Is sacubitril/valsartan (angiotensin‑receptor neprilysin inhibitor) appropriate for a symptomatic heart failure with preserved ejection fraction patient (ejection fraction ≥50%, NYHA class II‑III) who has stable renal function (eGFR ≥30 mL/min/1.73 m²), potassium ≤5.2 mmol/L, and systolic blood pressure ≥100 mm Hg?

Does ARNI Have a Role in HFpEF?

Yes, sacubitril/valsartan may be considered for selected HFpEF patients, particularly women and those with LVEF in the lower preserved range (45-57%), but it carries only a Class 2b recommendation and should not be first-line therapy. 1, 2

Evidence Base and Guideline Recommendations

The PARAGON-HF trial enrolled 4,822 patients with HFpEF (LVEF ≥45%) and 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). 1, 3 Despite this neutral primary result, the FDA approved sacubitril/valsartan for selected HFpEF patients in February 2021 based largely on post-hoc subgroup analyses. 1, 4

The 2022 AHA/ACC/HFSA guidelines assign sacubitril/valsartan a Class 2b recommendation for HFpEF, meaning it "may be considered" but with only moderate strength of evidence. 1, 2 This contrasts sharply with the Class I recommendation it holds for HFrEF, where it provides at least 20% mortality reduction. 5, 6

Patient Selection Criteria

Your patient meets the basic safety requirements for sacubitril/valsartan initiation:

• LVEF ≥50% (HFpEF confirmed) 1
• NYHA class II-III symptoms 5, 1
• eGFR ≥30 mL/min/1.73 m² (required threshold) 5, 1
• Potassium ≤5.2 mmol/L (acceptable) 5
• Systolic BP ≥100 mm Hg (meets minimum) 5, 1

However, sacubitril/valsartan showed the greatest benefit in specific subgroups:

Subgroups With Demonstrated Benefit

• Women: Rate ratio 0.73 (95% CI 0.59-0.90), primarily driven by reduction in HF hospitalizations 1, 3
• LVEF 45-57% (lower preserved range): Rate ratio 0.78 (95% CI 0.64-0.95) 1, 3

Subgroups With Minimal or No Benefit

• Patients with LVEF >57% showed no significant benefit 1
• Men had less robust responses compared to women 1

Treatment Algorithm for HFpEF

First-line therapy should prioritize SGLT2 inhibitors, not sacubitril/valsartan. 1, 2

Step 1: Initiate SGLT2 Inhibitor (Class 2a)

• Start dapagliflozin 10 mg daily (if eGFR >30 mL/min/1.73 m²) or empagliflozin 10 mg daily (if eGFR >60 mL/min/1.73 m²) 1, 2
• SGLT2 inhibitors have stronger evidence than sacubitril/valsartan in HFpEF, with significant reductions in HF hospitalizations and composite cardiovascular outcomes 1, 2
• DELIVER trial: dapagliflozin reduced worsening HF and CV death (HR 0.82; 95% CI 0.73-0.92) 2
• EMPEROR-PRESERVED trial: empagliflozin reduced HF hospitalization and CV death (HR 0.79; 95% CI 0.69-0.90) 2

Step 2: Optimize Diuretics for Congestion

• Use loop diuretics at the lowest effective dose to relieve symptoms 1, 2
• Titrate based on volume status, not fixed dosing 2

Step 3: Consider Mineralocorticoid Receptor Antagonist (Class 2b)

• Add spironolactone 12.5-25 mg daily, particularly if LVEF is in the lower preserved range (40-50%) 1, 2
• TOPCAT trial showed reduction in HF hospitalizations (HR 0.83; 95% CI 0.69-0.99) but no mortality benefit 2

Step 4: Consider Sacubitril/Valsartan (Class 2b) Only If:

• Patient remains symptomatic despite SGLT2 inhibitor therapy 1, 2
• AND patient is female 1, 2
• OR LVEF is 45-57% 1, 2
• AND systolic BP remains ≥100 mm Hg 5, 1

Dosing and Safety Considerations

If you decide to initiate sacubitril/valsartan in this patient:

Starting Dose

• Begin with 24/26 mg twice daily if patient is elderly (≥75 years), has moderate hepatic impairment, or severe renal impairment 1
• Otherwise, start 49/51 mg twice daily 1

Titration Schedule

• Double dose every 2-4 weeks as tolerated 1
• Target dose: 97/103 mg twice daily 1

Mandatory Washout Period

• 36-hour washout required when transitioning from ACE inhibitors to avoid angioedema 1
• No washout needed if transitioning from ARB 1

Monitoring Requirements

• Check renal function and electrolytes within 1-2 weeks after initiation and with each dose increase 1
• Monitor blood pressure closely, especially during titration 1
• Consider reducing diuretic doses in non-congested patients due to enhanced natriuresis 1

Critical Pitfalls to Avoid

• Do not use sacubitril/valsartan as first-line therapy in HFpEF—SGLT2 inhibitors have stronger evidence and a Class 2a recommendation 1, 2
• Do not treat all HFpEF patients the same as HFrEF patients—response to therapies differs significantly between these populations 2
• Do not overlook comorbidity management—hypertension, diabetes, obesity, and atrial fibrillation significantly impact HFpEF outcomes 1, 2
• Do not combine ACE inhibitor with sacubitril/valsartan due to angioedema risk 5, 1
• Do not expect mortality reduction—no pharmacological agent has demonstrated definitive mortality reduction as a standalone endpoint in HFpEF 2

Comparative Evidence: ARNI vs. Other Therapies

The recent PARAGLIDE-HF trial (2023) provides additional context: in patients with EF >40% stabilized after worsening heart failure, sacubitril/valsartan led to greater NT-proBNP reduction (ratio 0.85; 95% CI 0.73-0.999; p=0.049) but increased symptomatic hypotension (OR 1.73; 95% CI 1.09-2.76). 7 The treatment effect was larger in patients with EF ≤60% (win ratio 1.46; 95% CI 1.09-1.95). 7

Bottom Line for Your Patient

Start with dapagliflozin or empagliflozin immediately as the cornerstone of disease-modifying therapy. 1, 2 Optimize diuretics for symptom control. 1, 2 Only consider adding sacubitril/valsartan if the patient remains symptomatic despite SGLT2 inhibitor therapy AND is either female or has LVEF closer to 45-50%. 1, 2 Given your patient's LVEF of ≥50%, sacubitril/valsartan would be most appropriate if the patient is female and continues to have symptoms after optimizing other therapies. 1, 2