- Cannata A, McDonagh TA. Heart Failure with Preserved Ejection Fraction. N Engl J Med. 2025 Jan 9;392(2):173-184. doi: 10.1056/NEJMcp2305181. PMID: 39778171.
Heart failure with preserved ejection fraction (HFpEF) is a complex clinical syndrome characterised by the presence of symptoms and signs typical of heart failure despite a left ventricular ejection fraction (LVEF) ≥50%. HFpEF accounts for almost 50% of all cases of heart failure and its prevalence is increasing due to the aging population and the growing burden of comorbidities such as obesity, diabetes and hypertension. Mortality rates vary from 15% at one year to 75% within five to ten years after hospitalisation, underlining the urgent need for effective treatments. Furthermore, HFpEF disproportionately affects women and the elderly, with a strong association with metabolic and cardiovascular comorbidities. The heterogeneity of the condition complicates both diagnosis and management, making individualised care crucial.
HFpEF remains challenging to treat, with no therapies significantly reducing mortality. Current treatments focus on improving symptoms, quality of life, and reducing hospitalization risks. Treatment of the underlying cause and concomitant cardiovascular and noncardiovascular coexisting conditions is the basis for the treatment strategies in patients with heart failure with preserved ejection fraction.
Clinical trials on RAS inhibitors in HFpEF, including ARBs (e.g., candesartan, irbesartan) and ACE inhibitors (e.g., perindopril), have shown limited benefits. While the CHARM-Preserved and I-PRESERVE trials found no significant reduction in death or heart failure hospitalizations, ARBs slightly lowered hospitalization rates (e.g., candesartan: 15% vs. 18%, P = 0.02). Similarly, the PEP-CHF trial reported no significant impact on the primary endpoint but observed fewer hospitalizations within the first year with perindopril. Though their direct impact on HFpEF outcomes is minimal, RAS inhibitors remain useful for managing comorbidities like hypertension.
The PARAGON-HF trial, involving 4822 HFpEF patients with LVEF >45%, found no significant reduction in death or hospitalizations for heart failure with sacubitril–valsartan compared to valsartan. Subgroup analyses suggested possible benefits in women and patients with LVEF <57%.
The PARAGLIDE-HF trial, with 466 patients stabilized after decompensated HFpEF (LVEF >40%), showed sacubitril–valsartan reduced neurohormonal activation but increased symptomatic hypotension risk.
Similarly, the PARALLAX trial, involving 2572 patients (LVEF >40%), showed significant reductions in NT-proBNP levels over 12 weeks with sacubitril–valsartan but no improvement in exercise capacity.
These results support the FDA's indication for sacubitril–valsartan in specific HFpEF subgroups, particularly those with lower LVEF values.
The use of MRAs in HFpEF is supported by three key trials. The Aldo-DHF trial showed that spironolactone improved diastolic function and reduced left ventricular mass, but it had no impact on heart failure symptoms or quality of life. The larger TOPCAT trial did not find significant benefits with spironolactone regarding cardiovascular death, heart failure hospitalizations, or aborted cardiac arrest. In contrast, the FINEARTS-HF trial demonstrated that finerenone reduced cardiovascular deaths and heart failure events in patients with an LVEF of 40% or higher, supporting its use in HFpEF treatment.
Many patients with heart failure with preserved ejection fraction receive beta-blockers for other clinical indications. However, trials involving patients with the condition who have received either nebivolol or carvedilol have not shown a reduction in death or hospitalizations for heart failure or an improvement in quality of life.
Indicated for symptom relief by reducing pulmonary and systemic congestion. Loop diuretics are the mainstay for acute decompensation, while thiazides may be used in hypertensive patients. Guidelines emphasize the importance of using the lowest effective dose to avoid complications like hypokalemia and renal dysfunction.
Empagliflozin and dapagliflozin have shown efficacy in reducing heart failure hospitalizations in the EMPEROR-Preserved and DELIVER trials, respectively.
Meta-analyses suggest significant reductions in hospitalization rates, with benefits largely attributable to improved volume management. These agents are recommended as first-line therapy due to their dual benefits on heart failure and comorbid diabetes.
Semaglutide demonstrated improved exercise tolerance, weight loss, and quality of life in the STEP-HFpEF trial, particularly in patients with obesity.
Ongoing studies are exploring the broader applicability of GLP-1 receptor agonists beyond obesity-related HFpEF.
Lifestyle interventions addressing obesity and physical inactivity are critical adjuncts to medical therapy.
Pulmonary pressure monitoring systems, such as CardioMEMS, a small, invasive remote monitoring device that continuously measures pulmonary arterial pressure, have shown promise in reducing hospitalizations.
Cardiac rehabilitation programs tailored to HFpEF patients can improve exercise capacity and overall well-being.
Current international guidelines emphasize diuretics for congestion relief and endorse SGLT2 inhibitors as a class I recommendation (ESC, 2023). MRAs and ARNIs are recommended with lower strength (class IIa or IIb) in specific guidelines, reflecting varying levels of evidence. The American and Japanese guidelines also highlight the importance of managing comorbid conditions such as hypertension and atrial fibrillation. It should be noted that the European guidelines have recently updated their recommendations to include specific therapies targeting obesity-related HFpEF.
The management of HFpEF requires a personalized approach that addresses patient-specific comorbidities and phenotypes. Although recent therapeutic advances give hope, ongoing research is essential to identify treatments that improve long-term outcomes. The future of HFpEF management could be based on precision medicine approaches, which combine new pharmacological agents with personalized lifestyle interventions. Collaboration between cardiologists, endocrinologists and general practitioners will be crucial to optimise care for this growing patient population.