Recent Updates in Management of Heart Failure (2024-2026)

1. HFrEF: The "Fantastic Four" Quadruple Therapy is Now Standard of Care

2. Vericiguat: Toward "Quintuple Therapy" in HFrEF?

• The VICTOR trial (designed for ambulatory HFrEF on contemporary background therapy) failed its primary endpoint, but did show fewer cardiovascular and all-cause deaths
• Investigators have proposed vericiguat as a "5th drug" in an emerging quintuple therapy paradigm
• The 2025 network meta-analysis found quintuple therapy (ARNi + β-blocker + MRA + SGLT2i + vericiguat) provided ~6.0 additional life-years vs placebo, about 0.7 years more than quadruple therapy alone (exploratory finding; single trial)
• Currently: ESC gives a Class IIb recommendation; AHA/ACC/HFSA says "may be considered" in patients with recent worsening on optimal therapy

3. Finerenone (FDA Approved July 14, 2025): Major HFpEF/HFmrEF Breakthrough

• Finerenone (Kerendia) - a first-in-class nonsteroidal MRA (nsMRA) - received FDA approval on July 14, 2025 for adults with HF and LVEF ≥40% (HFmrEF and HFpEF)
• Approved to reduce cardiovascular death, HF hospitalization, and urgent HF visits
• Based on the FINEARTS-HF trial: finerenone reduced the primary composite endpoint by 16% vs placebo (worsening HF events + CV death)
• Advantages over steroidal MRAs: higher selectivity, less gynecomastia and sexual side effects, lower hyperkalemia risk at therapeutic doses
• This represents a major paradigm shift for HFpEF, where therapeutic options have historically been very limited
• Approval is currently US-only; EU, China, and Japan applications are under review

4. SGLT2 Inhibitors: Expanded to Full EF Spectrum

• SGLT2 inhibitors (dapagliflozin, empagliflozin) are now recommended across the entire LVEF spectrum (HFrEF, HFmrEF, and HFpEF) per the 2023 ESC focused update
• The DELIVER trial (dapagliflozin) and EMPEROR-Preserved trial (empagliflozin) established benefit in HFpEF/HFmrEF
• New 2025 data from the DAPA-EAT trial showed dapagliflozin reduces epicardial adipose tissue and improves diastolic filling even in asymptomatic HF
• SGLT2i are also now recommended for prevention of HF in patients with diabetic CKD

5. GLP-1 Receptor Agonists / Incretin Therapies in HFpEF with Obesity

• Semaglutide 2.4 mg/week (STEP-HFpEF and STEP-HFpEF-DM trials): significantly improved quality of life, 6-minute walk distance, and reduced body weight in obese HFpEF patients with and without diabetes
• Tirzepatide (dual GIP/GLP-1 agonist): positive results from SURMOUNT-HF trial, showing improvements in symptoms, functional capacity, and weight in obese HFpEF
• A 2025 JAMA observational study compared semaglutide vs tirzepatide in HFpEF patients in real-world settings (Krüger et al., JAMA 2025, PMID 40886075)
• These drugs are now being integrated into HFpEF management algorithms alongside SGLT2 inhibitors, particularly in obese patients

6. Specific Cardiomyopathies: New Targeted Therapies

Hypertrophic Cardiomyopathy (HCM)

• Mavacamten (cardiac myosin inhibitor): already approved for symptomatic obstructive HCM (oHCM), now well-established in clinical practice
• Aficamten (Myqorzo): FDA approved December 19, 2025 - a new allosteric, reversible cardiac myosin inhibitor, approved in 5/10/15/20 mg doses for oHCM, based on the SEQUOIA-HCM trial. It offers an alternative to mavacamten.

Transthyretin Cardiac Amyloidosis (ATTR-CM)

• Tafamidis remains the established standard of care
• The 2025 ACC Concise Clinical Guidance on ATTR-CM was published (PMID 41171219), updating evaluation and management protocols

7. IV Iron Supplementation: Upgraded to Class I

• ESC upgraded intravenous iron supplementation (ferric carboxymaltose or ferric derisomaltose) to Class IA recommendation for alleviating symptoms/improving quality of life in HFrEF with iron deficiency
• Class IIa for reducing HF hospitalization risk
• The FAIR-HFpEF trial also explored iron supplementation in HFpEF (ferric carboxymaltose)

8. New Diuretic Strategies

• Bumetanide nasal spray: FDA approved (2025) for edema associated with congestive heart failure - a novel delivery route for loop diuretic therapy
• PUSH-AHF trial: Supports natriuresis-guided diuretic therapy in acute HF (titrating diuretics based on urinary sodium output), showing superior decongestion
• Acetazolamide (ADVOR trial) + standard diuretics: showed improvement in decongestion in acute HF with fluid overload; ongoing discussion about routine use

9. Device Therapy Updates

10. Heart Failure Classification Refinement

• Often treated similarly to HFpEF
• SGLT2i recommended; finerenone now also FDA-approved for this group
• Often represents "recovered HFrEF" or a transitional phenotype

Summary of Key 2024-2026 Milestones

• iCARDIO Global HF Implementation Guidelines 2025 (PMID 40533340)
• van Essen et al. Network Meta-Analysis, JACC 2025 (PMID 40892608) - confirms quadruple > triple; quintuple therapy exploratory
• Beghini et al. "2024 Update in Heart Failure," ESC Heart Fail 2025 (PMID 38806171)
• FINEARTS-HF: Solomon et al., NEJM 2024 - basis for FDA July 2025 finerenone approval
• Braunwald's Heart Disease (10th ed.) - GDMT and device therapy framework