Heart Failure with Preserved Ejection Fraction (HFpEF): Treatment

Treatment Flowchart (Goldman-Cecil Medicine)

*Greater benefit in patients with LVEF closer to 50%

1. General Principles

1. Congestion control (diuretics)
2. Disease-modifying pharmacotherapy (SGLT2i as first-line, MRA as second)
3. Comorbidity management (BP, AF, obesity, diabetes, ischemia)
4. Lifestyle modification (exercise, weight loss)

• Harrison's Principles of Internal Medicine 22E, p. 2031
• Goldman-Cecil Medicine, p. 492

2. Pharmacological Treatment

A. SGLT2 Inhibitors (First-Line, Disease-Modifying)

• Dapagliflozin 10 mg once daily (EMPEROR-Preserved trial) and empagliflozin 10 mg once daily (DELIVER trial) both reduce the composite of CV death or worsening HF events.
• Empagliflozin reduced the primary composite endpoint by ~21% in EMPEROR-Preserved; dapagliflozin showed similar benefit in DELIVER.
• Reduces HF hospitalizations and improves symptoms and KCCQ quality-of-life scores.
• Benefit is considered a class effect - the agents are interchangeable.
• Recommended for NYHA class II-III patients with LVEF ≥50%.

• Avoid in type 1 diabetes
• Caution in type 2 DM with prior diabetic ketoacidosis (DKA)
• Avoid in pregnancy
• Hold perioperatively or during prolonged fasting
• Goldman-Cecil Medicine, p. 491
• Harrison's 22E, p. 2031

B. Mineralocorticoid Receptor Antagonists (MRAs)

• The TOPCAT trial (3,445 patients) failed to show a significant reduction in the primary composite of CV death, aborted cardiac arrest, or HF hospitalization overall - but spironolactone reduced HF hospitalizations by 17%. A post-hoc analysis showed a significant 18% reduction in primary outcome in patients enrolled from the Americas.
• Benefits appear greater in patients with LVEF closer to 50% (HFmrEF range).

• The FINEARTS-HF trial demonstrated that finerenone significantly reduced total HF events and CV death in HFpEF patients.
• Total HF events reduced by ~18% (RR 0.82, 95% CI 0.70-0.94).
• Benefit was consistent across the full EF spectrum, including EF ≥60% - a subgroup where steroidal MRAs had previously failed.
• FDA approved finerenone for HF with LVEF ≥40% in July 2025.
• Hyperkalemia occurred more in the finerenone arm (K+ >5.5 mmol/L: 14.3% vs 6.9%), but hyperkalemia-related hospitalization was low (0.5%).
• The 2025 CCS/CHFS and JCS/JHFS guidelines now include MRA recommendations for symptomatic HFpEF.
• Heart failure evidence update 2026 - PMC
• Braunwald's Heart Disease, p. 1035

C. ARNI - Sacubitril/Valsartan

• PARAGON-HF trial (4,822 patients with HFpEF, mean age 73, 53% women): 13% reduction in CV mortality + total HF hospitalizations, not statistically significant (p = 0.06).
• Subgroup analyses suggested benefit in:
  • Women
  • Patients with EF below the median (57%) - essentially HFmrEF range
• PARAGLIDE-HF trial: Greater NTproBNP reduction vs. valsartan alone, but clinical benefit mainly in EF ≤60%.
• FDA has approved sacubitril/valsartan across the full EF spectrum, but "benefits are greatest in those with LVEF below normal."
• Consider in patients with LVEF 41-60%, especially women - Braunwald's, p. 1035; Harrison's 22E, p. 2031

D. ACE Inhibitors / ARBs

• CHARM-Preserved (candesartan): Reduced HF hospitalizations significantly, no mortality benefit.
• I-PRESERVE (irbesartan): No benefit on CV death or HF hospitalization.
• PEP-CHF (perindopril): Early benefit on HF hospitalizations attenuated at longer follow-up.
• Verdict: ACE inhibitors and ARBs are not recommended as primary HFpEF-specific therapy but should be used when indicated for comorbidities (hypertension, CKD, diabetes).
• Harrison's 22E, p. 2031

