In this article we focus on areas of the European Society for Cardiology (ESC) heart failure guideline 2023 update that will be most relevant in the day-to-day management of patients with heart failure. These include an expanded indication for sodium-glucose cotransporter 2 (SGLT2) inhibitors and intravenous iron, together with rapid optimisation of foundation therapies. With important outcomes for patients, there will undoubtedly need to be modifications to service delivery to ensure that they are widely available for patient benefit.
Introduction
The European Society of Cardiology (ESC) heart failure guideline has undergone major updates every few years, with recent publications being in 2016 and 2021, respectively.1,2 Advances within heart failure care continue at pace, with presentation and publication of key randomised-controlled trials (RCTs) and meta-analyses being seen at the major cardiology scientific congresses. Given the likely impact of several trials on heart failure management and patient outcomes, the decision was made to publish a focused update in 2023 incorporating the most recent data.3 After robust review by the ESC guideline task force, only trials that might lead to alterations in the class I/II level of recommendations for heart failure management were selected for inclusion.
These classes of recommendation help healthcare professionals make decisions based on the available evidence and the consensus among experts. Class I recommendations (to be recommended) are based on high-quality evidence with general agreement that a treatment is beneficial. Class IIa recommendations (should be considered) have evidence that favour their usefulness. Class IIb recommendations (may be considered) have less well-established evidence. Class III recommendations (not recommended) are based on general consensus that a given treatment is not beneficial or even harmful.
The level of evidence is categorised as A, B, or C. Level A evidence is derived from multiple randomised trials or meta-analyses. Level B evidence comes from a single randomised clinical trial or a large non-randomised trial. Level C evidence is based on the consensus of experts’ opinions.
In this article, we focus on areas of the update that will likely be the most relevant in the day-to-day management of patients with heart failure. With important outcomes for patients, there will undoubtedly need to be modifications to service delivery to ensure that they are widely available for patient benefit. The first relates to the use of sodium-glucose cotransporter 2 (SGLT2) inhibitors in patients with heart failure and a left ventricular ejection fraction (LVEF) >40%: heart failure with mildly reduced ejection fraction (HFmrEF) when LVEF is 40–49%, and heart failure with preserved ejection fraction (HFpEF) when LVEF is 50% or higher. The second relates to the rapid optimisation of foundation therapies and the third, the expanded and upgraded indication for intravenous (IV) iron in patients with heart failure and reduced ejection fraction (LVEF <40%) or HFmrEF, and associated iron deficiency. This manuscript will highlight some of the changes to the ESC guideline recommendations and their relevance to day-to-day clinical practice. It is important to remember that guidelines do not detract from the responsibility of health professionals to engage in shared decision-making with patients and their caregivers, as appropriate, to make the best-informed decision for care.
SGLT2 inhibitors
Recent data
Two large RCTs of SGLT2 inhibitors in patients with HFmrEF and HFpEF have informed the guideline update. EMPEROR-Preserved (Empagliflozin Outcome Trial in Patients with Chronic Heart Failure with Preserved Ejection Fraction) recruited 5,988 patients with New York Heart Association (NYHA) class II–IV symptoms, elevated N-terminal pro-B-type naturietic peptide (NT-proBNP) levels and LVEF >40%.4 The patients were randomised to empagliflozin 10 mg once daily versus placebo with a primary composite end point of cardiovascular (CV) death or heart failure hospitalisation.
In 2022, the DELIVER trial (Dapagliflozin Evaluation to Improve Lives of Patients with Preserved Ejection Fraction Heart Failure) was published looking at the efficacy of dapagliflozin 10 mg once daily versus placebo in 6,263 patients with NYHA class II–IV symptoms and LVEF >40%.5 Again, patients were required to have an elevated NT-proBNP. The primary composite end point was that of CV death or worsening heart failure defined as heart failure hospitalisation or urgent heart failure visit. Table 1 summarises a number of key aspects of both the DELIVER and EMPEROR-Preserved trials. The statistically significant primary outcomes of the EMPEROR-Preserved and DELIVER trials were predominantly driven by reduction in heart failure admissions for heart failure. The benefits were irrespective of whether a patient had diabetes or not.
