Updates on Acute and Chronic Heart Failure Guidelines

This guide does not nullify the individual responsibility of health professionals in making appropriate and accurate decisions considering the health condition of each patient, sharing the decision with the patient or their caregiver whenever appropriate and/or necessary. It is also the responsibility of the health professional to verify the standards and regulations for medicines and devices currently applicable in each country of prescription and, where appropriate, to respect the ethical standards of their profession.

ESC recommendations represent the ESC’s official position on a given topic, which are updated periodically. The ESC Policies and Procedures for the formulation and issuance of its guidelines can be found on the ESC website ( https://www.escardio.org/Guidelines ). This specific update provides new information and recommendations from the 2021 ESC Guide.

Since the publication of the 2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure (HF), several randomized controlled trials have been published that should change the treatment guidelines before completing the next scheduled guidelines. This 2023 update considers changes in recommendations for the treatment of HF due to the emergence of new evidence (up to March 31, 2023).

The main randomized controlled clinical trials and meta-analyses were presented and discussed. Trials were included by vote, presented and discussed in detail before consensus was reached on any possible class of recommendations and level of evidence to be assigned.

The Working Group considered and discussed the following new trials and any meta-analyses that include them: ADVOR (Acetazolamide in Decompensated HF with Volume Overload), CLOROTIC (Combination of Loop Diuretics with Hydrochlorothiazide in Patients with Acute HF), COACH (Comparison Outcomes and Access to HF Care), DAPA-CKD (Dapagliflozin and Prevention of Adverse Outcomes in Chronic Kidney Disease), DELIVER (Evaluating Dapagliflozin to Improve the Lives of HF Patients with Preserved Ejection Fraction) , EMPA-KIDNEY (EMPAglifloz1 time/day to evaluate cardiorenal outcomes in patients with chronic kidney disease), EMPEROR-Preserved (Empagliflozin outcome trial in patients with chronic HF and preserved ejection fraction), EMPULSE (Empagliflozin in hospitalized patients with acute HF stabilized, FIDELIO-DKD (Finerenone in progressive diabetic nephropathy), FIGARO-DKD (Finerenone in reducing cardiovascular mortality and morbidity in diabetic nephropathy), IRONMAN (Effectiveness of treatment with intravenous iron vs. standard care in patients with HF and iron deficiency), PIVOTAL (Proactive IV iron therapy in patients on hemodialysis) REVIVED-BCIS2 (Revascularization for ischemic ventricular dysfunction), STRONG-HF (HF: heart failure) (Safety, tolerance, efficacy of Rapid Optimization Assisted by NT-proBNP Testing, of Heart Failure Therapies), TRANSFORM-HF (Comparison of Torsemide with Furosemide for the Management of HF) and, TRILUMINATE Pivotal (Clinical Study to Evaluate Cardiovascular Outcomes in Patients Treated with the Pyrovtal Tricuspid Valve Repair System).

Trials that would have an impact on the recommendations of other ESC guidelines in preparation were not included to avoid discordance. This is the case of REVIVED-BCIS2, which will be considered in the next guidelines on chronic coronary syndrome.

In addition to selecting trials to include, the Working Group also discussed the change in the description of HF with preserved ejection fraction (HFpEF) to HF with normal ejection fraction (HFnEF) and the ejection fraction threshold. left ventricular (LVEF) for HFnEF. Ultimately, the Working Group decided to retain the term HFpEF and abandoned the intention to make any future changes to the terminology used in the upcoming ESC HF Guidelines.

When assigning recommendations, as in the 2021 ESC HF Guidelines, the Task Force focused on the primary endpoints of the trials. This means that, for most HF trials, effective treatments are those that reduce the risk of time to first occurrence of the combination of HF hospitalization or cardiovascular (CV) death. Of course, that doesn’t mean that each component can be reduced individually.

