What are the considerations for using sacubitril (Angiotensin Receptor-Neprilysin Inhibitor) with valsartan (Angiotensin II Receptor Blocker) in a patient with heart failure with preserved ejection fraction (HFpEF)?

Sacubitril/Valsartan in Heart Failure with Preserved Ejection Fraction

Sacubitril/valsartan can be considered for HFpEF patients, but SGLT2 inhibitors should be prioritized as first-line disease-modifying therapy, with sacubitril/valsartan reserved for specific subgroups—particularly women and those with LVEF in the 45-57% range—who remain symptomatic despite optimal therapy. 1

Current Guideline Recommendations and Evidence Base

The 2022 AHA/ACC/HFSA guidelines assign sacubitril/valsartan a Class 2b recommendation for HFpEF, indicating it "may be considered" rather than being strongly recommended. 2, 1 This weaker recommendation stems from the PARAGON-HF trial, which enrolled 4,822 patients with LVEF ≥45% and failed to achieve statistical significance for its primary composite endpoint of cardiovascular death or total heart failure hospitalizations (rate ratio 0.87,95% CI 0.75-1.01, p=0.06). 2

Importantly, sacubitril/valsartan showed no mortality benefit in HFpEF—neither for cardiovascular death (HR 0.95) nor all-cause mortality (HR 0.97). 2 This contrasts sharply with its robust mortality reduction in HFrEF and explains the cautious guideline stance.

Patient Selection: Who Benefits Most

Despite the overall neutral trial result, prespecified subgroup analyses revealed two populations with meaningful benefit:

Women with HFpEF

Women demonstrated a significant treatment effect with rate ratio 0.73 (95% CI 0.59-0.90), driven primarily by reduction in heart failure hospitalizations. 2, 1 This represents a 27% relative risk reduction and constitutes the strongest evidence for sacubitril/valsartan use in HFpEF.

Lower-Range Preserved EF (45-57%)

Patients with LVEF below the median (45-57%) showed rate ratio 0.78 (95% CI 0.64-0.95), suggesting greater benefit as ejection fraction approaches the mildly reduced range. 2, 1 The FDA explicitly acknowledged this continuous relationship in its 2021 approval, noting benefits are "most clearly evident in patients with LVEF below normal." 3

Treatment Algorithm for HFpEF

First-Line Therapy

Start with SGLT2 inhibitors (dapagliflozin or empagliflozin), which carry a stronger Class 2a recommendation and demonstrated consistent reductions in heart failure hospitalizations across the entire HFpEF spectrum. 1, 4 SGLT2 inhibitors should be prioritized over sacubitril/valsartan in most patients. 1

Second-Line Considerations

After initiating SGLT2 inhibitors and optimizing diuretics for congestion, consider adding sacubitril/valsartan if:

• Patient is female, OR
• LVEF is 45-57%, OR
• Elevated natriuretic peptides persist despite SGLT2 inhibitor therapy, OR
• Patient has reduced kidney function 1

Third-Line Options

Spironolactone (Class 2b) may be added, particularly if LVEF is in the lower preserved range (40-50%). 1, 4

Practical Implementation

Dosing Strategy

• Starting dose: 24/26 mg twice daily for most HFpEF patients, given they often have borderline blood pressure 1
• Titration: Double dose every 2-4 weeks as tolerated 1
• Target dose: 97/103 mg twice daily if blood pressure permits 1

Mandatory Washout Period

A 36-hour washout is required when switching from ACE inhibitors to avoid angioedema. 1 No washout is needed when switching from ARBs. 1

Monitoring Requirements

• Blood pressure within 1-2 weeks after initiation and each dose increase 1
• Renal function and potassium within 1-2 weeks, especially when combined with mineralocorticoid receptor antagonists 1
• Consider reducing diuretic doses in non-congested patients due to enhanced natriuresis 1

Safety Profile and Adverse Effects

Sacubitril/valsartan carries a higher risk of hypotension compared to valsartan alone (OR 1.67,95% CI 1.27-2.19). 5 However, it does not increase hyperkalemia or worsen renal function compared to ARBs. 2, 5

Meta-analysis data confirm sacubitril/valsartan reduces heart failure hospitalizations (RR 0.78,95% CI 0.65-0.85) and improves NYHA functional class (RR 1.25,95% CI 1.10-1.43) compared to ACE inhibitors/ARBs in HFpEF. 6

Clinical Outcomes Beyond Mortality

While sacubitril/valsartan does not reduce mortality in HFpEF, it provides meaningful improvements in:

• Quality of life: Small but significant improvement in KCCQ Clinical Summary Score (mean difference 1.13,95% CI 0.15-2.11) 5
• NYHA functional class: 32% greater odds of improvement compared to valsartan 5
• NT-proBNP levels: Significant reduction (weighted mean difference -266.67 pg/mL) 6
• Cardiac remodeling: Improved global circumferential strain (Δ4.42%, 95% CI 0.67-8.17) in the PARAMOUNT trial 7

Critical Pitfalls to Avoid

• Do not use sacubitril/valsartan as first-line therapy in HFpEF—SGLT2 inhibitors have stronger evidence and guideline support 1, 4
• Do not expect mortality reduction—the benefit is limited to reducing hospitalizations and improving symptoms 2, 6
• Do not apply HFrEF dosing strategies—HFpEF patients require more cautious blood pressure management 1
• Do not overlook the importance of patient sex and LVEF when making treatment decisions—these are the strongest predictors of benefit 2, 1