Table 1. Summary of the DELIVER and EMPEROR-Preserved trials
| DELIVER trial | EMPEROR-Preserved trial |
| Inclusion criteria | |
|
|
| Population and intervention | |
|
|
| Primary outcomes | |
| Composite of CV death, urgent visit or hospitalisation for heart failure, % Dapagliflozin 16.4% vs. 19.5% placebo 7.8 vs. 9.6 events per 100 patient-years HR 0.82; 95%CI 0.73 to 0.92, p<0.001 |
Composite of CV death or hospitalisation for heart failure, % Empagliflozin 13.8% vs. 17.1% placebo 6.9 vs. 8.7 events per 100 patient-years HR 0.79, 95%CI 0.69 to 0.90, p<0.001 |
| Secondary outcomes | |
| Total heart failure events and CV death Dapagliflozin < placebo HR 0.77, 95%CI 0.67 to 0.89, p<0.001 |
Hospitalisations for heart failure Empagliflozin < placebo HR 0.73, 95%CI 0.61 to 0.88, p<0.001 |
| Serious adverse events | |
| Dapagliflozin 43.5% vs. 45.5% placebo | Empagliflozin 47.9% vs. 51.6% placebo |
| Key: AF = atrial fibrillation; BMI = body mass index; CI = confidence interval; CV = cardiovascular; eGFR = estimated glomerular filtration rate; HR = hazard ratio; LAE = left atrial enlargement; LVEF = left ventricular ejection fraction; LVH = left ventricular hypertrophy; NT-proBNP = N-terminal pro-B-type naturietic peptide; NYHA = New York Heart Association | |
2023 recommendation
The SGLT2 inhibitors empagliflozin and dapagliflozin now have a Class I level A recommendation for patients with HFmrEF/HFpEF. For patients with HFmrEF, this is a higher class of recommendation than that given for angiotensin-converting enzyme inhibitors (ACEi), angiotensin-receptor blockers (ARB), angiotensin-receptor/neprilysin inhibitors (ARNI), mineralocorticoid-receptor antagonists (MRA) and beta blockers (all class IIb, level of evidence C).3 In the updated guideline, SGLT2 inhibitors are the only treatment with a Class I level A recommendation in patients with HFpEF.
Implications for practice
This change in recommendation has significant implications for how patients with heart failure are managed. Fortunately, both empagliflozin and dapagliflozin are relatively straightforward to use in clinical practice, with a single daily dose and little impact on blood pressure. While there may be an early decrease in estimated glomerular filtration rate (eGFR), due to mechanism of action, over time they have a protective effect on renal function. Both drugs have received a National Institute for Health and Care Excellence (NICE) Technology appraisal (TA) for treatment of patients with HFmrEF and HFpEF on the advice of a heart failure specialist (dapagliflozin TA902 June 2023, empagliflozin TA929 November 2023).
Given their benefit across the full range of LVEF, and that significant reduction on major adverse outcomes are seen very early in the trials (within weeks) it is the authors’ opinion that initiation should be considered in patients with high-risk features of heart failure (for example marked symptoms, clinical features of congestion and/or very high natriuretic peptide levels) while waiting for specialist assessment (e.g. via recommendation through the advice and guidance pathway). This may be alongside a diuretic.
Patients in the trials were recruited from outpatient and inpatient settings and healthcare professionals should look to commence SGLT2 inhibitors in symptomatic patients with heart failure as soon as possible to improve patient outcome, including reducing the risk of hospitalisation for heart failure. This includes initiation during acute hospitalisation for heart failure. SGLT2 inhibitors are recommended in all patients with HFmrEF, without contraindications, before any of the other specific heart failure treatments based on the weight of evidence. Noting the comorbidity profile of this group of patients, many will already be receiving disease-modifying drugs for other indications (e.g. for hypertension, ischaemic heart disease).
Management strategy for rapid use of foundation therapies
The STRONG-HF (Safety, Tolerability, and Efficacy of Rapid Optimization, Helped by NT-proBNP Testing of Heart Failure Therapies) trial showed us that early and rapid optimisation of heart failure medications in patients discharged after an acute heart failure episode was feasible and significantly improved outcomes. In this trial, 1,078 patients from 14 countries with acute heart failure who were haemodynamically stable were randomly allocated to receive standard care or high-intensity care. Nearly 90% were recruited from Africa and Russia. There were no exclusions based on LVEF, which was higher than 40% in about a third of patients. Around 16% of patients had LVEF of 50% or more.6 Patients in the high-intensity group were initially given half the optimal dose of heart failure medications in the hospital with rapid intensification of oral heart failure treatment within two weeks.
Results showed that an approach of early, rapid up-titration of foundation therapies in patients hospitalised with heart failure, compared with usual-care, reduced their six-month risk for death or heart failure readmission by 34% (p=0.0021). On the flip side, adverse events occurred in 41% of the high-intensity arm versus 29% of the usual-care arm, mainly related to low blood pressure, hyperkalaemia, and renal impairment. The trial was terminated early for benefit.
Medications included in rapid optimisation were a beta blocker, a MRA, and a renin–angiotensin-system inhibitor. Since SGLT2 inhibitors have single dose and no titration, most patients will be on full dose predischarge.