All new recommendations are in addition to the ESC HF 2021 recommendations and the modified recommendations replace those of the ESC HF 2021 guidelines. After due deliberation, the Working Group decided to update the recommendations for the following sections of the ESC H guidelines[ F 2021:

• Chronic HF : HF with slightly reduced ejection fraction (HFrEF) and HFpEF

• Acute HF

• Comorbidities and prevention of HF.

The original 2021 ESC HF guideline adopted the classification of chronic HF based on LV ejection fraction (LVEF).

For those with HFrEF (reduced) and LVEF between 41% and 49%, the Task Force made weak recommendations for disease-modifying therapies that have class I evidence for use in HFrEF. The Working Group made no recommendations for the use of sodium-glucose cotransporter 2 (SGLT2) inhibitors.

For those with HFpEF (preserved), the Task Force made no recommendations for the use of HFrEF-modifying therapies since clinical trials with angiotensin-converting enzyme inhibitors (ACE inhibitors), angiotensin receptor blockers (ARBs), Mineralocorticoid receptor antagonists (MRAs) and angiotensin-neprilysin receptor inhibitors (ARNIs) did not meet their primary endpoints.

Two trials of SGLT2 inhibitors, empagliflozin and dapagliflozin , have been published in patients with HF and LVEF >40%, which justify an update of the recommendations, both for HFrEF and HFpEF.

The first trial was EMPEROR-Preserved, which enrolled 5988 patients with HF (NYHA Class II-IV [New York Heart Association]) whose LVEF was >40% and had elevated plasma concentrations of N-terminal pro-B-type natriuretic peptide. (NT-proBNP) (>300 pg/ml for those with sinus rhythm or >900 pg/ml in the presence of atrial fibrillation). They were randomly assigned to empagliflozin (10 mg, once/day) or placebo.

The primary outcome was a composite of HF hospitalization or CV death. After a median follow-up of 26.2 months, empagliflozin reduced the primary endpoint. The effect was primarily driven by a reduction in HF hospitalizations with empagliflozin but no reduction in CV death. The effects were observed in patients with and without DM2. Most patients were taking ACEI/ARB/ARNI (80%) and a ß-blocker (86%); 37% received an ARM.

One year later, the DELIVER trial reported the effects of dapagliflozin (10 mg, once/day) compared with placebo in 6263 patients with HF. Patients had to have an LVEF >40% at the time of recruitment, but those with a previous LVEF ≤40% who had improved to >40% were also enrolled. Eligible patients were outpatients and those who had been hospitalized for HF. A mandatory inclusion criterion was an elevated concentration of natriuretic peptides (≥300 pg/ml in sinus rhythm or ≥600 pg/ml in atrial fibrillation).

Dapagliflozin reduced the primary endpoint of death or worsening HF (HF hospitalization or HF emergency visit). Again, the main effect was due to a reduction in worsening HF and no reduction in CV death. Dapagliflozin also improved symptom burden. The effects were independent of T2DM status.

The efficacy of dapagliflozin was consistent in those who remained symptomatic despite improvement in LVEF, suggesting that these patients may also benefit from SGLT2 inhibitors. The benefit of dapagliflozin was also consistent across the LVEF range studied.

Previous use of therapies for concomitant CV disease was high: 77% were taking a loop diuretic, 77% were taking an ACEI/ARB/ARNI, 83% were taking a ß-blocker, and 43% were taking an MRA.

A subsequent meta-analysis of aggregate data from the 2 trials confirmed a 20% reduction in the composite endpoint of CV death or first HF hospitalization. CV death was not significantly reduced. Heart rate at hospitalization was reduced by 26%. There were consistent reductions in the primary endpoint across the LVEF range studied. Another individual patient data meta-analysis incorporating data from DAPA-HF (dapagliflozin and prevention of adverse outcomes in HF) in HFrEF with DELIVER confirmed that there was no evidence that the effect of dapagliflozin was different by ejection fraction.

Dapagliflozin was also shown to reduce the risk of death from CV causes. The Working Group discussed the results of these trials in depth, focusing particularly on the fact that both met their primary endpoints, but did so by reducing HF hospitalizations and not CV death.

