Is sacubitril‑valsartan recommended for patients with heart failure with preserved ejection fraction?

Sacubitril-Valsartan in HFpEF: Conditional Recommendation

Sacubitril-valsartan can be considered for HFpEF patients, but benefits are most evident in those with LVEF below normal (particularly LVEF 45-60%) and in women, while patients with LVEF ≥60% should generally receive alternative therapies due to unfavorable benefit-risk ratios. 1, 2

Evidence-Based Guidance

FDA-Approved Indication

The FDA label explicitly states that sacubitril-valsartan is indicated for chronic heart failure with "benefits most clearly evident in patients with left ventricular ejection fraction (LVEF) below normal" 3. This is critical—the drug is not broadly approved for all HFpEF patients.

Guideline Recommendations

The 2022 AHA/ACC/HFSA guidelines acknowledge that the PARAGON-HF trial did not meet its primary endpoint for the overall HFpEF population (rate ratio 0.87,95% CI 0.75-1.01, p=0.06) 1. However, pre-specified subgroup analyses revealed important treatment effect modifiers:

• LVEF below median (45-57%): Rate ratio 0.78 (95% CI 0.64-0.95) - significant benefit
• Women: Rate ratio 0.73 (95% CI 0.59-0.90) - significant benefit
• No benefit on cardiovascular or all-cause mortality in the overall population 1

Who Benefits Most

Initiate sacubitril-valsartan in:

• Patients with LVEF 45-60% (the "mildly reduced" to lower-normal range)
• Women with HFpEF across the LVEF spectrum
• Patients with recent HF hospitalization (within 30 days) 2
• Frail patients may derive greater benefit, though hypotension risk increases 4

The most recent pooled analysis of PARAGLIDE-HF and PARAGON-HF (2023) demonstrated that sacubitril-valsartan significantly reduced total worsening HF events and cardiovascular death (RR 0.86,95% CI 0.75-0.98, p=0.027), with treatment benefits larger in those with LVEF ≤60% (RR 0.78) compared to LVEF >60% (RR 1.09, p-interaction=0.021) 2.

Who Should NOT Receive It

Avoid sacubitril-valsartan in:

• Patients with LVEF ≥60%: Substantially higher risk of hypotension without clinical benefit 5
• Baseline systolic BP <100 mmHg
• History of angioedema with ACE inhibitors or ARBs 3
• Severe hepatic impairment 3

Safety Considerations

Common Adverse Effects

Hypotension is the primary concern, occurring in 13% of PARAGON-HF patients, more frequently with sacubitril-valsartan than valsartan 5. Critically, patients who developed hypotension had higher subsequent risks of cardiovascular death and HF hospitalizations (adjusted RR 1.63) and all-cause death (adjusted HR 1.62) 5. This underscores that hypotension is not merely a nuisance but a marker of worse outcomes.

Age modifies hypotension risk (p-interaction=0.026), with older patients experiencing more hypotension, though treatment benefits are retained 6.

Monitoring Protocol

• Start at 49/51 mg twice daily (or half-dose if severe renal impairment or not previously on ACE-I/ARB) 3
• Check BP within 1-2 weeks of initiation
• Monitor potassium and renal function (sacubitril-valsartan actually reduces renal dysfunction risk: RR 0.60,95% CI 0.44-0.83) 2, 7
• Titrate to 97/103 mg twice daily every 2-4 weeks as tolerated 3

Critical Contraindications

Absolute contraindications:

• Concomitant ACE inhibitor use (requires 36-hour washout) 3
• Concomitant aliskiren in diabetic patients 3
• Pregnancy (fetal toxicity) 3
• History of angioedema 3

Clinical Decision Algorithm

1. Confirm HFpEF diagnosis (exclude mimics like cardiac amyloidosis, hypertrophic cardiomyopathy) 8
2. Determine LVEF precisely:
   • LVEF 45-60%: Strong consideration for sacubitril-valsartan
   • LVEF >60%: Generally avoid; unfavorable benefit-risk ratio
3. Assess sex: Women derive greater benefit across LVEF spectrum
4. Check baseline BP: If SBP <100 mmHg, do not initiate
5. Recent hospitalization: Increases likelihood of benefit 2
6. Evaluate frailty: Not a contraindication; may predict greater benefit 4

Nuances and Pitfalls

The 2023 ACC Expert Consensus emphasizes that not all patients with preserved EF and congestion have true HFpEF—many have specific cardiomyopathies requiring disease-directed therapy 8. Always exclude infiltrative diseases, hypertrophic cardiomyopathy, and valvular disease before labeling as HFpEF.

Real-world data from insurance claims databases showed no significant difference between sacubitril-valsartan and ARBs for HF-related hospitalization (aHR 1.33,95% CI 0.99-1.77) or all-cause hospitalization 9, suggesting that trial benefits may not fully translate to unselected populations, reinforcing the importance of patient selection based on LVEF and sex.

The renal benefits are consistent: sacubitril-valsartan reduces the composite renal endpoint (≥50% eGFR decline, ESRD, or renal death) by 40% (HR 0.60) 2, making it particularly attractive in HFpEF patients with concurrent CKD.