Management of Heart Failure with Preserved Ejection Fraction (HFpEF)

Introduction to HFpEF Management

• The American College of Cardiology recommends sacubitril/valsartan (ARNI) as part of guideline-directed medical therapy (GDMT) for HFpEF management, alongside SGLT2 inhibitors, mineralocorticoid receptor antagonists (MRAs), and ARBs 1
• First-line therapy for HFpEF should focus on risk factor management (hypertension, diabetes, obesity, atrial fibrillation) and symptom control with diuretics 1, 2

Treatment Considerations

• SGLT2 inhibitors (dapagliflozin, empagliflozin) have shown significant benefits in HFpEF and should be considered early in treatment 1
• Mineralocorticoid receptor antagonists (spironolactone) may be considered for selected HFpEF patients with elevated natriuretic peptides or recent hospitalization 1, 2
• Sacubitril/valsartan can be considered for patients who remain symptomatic despite other therapies, particularly those with ejection fraction in the lower range of preservation (EF 40-60%) 1

Safety and Monitoring

• Monitor blood pressure closely during initiation and dose titration of sacubitril/valsartan, particularly in patients with borderline blood pressure 3
• A 36-hour washout period is mandatory when transitioning from ACE inhibitors to sacubitril/valsartan to avoid angioedema 4

Dosing and Administration

• Start with lower doses (24/26 mg twice daily) in patients with severe renal impairment, moderate hepatic impairment, or elderly patients (≥75 years) 4
• Titrate dose gradually, doubling every 2-4 weeks as tolerated, aiming for the target dose of 97/103 mg twice daily if possible 4
• Consider reducing diuretic doses in non-congested patients when initiating sacubitril/valsartan due to enhanced natriuresis 4
• Monitor renal function and electrolytes within 1-2 weeks after initiation and with each dose increase 4

Entresto in Heart Failure with Preserved Ejection Fraction

Evidence for Entresto in HFpEF

• The 2022 AHA/ACC/HFSA Heart Failure Guidelines indicate that sacubitril/valsartan was studied in the PARAGON-HF trial for HFpEF patients (LVEF ≥45%), but did not achieve a significant reduction in the primary composite endpoint of cardiovascular death or total heart failure hospitalizations (rate ratio 0.87, 95% CI 0.75-1.01, p=0.06) 5
• The 2022 AHA/ACC/HFSA Heart Failure Guidelines also showed a benefit of sacubitril/valsartan compared with valsartan in patients with LVEF below the median (45%-57%; rate ratio 0.78, 95% CI 0.64-0.95) 5
• The 2022 AHA/ACC/HFSA Heart Failure Guidelines showed a benefit of sacubitril/valsartan compared with valsartan in women (rate ratio 0.73, 95% CI 0.59-0.90) 5

FDA Approval Status and Guidelines

• The FDA approved sacubitril/valsartan for selected patients with HFpEF based largely on the PARAGON-HF trial, despite not meeting its primary endpoint 6

Treatment Algorithm for HFpEF

• Consider sacubitril/valsartan for patients who remain symptomatic despite other therapies, particularly those with ejection fraction in the lower range of preservation (EF 45-57%) 5
• Consider SGLT2 inhibitors (dapagliflozin, empagliflozin) which have shown significant benefits in HFpEF 6

Sacubitril/Valsartan Therapy in Heart Failure with Preserved Ejection Fraction

Patient Selection and Treatment Benefits

• The American Heart Association, American College of Cardiology, and Heart Failure Society of America give sacubitril/valsartan a Class 2b recommendation for HFpEF, specifically noting potential benefit in patients with LVEF on the lower end of the spectrum and in women, with a moderate strength of evidence 7
• Women with HFpEF experienced significant benefit with sacubitril/valsartan, with a rate ratio of 0.73 and 95% CI 0.59-0.90, primarily driven by reduction in HF hospitalizations, based on a prespecified subgroup analysis with a high strength of evidence 8
• Patients with LVEF in the lower range of preservation (45-57%) showed greater benefit with sacubitril/valsartan, with a rate ratio of 0.78 and 95% CI 0.64-0.95, compared to those with higher LVEF, based on a subgroup analysis with a moderate strength of evidence 7

Guideline Recommendations and Treatment Prioritization

• The American Heart Association, American College of Cardiology, and Heart Failure Society of America recommend prioritizing SGLT2 inhibitors over sacubitril/valsartan in most HFpEF patients, with SGLT2 inhibitors receiving a stronger Class 2a recommendation, based on a systematic review with a high strength of evidence 7
• Sacubitril/valsartan may be considered in HFpEF patients who meet specific criteria, including LVEF 45-57%, female sex or reduced kidney function, elevated natriuretic peptides, and symptomatic disease despite SGLT2 inhibitor therapy, based on a clinical algorithm with a moderate strength of evidence 7, 8