The Working Group decided to make recommendations on the primary endpoints. This is consistent with all recommendations made in the 2021 ESC HF guidelines but 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 HF diagnostic algorithm in the ESC HF 2021 guidelines involves the high concentration of natriuretic peptides. Based on these 2 trials, the following recommendations were made for HFrEF and HFpEF.

The treatment of acute HF and a scientific statement from the Heart Failure Association on HF were described in the ESC HF 2021 guideline. Based on these publications, trials have been carried out with diuretics and also on management strategies for patients with acute HF. The results are summarized as follows.

> Diuretics

ADVOR was a multicenter, randomized, parallel-group, double-blind, placebo-controlled study that enrolled 519 patients with acute HF, clinical signs of volume overload (edema, pleural effusion, or ascites), and an NT-proBNP level (portion N terminus of brain natriuretic peptide) >1000 pg/ml or a B-type natriuretic peptide level >250 pg/ml. Randomly distributed, patients received IV acetazolamide (500 mg, once/day) or placebo added to treatment with a standardized IV loop diuretic solution.

The primary endpoint, successful decongestion defined as the absence of signs of volume overload, 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. within 3 days of randomization and without an indication to increase decongestive therapy. One rehospitalization for HF or death from all causes occurred. In 76 patients (29.7%) in the acetazolamide group and in 72 patients (27.8%) in the placebo group.

The length of hospital stay was 1 day shorter with acetazolamide compared with placebo). No difference was found between the acetazolamide and placebo groups. for other outcomes and adverse events. Although these results may support the addition of acetazolamide to a standard diuretic regimen. More data on outcomes and safety are needed to help decongest. The CLOROTIC trial included 230 patients with acute HF and randomized to oral hydrochlorothiazide (25 to 100 mg/day, depending on estimated glomerular filtration rate: eGFR) or placebo, in addition to IV furosemide.

The trial had 2 coprimary endpoints, change in body weight and change in patient-reported dyspnea from baseline to 72 h after randomization. Patients treated with hydrochlorothiazide had a greater decrease in body weight at 72 hours compared to those receiving placebo. The changes in patients with dyspnea were similar between the 2 groups. There was an increase in serum creatinine that occurred more frequently in patients treated with hydrochlorothiazide (46.5%) than in those receiving placebo (17.2%).

Rates of HF rehospitalization and all-cause death were similar between groups, as was length of stay. The lack of an impact on clinical outcomes precludes any recommendations in the present guideline update. More data on outcomes and safety are needed.

Sodium-glucose cotransporter 2 inhibitors EMPULSE tested the efficacy of early initiation of empagliflozin in patients hospitalized for acute HF. The primary endpoint was “clinical benefit,” defined using a hierarchical combination of death from any cause, number of HF events, and time to first HF event, or a ≥5-point change difference from baseline in the total Kansas City Cardiomyopathy Questionnaire symptom score at 90 days, assessed using the “win-ratio” index method (NT: gain analysis). HF events were defined as HF hospitalizations, urgent HF visits, and unplanned HF outpatient visits.

An HF-related event was considered only if there was a worsening of HF signs and symptoms with treatment intensification (defined as an increase in oral or IV diuretics, increase in a vasoactive agent, or initiation of mechanical or surgical intervention). ). Patients were randomized in the hospital when they were 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 met in more patients treated with empagliflozin than placebo. Efficacy was independent of LVEF and diabetes status.

From the safety aspect , the rate of adverse events was similar in both treatment groups. These results are consistent with those found with SGLT2 inhibitors in patients with chronic HF, regardless of LVEF, and also in those recently hospitalized for HF, once they were clinically stable. However, caution should be exercised in patients with type 2 diabetes mellitus (T2DM) at risk of ketoacidosis, particularly those treated with insulin, when reducing carbohydrate intake or changing insulin dosage. SGLT2 inhibitors are not indicated in patients with type 1 diabetes.

Since the last guidelines, 2 large trials have been published: COACH and STRONG-HF.

