status and quality of life, and they provide no recommendation for i.v. iron to improve the risk of cardiovascular mortality or heart failure hospitalizations.4Heidenreich PA, Bozkurt B, Aguilar D, Allen LA, Byun JJ, Colvin MM, Deswal A, Drazner MH, Dunlay SM, Evers LR, Fang JC, Fedson SE, Fonarow GC, Hayek SS, Hernandez AF, Khazanie P, Kittleson MM, Lee CS, Link MS, Milano CA, Nnacheta LC, Sandhu AT, Stevenson LW, Vardeny O, Vest AR, Yancy CW. 2022 AHA/ACC/HFSA Guideline for the Management of Heart Failure: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. J Card Fail 202;28(5):810-830.Google Scholar Somewhat unexpected, this guideline update for the diagnosis and treatment of acute and chronic heart failure also provides class I (level of evidence A) recommendations for patients without heart failure. The recommendation is related to the prevention of heart failure in patients with type 2 diabetes and chronic kidney disease. These patients have an increased risk of development of heart failure. Specific recommendations are provided for the use of SGLT2-inhibitors (empagliflozin and dapagliflozin) to prevent heart failure in patients with chronic kidney disease. This is based on two large outcome trials, DAPA-CKD and EMPA-kidney, both showing a reduction in kidney failure or cardiovascular death.14Heerspink HJL Stefansson BV Correa-Rotter R Chertow GM Greene T Hou FF et al.Dapagliflozin in patients with chronic kidney disease.N Engl J Med. 2020; 383: 1436-1446https://doi.org/10.1056/NEJMoa2024816Crossref PubMed Scopus (1831) Google Scholar,15The EMPA-KIDNEY Collaborative GroupEmpagliflozin in patients with chronic kidney disease.N Engl J Med. 2023; 388: 117-127https://doi.org/10.1056/NEJMoa2204233Crossref PubMed Scopus (225) Google Scholar The prevention of heart failure hospitalizations was only part of the secondary endpoints, while in EMPA-kidney, the risk of cardiovascular death or heart failure hospitalization was not even significantly reduced. The class I (level of evidence A) recommendation to treat patients with T2DM and CKD with finerenone to reduce the risk of HF hospitalization is based on two large outcome trials: FIGARO and FIDELIO-DKD.16Bakris GL Agarwal R Anker SD Pitt B Ruilope LM Rossing P et al.Effect of finerenone on chronic kidney disease outcomes in type 2 diabetes.N Engl J Med. 2020; 383: 2219-2229https://doi.org/10.1056/NEJMoa2025845Crossref PubMed Scopus (797) Google Scholar,17Pitt B Filippatos G Agarwal R Anker SD Bakris GL Rossing P et al.Cardiovascular events with finerenone in kidney disease and type 2 diabetes.N Engl J Med. 2021; 385: 2252-2263https://doi.org/10.1056/NEJMoa2110956Crossref PubMed Scopus (389) Google Scholar FIDELIO-DKD showed a significant reduction of the development of kidney failure, and showed no significant reduction in the risk of heart failure hospitalizations. FIGARO enrolled 7436 patients with CKD and T2DM and showed that after 3.4 years of treatment, finerenone reduced the rate of the primary outcome, CV death, non-fatal myocardial infarction, non-fatal stroke, or HF hospitalization. Finerenone significantly reduced the risk of heart failure hospitalization by 29%. Since none of these trials were primarily designed to study the prevention of incident heart failure, one might question the validity of their class I (level of evidence A) recommendations. The 2022 AHA/ACC/HFSA Guideline for the Management of Heart Failure provide much broader guidance to prevent heart failure in so-called stage A and B heart failure, which are stages before symptomatic heart failure develops.4Heidenreich PA, Bozkurt B, Aguilar D, Allen LA, Byun JJ, Colvin MM, Deswal A, Drazner MH, Dunlay SM, Evers LR, Fang JC, Fedson SE, Fonarow GC, Hayek SS, Hernandez AF, Khazanie P, Kittleson MM, Lee CS, Link MS, Milano CA, Nnacheta LC, Sandhu AT, Stevenson LW, Vardeny O, Vest AR, Yancy CW. 2022 AHA/ACC/HFSA Guideline for the Management of Heart Failure: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. J Card Fail 202;28(5):810-830.Google Scholar The recommendations of the 2022 AHA/ACC/HFSA Guideline includes the use of SGLT2-inhibitors, but also the treatment of hypertension and cardiovascular disease. Overall, the Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology provide balanced and well-validated novel recommendations for the treatment of heart failure, based on novel evidence that has appeared since the presentation of the 2021 ESC Heart Failure guidelines.1McDonagh TA Metra M Adamo M Gardner RS Baumbach A Böhm M Burri H Butler J Čelutkienė J Chioncel O Cleland JGF Crespo-Leiro MG Farmakis D Gilard M Heymans S Hoes AW Jaarsma T Jankowska EA Lainscak M Lam CSP Lyon AR McMurray JJV Mebazaa A Mindham R Muneretto C Francesco Piepoli M Price S Rosano GMC Ruschitzka F Skibelund AK ESC Scientific Document Group2023 Focused Update of the 2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure.Eur Heart J. 2023 Aug 25; : ehad195https://doi.org/10.1093/eurheartj/ehad195Crossref Google Scholar,18McDonagh TA Metra M Adamo M Gardner RS Baumbach A Böhm M et al.2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure.Eur Heart J. 2021; 42: 3599-3726https://doi.org/10.1093/eurheartj/ehab368Crossref PubMed Scopus (3736) Google Scholar Most importantly, SGLT2-inhibitors now have a class IA recommendation for the treatment of patients with HFmrEF and HFpEF. After so many years, we finally have an evidence-based treatment for our increasing number of patients with HFmrEF and HFpEF. Second, we have learned a lot about the treatment of acute heart failure. The addition of hydrochlorothiazide and acetazolamide to standard loop diuretics improves decongestion, but this was not accompanied by a reduction in symptoms and heart failure rehospitalizations. At the same time, there is increasing evidence that initiation and uptitration of guideline directed chronic heart failure therapies during a hospitalization for acute heart failure improves clinical outcomes. Third, the evidence for a beneficial effect of i.v. iron in patients with HFrEF to improve symptoms and exercise capacity has become stronger, and additional studies have confirmed a potential modest beneficial effect on reducing the risk of heart failure hospitalizations. Finally, appropriate treatment of patients at high risk of heart failure might reduce the development of heart failure. Heart failure remains a syndrome that is associated both with disabling symptoms and a high morbidity and mortality. However, if we sensibly apply these recommendations in clinical practice, we can substantially lower the worldwide burden of heart failure.

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