Sacubitril/Valsartan Efficacy in Heart Failure with Preserved Ejection Fraction (EF > 40%)

Clinical Trial Evidence

• The PARAGON‑HF randomized trial enrolled 4,822 patients with heart failure and left‑ventricular ejection fraction ≥ 45%; sacubitril/valsartan did not achieve statistical significance for the primary composite endpoint of cardiovascular death or total heart‑failure hospitalizations (rate ratio 0.87; 95 % CI 0.75‑1.01; p = 0.06) 9.

Subgroup Benefits

• In a prespecified subgroup analysis, women with HFpEF derived a significant benefit from sacubitril/valsartan, with a reduction in heart‑failure hospitalizations (rate ratio 0.73; 95 % CI 0.59‑0.90) 9.
• Patients whose LVEF was 45 %–57 % (the lower half of the enrolled range) also showed a significant benefit (rate ratio 0.78; 95 % CI 0.64‑0.95) compared with those with higher LVEF 9.

Comparison with HFrEF Evidence

• In heart failure with reduced ejection fraction (EF ≤ 40 %), sacubitril/valsartan carries a Class I recommendation from the American College of Cardiology/American Heart Association, based on a 20 % relative reduction in cardiovascular death and heart‑failure hospitalization versus enalapril 9.

Role of Sacubitril/Valsartan (ARNI) in HFpEF – Evidence‑Based Guidance

Guideline Recommendations

• The 2022 AHA/ACC/HFSA guideline assigns sacubitril/valsartan a Class 2b recommendation for heart‑failure with preserved ejection fraction (HFpEF), indicating it “may be considered” and is supported by moderate‑strength evidence. 10
• For heart‑failure with reduced ejection fraction (HFrEF), the same guideline gives sacubitril/valsartan a Class I recommendation, reflecting strong evidence that the drug reduces mortality by at least 20 %. 10

Patient Selection – Safety Eligibility Criteria

All of the above eligibility thresholds are endorsed by the American College of Cardiology within the 2022 AHA/ACC/HFSA guideline. 10

Dosing and Safety Considerations

• Mandatory 36‑hour washout is required when switching from an ACE inhibitor to sacubitril/valsartan to prevent angio‑edema; no washout is needed when transitioning from an ARB. This precaution is a Class I recommendation with strong evidence. 10
• Co‑administration of an ACE inhibitor with sacubitril/valsartan is contraindicated because of the heightened risk of angio‑edema; this is a Class III (harm) recommendation with strong evidence. 10

Sacubitril/Valsartan in Heart Failure with Preserved Ejection Fraction (HFpEF)

Guideline Recommendation and Evidence Strength

• The 2022 AHA/ACC/HFSA guidelines assign sacubitril/valsartan a Class 2b recommendation (Level B‑R) for HFpEF, indicating it “may be considered” in selected patients and reflecting a substantially weaker endorsement than its Class I recommendation for HFrEF. 11

Overall Efficacy in PARAGON‑HF

• In the pivotal PARAGON‑HF trial (4,822 participants with LVEF ≥ 45 %), sacubitril/valsartan did not reach statistical significance for the primary composite endpoint of cardiovascular death or total HF hospitalizations (rate ratio 0.87; 95 % CI 0.75–1.01; p = 0.06). [12][11]
• No mortality benefit was observed in the overall cohort (hazard ratio for all‑cause mortality 0.97; for cardiovascular death 0.95). [12][11]
• The modest signal of benefit was confined to HF hospitalizations (rate ratio 0.85; 95 % CI 0.72–1.00; p = 0.056). [12][11]

Subgroup Benefits that Drive Selective Use

• Women experienced a significant reduction in the composite endpoint (rate ratio 0.73; 95 % CI 0.59–0.90), driven mainly by fewer HF hospitalizations. 11
• Patients with LVEF 45–57 % (below the trial median) also showed a significant benefit (rate ratio 0.78; 95 % CI 0.64–0.95). [12][11]

Patient Selection Considerations

• The guideline advises prioritizing female patients and those with LVEF 45–57 % when contemplating sacubitril/valsartan for HFpEF. 11
• Sacubitril/valsartan should not be used in patients with LVEF > 60 %, as no evidence of benefit exists for this group. 11

Renal Outcomes

• In PARAGON‑HF, sacubitril/valsartan was associated with more favorable renal outcomes than valsartan, demonstrating a lower incidence of the composite renal‑decline endpoint. [12][11]