> Admission phase

The COACH trial was a cross-sectional, stepwise, cluster-randomized study and included 5452 patients (2972 during the control phase and 2480 during the intervention phase) enrolled at 10 centers in Ontario, Canada. During the intervention phase, hospital staff used the Emergency Heart Failure Mortality Risk Grade 30 Day Mortality-ST Depression (’EHMRG30-ST’) to determine whether patients were at low, intermediate, or high risk of death within 7 days. days or within 30 days.

The study protocol recommended early discharge of low-risk patients (≤3 days) and treated with standardized outpatient care, with follow-up of up to 30 days while it was recommended that intermediate- and high-risk patients be admitted to Hospital. Although early discharge occurred at a similar rate in the intervention and control groups (57% vs. 58%), the trial was able to show a 12% reduction in the outcome of all-cause death or CV hospitalization in the group primary care interventionist, compared to the control arm consistent with a favorable effect of post-discharge care. The trial may need further multinational confirmation before a recommendation can be included in a guideline.

> Phases prior to discharge and first phases after discharge

The importance of pre-discharge and early post-discharge evaluation in patients hospitalized for an episode of acute HF was already underlined in the original 2021 ESC HF guideline.

Recently, the STRONG-HF trial demonstrated the safety and efficacy of an approach based on initiating and titrating oral medical treatment for HF within 2 days before planned hospital discharge and at follow-up visits planned shortly after discharge. In this trial, 1078 patients hospitalized for acute HF who were not yet receiving full doses of evidence-based HF treatment and were hemodynamically stable, with elevated NT-proBNP concentrations at screening (>2500 pg/ml) ) and a >10% decrease in concentration between screening and randomization, before discharge they were randomly assigned to usual care or intensive care.

Patients in the intensive care group received early and rapid intensification of oral HF treatment with ACEIs (or ARBs) or ARNIs, β-blockers, and MRAs. The goal of the first titration visit, which occurred within 48 h before hospital discharge, was to achieve at least half of the recommended drug target doses. Titration to full target doses of oral therapies was attempted within 2 weeks of discharge, with appropriate measurements for safety monitoring.

At follow-up visits, in addition to the physical and biochemical examination, evaluations such as measurement of NT-proBNP were performed at 1, 2, 3, and 6 weeks after randomization, to evaluate the safety and tolerance of medical treatment. Patients assigned to intensive care were more likely to receive full doses of oral treatments than those in the usual care group (ACEIs 55% vs. 2%, β-blockers 49% vs. 4%, and MRAs 84% ​​vs. 46%). The study was stopped early due to the benefits obtained. At 180 days, the primary outcome of readmission for HF or death from all causes occurred in 15.2% of the intensive treatment group and 23.3% of the usual care group.

Readmissions for HF decreased while death from all causes remained unchanged. Similar rates of serious adverse events (16% vs. 17%) and fatal adverse events (5% vs. 6%) were observed in each group. Based on the results of STRONG-HF, initial intensive care and rapid dose escalation of oral HF therapy, and close monitoring of acute HF hospitalization during the first 6 weeks after discharge, are recommended to reduce HF readmissions or death from all causes.

During follow-up visits, special attention should be paid to symptoms and signs of congestion, blood pressure, heart rate, NT-proBNP values, potassium, and eGFR.

The STRONG-HF trial has several limitations. First, the population was carefully selected based on baseline NT-proBNP concentrations and their decline during hospitalization. Second, most patients in the control group received less than half of the full optimal doses of ACE-I/ARB/ARNI and β-blockers and, although similar to many real-world clinical settings, their relative undertreatment may have favored the high-intensity care arm. Third, the study was initiated before current evidence and recommendations for SGLT2 inhibitors, which were not mandated in the protocol.

