For HF with reduced ejection fraction (HFrEF) and a left ventricular ejection fraction (LVEF) ≤ 40%, as well as for HF with moderately reduced ejection fraction (LVEF between 41% and 49%), the 2021 European Society of Cardiology (ESC) guidelines recommend a quadruple combination of angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor/neprilysin inhibitors (ARNI), beta-blockers, mineralocorticoid receptor antagonists (MRAs), and sodium-glucose cotransporter 2 (SGLT2) inhibitors.
A loop diuretic is added in cases of fluid retention. Studies such as PARADIGM-HF (sacubitril and valsartan/enalapril) and dapagliflozin in HF have demonstrated significant reductions in cardiovascular mortality and hospitalization within 30 and 27 days, respectively.
The REVOLUTION HF study from Sweden, presented at last year’s ESC Heart Failure Congress, revealed that only 29% of patients with elevated natriuretic peptide levels > 2000 ng/L received an HF diagnosis within a year. On average, it took 40 days to perform the first transthoracic echocardiography.
Treatment Sequence
Once the diagnosis is confirmed, quadruple treatment should be initiated immediately to prevent complications. However, the order in which medications are introduced often depends on the phenotype of the patients with HF. General recommendations based on data analysis from six randomized controlled trials suggest an optimal sequence to maximize survival benefits within 1 year.
The recommended sequence for initiating quadruple treatment was as follows:
- SGLT2 inhibitors: Initiate and assess tolerability within 1 week.
- MRAs with SGLT2 inhibitors and assessment of tolerability after 1 week.
- Gradually titrate beta-blockers over 4 weeks.
- Titrate the ARNI for over 5 weeks and introduce it once the blood pressure stabilizes.
From a clinical perspective, Assmus noted that SGLT2 inhibitors and MRAs can be initiated simultaneously. Depending on the patient’s phenotype, beta-blockers may also be administered immediately followed by ARNI.
Longevity Benefits
The benefits of the optimized treatment were remarkable. An analysis of three randomized studies from 2020 demonstrated that a 55-year-old patient with HF could gain an additional 6.3 years of life by switching from conventional dual treatment (ACE inhibitor/ARNI and beta-blocker) to quadruple treatment. Even for an 80-year-old patient, life expectancy increased by 1.4 years.
Innovations in Medications
The current quadruple combination of ACE inhibitors or ARNI, beta-blockers, MRAs, and SGLT2 inhibitors may evolve with the emergence of novel treatment options.
Advances in HF
Iron deficiency is a common comorbidity in HF, and intravenous iron carboxymaltose is recommended (Class IIa) to improve symptoms and exercise capacity and reduce hospitalization in hospitalized patients.
Since the 2021 guidelines, several new studies, including IRONMAN, HEART-FID, and FAIR-HF2, have been initiated by the German Center for Cardiovascular Research. These studies have shown trends toward improved outcomes but lack statistical significance due to the limited number of participants.
A meta-analysis of six major studies, led by Stefan Anker, MD, cardiologist at Charité-Universitätsmedizin Berlin, Berlin, Germany, and published in Nature Medicine, found a 28% reduction in the combined endpoint of recurrent HF hospitalizations and cardiovascular death.
For HF with preserved ejection fraction, current guidelines recommend SGLT2 inhibitors and diuretics for fluid retention, in addition to managing comorbidities. However, the 2026 guidelines may also include new options.
The FINEARTS-HF study demonstrated that the nonsteroidal MRA finerenone significantly improved the primary endpoint of HF events and cardiovascular death compared with standard care. This reduction was primarily driven by fewer HF-related hospitalizations.
Finerenone is recommended for the prevention of HF in patients with diabetic nephropathy and significant albuminuria to prevent HF. Based on the current data, HF-specific treatments may be used in the future.
https://www.medscape.com/viewarticle/new-drug-combos-could-cut-heart-failure-mortality-60-2025a1000bzz
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