Recent Leaps in Heart Failure Therapy Spur ESC Guideline-Focused Update

September 12, 2023

Two years is a long time in the world of heart failure (HF) management, enough to see publication of more than a dozen studies with insights that would supplant and expand key sections a far-reaching European Society of Cardiology (ESC) clinical practice guideline on HF unveiled in 2021.

"Back in 2021, we had three and a half decades of data to consider," but recent years have seen "an amazing amount of progress" that has necessitated some adjustments and key additions, including several Class I recommendations, observed Roy S. Gardner, MB, ChB, MD, Golden Jubilee National Hospital, Clydebank, United Kingdom.

Much of that recent progress, driven by trials like EMPEROR-Preserved, DELIVER, STRONG-HF, and IRONMAN, has been crystalized into the "2023 Focused Update of the 2021 ESC Guidelines" on HF management, which Gardner helped unveil over several days at the European Society of Cardiology (ESC) Congress 2023, held in Amsterdam, the Netherlands.

The new document was also published in the European Heart Journal during the ESC sessions. Gardner is a co-author on both the 2021 and 2023 documents.

The task force that was charged with the focused update's development "considered a large number of trials across the spectrum of acute chronic heart failure and the comorbidities associated with it," Ultimately, it considered only those with "results that would lead to new or changed Class I or Class IIa recommendations," noted Theresa A. McDonagh, MD, during the ESC sessions.

McDonagh, of King's College Hospital, London, United Kingdom, chaired the task force and led the document's list of authors along with Marco Metra, MD, University of Brescia, Italy.

Chronic HF Management

The 2021 document's "beautiful algorithm" on managing HF with reduced ejection fraction (HFrEF), that is HF with an LVEF <40%, had helped enshrine the expeditious uptitration of the "four pillars" of drug therapy as a top management goal. That remains unchanged in the focused update, Gardner noted.

But the new document gives a boost to recommendations for HF with mildly reduced ejection fraction (HFmrEF), characterized by an LVEF >40% to <50%. For that, the 2021 document recommended three of the four pillars of HF medical therapy: beta blockers, mineralocorticoid receptor antagonists (MRA), renin-angiotensin system (RAS) inhibitors.

The focused update, however, adds the fourth pillar — SGLT2 inhibitors — to core therapy for both HFmrEF and HF with preserved ejection fraction (HFpEF), the latter defined by an LVEF >50%. Publication of trials supporting those new recommendations had narrowly missed availability for the 2021 document.

EMPEROR-Preserved, for example, was published during the same ESC 2021 sessions that introduced the 2021 guidelines. Its patients with HFpEF (which at the time included patients meeting the current definition of HFmrEF) assigned to the SGLT2 inhibitor empagliflozin (Jardiance) showed a 21% reduction in risk for a composite primary endpoint that was driven by the HF-hospitalization component.

"This wasn't a fluke finding," Gardner said, as the following year saw publication of the DELIVER trial, which resembled EMPEROR-Preserved in design and outcomes using the SGLT2 inhibitor dapagliflozin (Farxiga).

The two trials, backed up by meta-analyses that also included DAPA-HF and other studies, suggested as well that the two SGLT2 inhibitors "work across the spectrum of ejection fraction," Gardner said.

The 2023 focused update indicates an SGLT2 inhibitor, either empagliflozin or dapagliflozin, for patients with either HFmrEF or HFpEF to reduce the risk of HF hospitalization or cardiovascular death. Both recommendations are of Class I, level of evidence A.

The new indications make SGLT2 inhibitors and diuretics (as needed for fluid retention) the only drugs for HFmrEF or HFpEF with a Class I recommendation. Previously established "rather weaker" Class IIb recommendation for RAS inhibitors, MRAs, and beta blockers that had been "based on subgroup analyses of neutral trials" remained unchanged in the focused update, McDonagh noted.

Patients Hospitalized With HF

The 2021 guidelines had recommended that patients hospitalized with acute HF be started on evidence-based meds before discharge and that they return for evaluation 1 to 2 weeks after discharge. But the recommendation was unsupported by randomized trials.