> Chronic kidney disease and type 2 diabetes mellitus

ESC HF 2021 issued recommendations for the prevention of HF in patients with diabetes. This update provides new recommendations for the prevention of HF in patients with chronic kidney disease (CKD) and T2DM. Previous trials have demonstrated the effects of ARBs in preventing HF events in patients with diabetic nephropathy. Both the Kidney Disease: Improving Global Outcomes (KDIGO) and the 2022 American Diabetes Association Standards of Medical Care in Diabetes recommendations indicate treatment with an ACEI or an ARB for patients with CKD, diabetes, and hypertension or albuminuria.

> Sodium-glucose cotransporter 2 inhibitors

Recently, 2 randomized controlled trials that were suspended early for reasons of efficacy, and a meta-analysis, were published. DAPA-CKD was a multicenter, double-blind, placebo-controlled, randomized trial that included diabetic and non-diabetic patients with urinary problems, albumin-creatinine ratio ≥200 mg/g and eGFR 25 to 75 ml/min/1.73 m2 , who were randomly assigned 1:1 to 10 mg of dapagliflozin, once/day or placebo.

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 combination of sustained eGFR decline ≥50%, end-stage renal disease or kidney-related disease, or CV death, was observed by 39% with dapagliflozin. compared to placebo.

Furthermore, the risk of the secondary outcome of HF hospitalization or CV death was decreased with dapagliflozin compared with placebo. EMPA-KIDNEY enrolled a larger group of CKD patients and compared them with those in 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 an albumin:creatinine ratio in urine ≥200 mg/g.

Patients were randomized 1:1 to receive empagliflozin 10 mg once/day or placebo. Overall, 658 of the 6609 enrolled patients (10%) had a history of HF. During a median follow-up of 2 years, a reduction in the primary composite endpoint of kidney disease progression or CV death was observed. The risk of HF hospitalization or CV death was not significantly reduced.

DAPA-CKD, EMPA-KIDNEY, CREDENCE (Canagliflozin and renal events in diabetes with clinical evaluation of established nephropathy) and SCORED (Effect of sotagliflozin on cardiovascular and renal health in patients with T2DM and moderate renal failure who are at cardiovascular risk) recently were included in a meta-analysis with CI trials. When HF and CKD trials were included, the reduction in HF hospitalizations and CV death was similar, regardless of the history of diabetes in patients with T2DM. However, the results were not significant in patients without diabetes when only CKD trials were included.

Based on these results, SGLT2 inhibitors are recommended in patients with CKD and T2DM, and with additional characteristics of participants in these trials, including an eGFR >20–25 ml/min/1.73 m2, to reduce risk of hospitalization for HF or CV death.

> Finerenone

Finerenone is a selective non-steroidal MRA that was tested in 2 trials in patients with diabetic nephropathy. The FIDELIO-DKD trial enrolled 5734 patients with a urinary albumin:creatinine ratio of 30 to 300 mg/g, an eGFR of 25 to 60 mL/min/1.73 m2, and diabetic retinopathy or urinary disease with an albumin:creatinine ratio of 300-5000 mg/g and an eGFR of 25-75 ml/min/1.73 m2.

The primary outcome of the trial, assessed in a time-to-event analysis, was a composite of renal failure, ≥40% decline in eGFR from baseline over a period of ≥4 weeks, or death from renal causes. Renal failure was defined as end-stage renal disease or eGFR <15 ml/min/1.73 m2.

End-stage renal disease was defined as initiation of long-term dialysis (for ≥90 days) or kidney transplantation. The trial’s primary endpoint in the finerenone group was reduced by 18% compared to placebo, over a median follow-up of 2.6 years. With this drug there was no evidence of reduction in hospitalizations for HF vs. placebo, although finerenone was associated with a lower occurrence of the key secondary endpoint, a composite of CV death, nonfatal myocardial infarction, stroke, and hospitalization for HF.

Patients with HFrEF and NYHA (New York Heart Association) class II-IV HF were excluded from this study. However, asymptomatic patients or patients with NYHA class I HFrEF or those with HFrEF or HFpEF could be enrolled, so that 7.7% of the included patients had a history of HF. The effects of finerenone on combined CV and renal outcomes, including HF hospitalizations, were independent of a prior history of HF.

