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Optimal Evidence-Based Treatment of Heart Failure with Preserved Ejection Fraction (HFpEF)

By Dr. Abdelwahab Arrazaghi, MD, FABIM, FRCPC

Specialist in Internal Medicine and Cardiovascular Disease

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Introduction

Heart failure with preserved ejection fraction (HFpEF) represents nearly half of all heart failure (HF) cases. Despite its prevalence, HFpEF has long been considered one of the most challenging cardiovascular conditions to treat. Unlike heart failure with reduced ejection fraction (HFrEF), where therapies are well-established, HFpEF involves a complex interplay of diastolic dysfunction, systemic inflammation, vascular abnormalities, and comorbidities such as hypertension, obesity, and diabetes.

Fortunately, recent advances in clinical trials have shifted the treatment landscape, offering patients evidence-based options that go beyond symptom control to improve outcomes and quality of life.


Understanding the Pathophysiology

The difficulty in managing HFpEF stems from its heterogeneous mechanisms:

  • Diastolic dysfunction – impaired ventricular relaxation and increased stiffness.

  • Systemic contributors – hypertension, obesity, diabetes, atrial fibrillation, and chronic kidney disease.

  • Neurohormonal activation – sympathetic overdrive and renin–angiotensin–aldosterone system (RAAS) dysregulation.

  • Vascular dysfunction – endothelial abnormalities and reduced nitric oxide signaling.

This diversity means that treatment must be personalized, targeting both cardiac and systemic contributors.


Evidence-Based Medical Therapies

1. SGLT2 Inhibitors: A Breakthrough in HFpEF

Large trials such as EMPEROR-Preserved (empagliflozin) and DELIVER (dapagliflozin) have shown that SGLT2 inhibitors significantly reduce heart failure hospitalizations and improve quality of life—regardless of whether patients have diabetes. Current guidelines now position SGLT2 inhibitors as first-line therapy in HFpEF.

2. Mineralocorticoid Receptor Antagonists (MRAs)

The TOPCAT trial demonstrated that spironolactone reduces HF hospitalizations in select patients, particularly those with elevated natriuretic peptides and comorbidities such as hypertension or diabetes.

3. ARNIs (Sacubitril/Valsartan)

Although the PARAGON-HF trial did not meet its primary endpoint, subgroup analyses revealed benefits in women and patients with EF closer to 50%. ARNIs may therefore be considered for patients at the lower end of the preserved EF spectrum.

4. ACE Inhibitors and ARBs

Evidence from the CHARM-Preserved trial supports their role in reducing hospitalizations and controlling blood pressure, especially in hypertensive HFpEF patients.

5. Beta-Blockers

While not proven to reduce mortality in HFpEF, beta-blockers remain valuable for rate control in atrial fibrillation and for managing coexisting hypertension or ischemic heart disease.


Beyond Medications: Non-Pharmacological Strategies

  • Exercise training improves peak VO₂ and overall functional capacity.

  • Dietary modification such as sodium restriction, weight management, and adherence to the DASH or Mediterranean diet can reduce symptoms and improve health.

  • Fluid management is important for symptomatic relief.


Risk Factor and Comorbidity Control

Since comorbidities often drive HFpEF, aggressive management is critical:

  • Blood pressure control to <130/80 mmHg.

  • Treatment of diabetes, obesity, chronic kidney disease, and sleep apnea.

  • Management of atrial fibrillation, including ablation in select patients, can improve outcomes.


Device and Procedural Therapies

While options are limited, certain patients may benefit from:

  • Atrial fibrillation ablation to restore rhythm control.

  • CRT (cardiac resynchronization therapy) in those with conduction disease and disproportionate symptoms.

  • Investigational devices such as interatrial shunt devices, which are being studied to reduce left atrial pressure.


A Stepwise Approach to HFpEF Management

  1. Confirm the diagnosis – preserved LVEF (≥50%) with elevated natriuretic peptides and evidence of diastolic abnormalities.

  2. Start evidence-based therapy – SGLT2 inhibitors first; add MRAs, ARNI, ACEi/ARB, or beta-blockers as indicated by comorbidities and EF range.

  3. Address comorbidities – hypertension, diabetes, obesity, CKD, AF, and sleep apnea.

  4. Implement lifestyle measures – structured exercise, sodium restriction, weight control.

  5. Consider device therapy – AF ablation or investigational devices for select patients.

  6. Ongoing monitoring – reassess symptoms, volume status, and comorbidities regularly through a multidisciplinary care model.


Conclusion

The treatment of HFpEF has evolved significantly. Where once management focused mainly on symptom relief, we now have therapies—most notably SGLT2 inhibitors—that improve outcomes across the spectrum of patients. Alongside MRAs, ARNIs, ACEi/ARBs, and targeted use of beta-blockers, these advances provide a stronger evidence base for clinicians.

Yet, pharmacological treatment is only part of the picture. Lifestyle interventions, comorbidity control, and a coordinated multidisciplinary approach remain indispensable. By tailoring therapy step by step, clinicians can optimize outcomes and improve the lives of patients living with HFpEF.


 
 
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