This high-intensity strategy has received class I recommendation for initiation and rapid up-titration of oral heart failure medications in the first six weeks following discharge. The prospect of implementation of this high-intensity strategy presents both opportunities and challenges. This will require close working between secondary and primary care and need local champions to help make change happen. To use the words of Winston Churchill “It is no use saying, we are doing our best. We have got to succeed in doing what is necessary.”
Intravenous iron for patients with heart failure
Recent data
IRONMAN (Effectiveness of Intravenous Iron Treatment Versus Standard Care in Patients With Heart Failure and Iron Deficiency) randomised patients with heart failure and LVEF <45% with either transferrin saturation (TSAT) <20% or serum ferritin <100 µg/L to IV ferric derisomaltose versus usual-care.7 The data showed a reduction in heart failure hospitalisations and CV death (hazard ratio [HR] 0.82, 95% confidence interval [CI] 0.66 to 1.02, p=0.07). Given the trial was markedly impacted by the COVID-19 pandemic, a pre-specified sensitivity analysis was performed (including 93% of the patients) and this showed HR 0.76, 95%CI 0.58 to 1.00, p=0.046, for the primary end point. These data in combination with the results of the previously published AFFIRM-AHF (a randomised, double-blind placebo-controlled trial comparing the effect of intravenous ferric carboxymaltose on hospitalisations and mortality in iron-deficient subjects admitted for acute heart failure) trial and other smaller studies were assessed in a meta-analysis by Graham et al. with 3,373 patients. Intravenous high-dose iron was associated with a significant reduction in a composite of heart failure hospitalisation and CV death (relative risk [RR] 0.75, 95%CI 0.61 to 0.93, p<0.01).8,9
2023 recommendation
It is now a Class I level A recommendation to offer IV iron for symptomatic relief and to help improve quality of life in patients with HFrEF and HFmrEF. The expert ESC task force also recommended the consideration of IV iron (ferric carboxymaltose or ferric derisomaltose) in this patient cohort to reduce the risk of heart failure hospitalisation (Class IIa).
Implications for practice
All patients with symptomatic HFrEF or HFmrEF should have their iron status checked periodically, including ferritin and TSAT. The guidelines have typically used ferritin <100 µg/L or TSAT <20% (if ferritin 100–299 µg/L) as the definition for iron deficiency. There are increasing data to suggest that patients with a TSAT <20% have most to gain (with little benefit, if any, for IV iron in patients with ferritin <100 µg/L but TSAT of 20% or more).10
Administering IV iron to hospitalised patients is more straightforward and, therefore, this group of patients should be assessed early in their admission to permit planning for treatment pre-discharge. Changing services to permit routine delivery of IV iron in cardiology outpatients may take time. If there is no availability in the cardiology department (e.g. day case wards, outpatients) then it is worth working with other departments who may have a mature IV iron service, such as in haematology, renal or gastroenterology, and utilise their pathways for patient benefit.
Conclusion
The 2023 heart failure update from the ESC highlights a major advancement in the management of HFmrEF and HFpEF with the Class I level A recommendation for the use of SGLT2 inhibitors to reduce heart failure hospitalisations and CV death. The relationship between iron deficiency and heart failure, and the opportunity to intervene with IV iron, with benefits on quality of life and risk of heart failure hospitalisation, adds to the therapeutic options available. Patients who have been hospitalised for heart failure are at particularly high risk of adverse events and we now have solid data to show that rapid optimisation of foundation therapies is of benefit and achievable. We have the evidence; our challenge now is to ensure we offer these treatments to all patients who might benefit.
Key messages
- The 2023 heart failure update from the European Society of Cardiology (ESC) includes an expanded indication for sodium-glucose cotransporter 2 (SGLT2) inhibitors and intravenous iron, together with rapid optimisation of foundation therapies.
- SGLT2 inhibitors receive a Class I level A recommendation in the entire spectrum of heart failure for their use to reduce heart failure hospitalisations and cardiovascular death
- The opportunity to intervene with intravenous iron, with benefits on quality of life and risk of heart failure hospitalisation, adds to the therapeutic options available
- This update strengthens the recommendation not only for rapid optimisation of heart failure foundation therapies, but also the need for early visits after discharge
Conflicts of interest
PRK: Grant/research support from Pharmacosmos, and consulting fees/honoraria received from AstraZeneca, Bayer, Boehringer Ingelheim, CSL Vifor, Novartis and Pharmacosmos. AR and MW: none declared.
Funding
None.
References
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7. Kalra PR, Cleland JGF, Petrie MC 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;400:2199–209. https://doi.org/10.1016/S0140-6736(22)02083-9
8. Ponikowski P, Kirwan BA, Anker SD et al. Ferric carboxymaltose for iron deficiency at discharge after acute heart failure: a multicentre, double-blind, randomised, controlled trial. Lancet 2020;396:1895–904. https://doi.org/10.1016/S0140-6736(20)32339-4
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