In the most recent FIGARO-DKD trial, the primary outcome, assessed in a time-to-event analysis, was a composite of CV death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for HF. The trial enrolled adult patients with T2DM and CKD treated with ACEIs at the maximum tolerated dose. CKD was defined by 1 of 2 sets of criteria: persistent, moderately elevated albuminuria (urine albumin:creatinine ratio 30 to <300 mg/g) and an eGFR of 25 to 90 mL/min/1.73 m2 (CKD in stage 2 to 4); or albuminuria and severely elevated urine albumin:creatinine ratio, 300 to 5000 mg/g) and an eGFR >60 ml/min/1.73 m2 (CKD stage 1-2).

Patients with a serum potassium level of ≤4.8 mmol/L at screening were required. The trial included 7,437 patients randomly assigned to finerenone or placebo. At a median follow-up of 3.4 years, rates of CV death, nonfatal myocardial infarction, nonfatal stroke, or HF hospitalization were lower in the treatment group compared with placebo. The benefit was driven by a numerically small but statistically significant lower incidence of HF hospitalization with finerenone compared with placebo, with no difference in CV death.

In the FIDELIO-DKD and FIGARO-DKD trials, the occurrence of hyperkalemia was greater in the finerenone group than in the placebo group. However, the rate of adverse events was similar between the two groups.

A prespecified pooled analysis at the individual patient level, including 13,026 patients with diabetic nephropathy with a median follow-up of 3 years in the FIDELIO-DKD and FIGARO-DKD trials, showed a reduction in the composite CV outcome, including CV death, non-stroke fatal, nonfatal myocardial infarction, and HF hospitalizations, as well as HF hospitalizations alone, with finerenone vs. placebo. Therefore, finerenone is recommended for the prevention of hospitalization for HF in patients with CKD and T2DM.

ESC HF 2021 made strong recommendations (COR I, LOE C) for the diagnosis of iron deficiency, moderate recommendations (COR IIa, LOE A) for improving HF symptoms, exercise tolerance and quality of life, and weak recommendations ( COR IIa, LOE B) to reduce hospitalizations due to HF, for treatment with ferric carboxymaltose.

IRONMAN is a new prospective, randomized, open-label, blinded trial, with endpoints that included patients with HF, LVEF ≤45%, and transferrin saturation <20% or serum ferritin <100 μg/L, who were randomly assigned 1: 1 to treatment with IV ferric derisomaltose or usual treatment. Patients included were primarily outpatients, although 14% were enrolled during a hospitalization for HF and 18% were hospitalized for HF in the previous 6 months. After a median follow-up of 2.7 years, the rate ratio for the primary endpoint, a composite of HF hospitalizations and total CV deaths (first and recurrent), was 0.82.

The total number of hospital admissions for HF was not significantly reduced with ferric derisomaltose vs. usual therapy. These results have been included in a meta-analysis of randomized controlled trials that compared the effects of IV iron administration with standard care or placebo in patients with HF and iron deficiency.

In the analysis by Graham et al. which included 10 trials with 3373 patients, IV iron reduced the composite of total hospitalizations for HF and CV death and first hospitalization for HF or CV death. There was no effect on CV mortality or all-cause mortality. Similar results were found in other meta-analyses. In the PIVOTAL trial, a high-dose IV iron regimen compared with a low-dose regimen reduced the occurrence of first and recurrent HF in patients undergoing dialysis for end-stage CKD.

According to recent trials and meta-analyses, IV iron supplementation is now recommended in patients with HFrEF or HFrEF and iron deficiency, to improve symptoms and quality of life. It should be taken into account that it reduces the risk of hospitalization due to HF. Iron deficiency was diagnosed by a low transferrin saturation (<20%) or a low concentration (<100 μg/L) of serum ferritin. In particular, in IRONMAN patients with hemoglobin >13 g/dl (in women) and >14 g/dl (in men) were excluded.

The new recommendations are as follows.