E. Beta-Blockers

• No dedicated RCT in HFpEF has shown mortality benefit.
• Subgroup analysis of SENIORS trial (nebivolol) in elderly HFpEF patients: no significant CV mortality reduction.
• Indicated for: rate control in atrial fibrillation, symptom management.
• Caution: Excessive heart rate lowering can worsen exercise tolerance (chronotropic incompetence is a key feature of HFpEF).
• Harrison's 22E, p. 2031; Goldman-Cecil Medicine

F. GLP-1 / GIP Receptor Agonists (Obese HFpEF Phenotype)

• SUMMIT trial (tirzepatide, dual GIP/GLP-1 agonist): 731 patients with HFpEF + BMI ≥30 kg/m²
  • Reduced the composite of CV death or worsening HF events by 38% vs. placebo (HR 0.62, 95% CI 0.41-0.95, p = 0.026).
  • This represents direct CV risk reduction beyond weight loss/QoL improvement.
• Semaglutide (STEP-HFpEF trial): Improved symptoms, functional status, and reduced body weight in obese HFpEF - but an HF hospitalization/mortality benefit was not the primary endpoint.
• 2025 CCS/CHFS guidelines now recommend GLP-1 receptor agonist activity drugs for symptomatic patients with LVEF ≥45% and BMI ≥30 kg/m².
• Harrison's 22E lists GLP-1 agonists as improving QoL "irrespective of diabetes mellitus" in obese HFpEF.

G. Diuretics

• Loop diuretics (furosemide, torsemide) are used to maintain euvolemia and relieve congestion symptoms (dyspnea, edema).
• Must be used judiciously - HFpEF patients have a narrow window for optimal volume: even modest overdiuresis can reduce LV filling, cause prerenal azotemia, and worsen symptoms due to the stiff, non-compliant ventricle.
• No mortality benefit demonstrated; purely symptom-focused.
• Braunwald's Heart Disease, p. 1035

H. Agents Shown to be Ineffective

• Harrison's 22E, p. 2031; Goldman-Cecil Medicine

3. Non-Pharmacological / Lifestyle Interventions

Exercise Training

• The only intervention consistently shown to increase exercise capacity (peak VO2) in HFpEF.
• Aerobic exercise improves exercise tolerance and quality of life.
• An AHA/ACC 2023 Scientific Statement specifically endorses supervised exercise training for chronic HFpEF.
• Both aerobic and combined aerobic + resistance training are recommended (NYHA II-III).
• Goodman & Gilman's Pharmacological Basis, p. 1908

Weight Loss / Obesity Management

• Obese HFpEF patients have worse biventricular filling pressures during exercise and worse prognosis.
• Caloric restriction + aerobic exercise provides additive benefit to exercise alone.
• Weight loss reduces filling pressures, improves symptoms and peak VO2.
• Braunwald's Heart Disease, p. 1035

4. Comorbidity Management (Critical)

• Harrison's 22E, p. 2031; Fuster and Hurst's The Heart 15th Ed., p. 1540

5. Device Therapy

• No cardiac device has demonstrated unequivocal efficacy specific to HFpEF.
• ICD/CRT: Not indicated unless there is concurrent HFrEF criteria.
• Interatrial shunt devices (e.g., REDUCE LAP-HF trials): Reduce left atrial pressure; results inconclusive so far.
• Pacemakers for chronotropic incompetence: Likely ineffective as a primary strategy (Harrison's 22E).

6. Special Subtypes Requiring Specific Management

Cardiac Amyloidosis (ATTR)

• An increasingly recognized cause of HFpEF (~10-15% of older adults with HFpEF).
• Wild-type ATTR (ATTRwt): Predominantly male, age-related.
• Hereditary ATTR (ATTRh): Val122Ile variant in 3-4% of African Americans.
• Classic findings: low QRS voltage on ECG, "sparkling" myocardium on echo, bilateral carpal tunnel, peripheral neuropathy.
• Treatment: Tafamidis (TTR stabilizer) reduces CV mortality and HF hospitalizations in ATTR-CM (ATTR-ACT trial). Patisiran/inotersen for hereditary ATTR with neuropathy. Standard HFpEF diuretics for symptoms.
• Braunwald's Heart Disease, p. 1035

Hypertrophic Cardiomyopathy (HCM)

• Obstructive HCM can now be treated with mavacamten (cardiac myosin inhibitor), which improves obstruction and symptoms.

7. Emerging and Investigational Therapies (2025-2026)

• Heart failure evidence update 2026 - PMC

Summary Table: Evidence Hierarchy for HFpEF Pharmacotherapy