That changed with the 2022 publication of STRONG-HF, in which a strategy of early and rapid uptitration of guideline-directed meds, initiated predischarge regardless of LVEF, was led to a one third reduced 6-month risk for death or HF readmission.

Based primarily on STRONG-HF, the focused update recommends "an intensive strategy of initiation and rapid up-titration of evidence-based treatment before discharge and during frequent and careful follow-up visits in the first 6 weeks after hospitalization" to reduce readmission and mortality: Class I, level of evidence B.

"There was a large consensus around this recommendation," said STRONG-HF principal investigator Alexandre Mebazaa, MD, PhD, a co-author of both the 2021 and 2023 documents. Conducted before the advent of the four pillars of drug therapy, sometimes called quartet therapy, the trial's requirement for evidence-based meds didn't include SGLT2 inhibitors.

The new focused update considers the new status of those agents, especially with regard to their benefits independent of LVEF. So, it completed the quartet by adding empagliflozin or dapagliflozin to the agents that should be initiated predischarge, observed Mebazaa, University Hospitals Saint Louis‐Lariboisière, Paris, France, at the focused-update's ESC 2023 sessions.

The new document also follows STRONG-HF with its emphasis on "frequent and careful follow-up" by recommending certain clinical and laboratory evaluations known to be prognostic in HF. They include congestion status, blood pressure, heart rate, natriuretic peptide (NT-proBNP) and potassium levels and estimated glomerular filtration rate.

Mebazaa stressed the importance of monitoring NT-proBNP after discharge. "What we saw in STRONG-HF is that sometimes the clinical signs do not necessarily tell you that the patient is still congested."

After discharge, he said, NT-proBNP levels "should only go down." So, knowing whether NT-proBNP levels "are stable or increasing" during the med optimization process can help guide diuretic dosing.

HF With Comorbidities

The new document includes two new Class I recommendations for patients with HF and both type-2 diabetes and chronic kidney disease (CKD) based on several recent randomized trials and meta-analyses.

The focused update recommends SGLT2 inhibitors as well as the selective, non-steroidal MRA finerenone (Kerendia) in HF patients with CKD and type-2 diabetes. Both Class I recommendations are supported by a level of evidence A.

The SGLT2 indication is based on DAPA-CKD and EMPA-KIDNEY plus meta-analyses that included those trials along with others. The recommendation for finerenone derives from the FIDELIO-DKD and FIGARO-DKD trials and a pooled analysis of the two studies.

The 2023 focused update also accounts for new clinical-trial insights for patients with HF and iron deficiency. The 2021 document featured recommendations for the diagnosis and iron-repletion therapy in such cases, but only as Class IIa or at lower low levels of evidence. The focused update considers more recent studies, especially IRONMAN and some meta-analyses.

The 2023 document indicates intravenous iron supplementation for symptomatic patients with iron deficiency and either HFrEF or HFmrEF to improve symptoms and quality of life (Class I, level of evidence A), and says it should be considered (Class IIa, level of evidence A) to reduce risk for HF hospitalization.

When the task force assembled to plan the 2023 focused update, Gardner observed, "The first thing we thought about was the nomenclature around the phenotyping of heart failure."

Although the 2021 guidelines relied fundamentally the distinctions between HFrEF, HFmrEF and HFpEF, it had become apparent to some in the field that some meds, especially the SGLT2 inhibitors, were obscuring their LVEF-based boundaries, at least with respect to drug therapy.

The 2023 document's developers, Gardner said, seriously considered changing the three categories to two, that is HFrEF and — to account for all other heart failure — HF with normal ejection fraction (HFnEF).

That didn't happen, although the proposal was popular within the task force. Any changes to the 2021 document would require a 75% consensus on the matter, Gardner explained. When the task force took a vote on whether to change the nomenclature, he said, 71% favored the proposal.

Disclosures for members of the task force can be found in a supplement to the published 2023 Focused Update, available here.

European Society of Cardiology (ESC) Congress 2023: Focused update of the 2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure. Presented August 25, 2023. Full text

Eur Heart J. Published online August 25, 2023. Full text

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