Is Entresto (sacubitril/valsartan) indicated for an elderly patient with heart failure with preserved ejection fraction (HFpEF), normal blood pressure, and bradycardia?

Entresto in Heart Failure with Preserved Ejection Fraction

Yes, Entresto (sacubitril/valsartan) can be given to patients with HFpEF, but it should be reserved for specific subgroups who are most likely to benefit—particularly those with ejection fraction in the lower range of preservation (45-57%), women, and patients who remain symptomatic despite SGLT2 inhibitor therapy. 1

FDA Approval and Guideline Recommendations

• The FDA approved sacubitril/valsartan for HFpEF based on the PARAGON-HF trial, despite the trial not meeting its primary endpoint for the overall population (rate ratio 0.87,95% CI 0.75-1.01, p=0.06). 1

• The 2022 AHA/ACC/HFSA Heart Failure Guidelines give sacubitril/valsartan a Class 2b recommendation (may be considered) for HFpEF, indicating moderate strength of evidence but acknowledging benefit in select populations. 1

Patient Selection: Who Benefits Most

Prioritize sacubitril/valsartan for HFpEF patients meeting these criteria:

• LVEF 45-57% (lower range of preservation): These patients showed significant benefit with rate ratio 0.78 (95% CI 0.64-0.95) compared to valsartan. 1

• Female patients: Women demonstrated substantial benefit with rate ratio 0.73 (95% CI 0.59-0.90), primarily through reduction in HF hospitalizations. 1

• Symptomatic despite SGLT2 inhibitor therapy: SGLT2 inhibitors receive a stronger Class 2a recommendation and should be prioritized first in most HFpEF patients. 1

• Elevated natriuretic peptides and recent hospitalization: These markers identify higher-risk patients more likely to benefit. 1

Treatment Algorithm for HFpEF

First-line approach:

• Start with SGLT2 inhibitors (dapagliflozin or empagliflozin), which have stronger evidence (Class 2a recommendation) for HFpEF. 1
• Optimize risk factor management (hypertension, diabetes, obesity, atrial fibrillation) and symptom control with diuretics. 1

Second-line consideration:

• Add sacubitril/valsartan if the patient remains symptomatic AND meets the favorable subgroup criteria above (LVEF 45-57%, female sex, or reduced kidney function). 1

Special Considerations for Your Elderly Patient

Regarding normal blood pressure:

• While systolic BP ≥100 mmHg is preferred, lower BP is not an absolute contraindication. 1
• Start with the lowest dose (24/26 mg twice daily) in elderly patients ≥75 years. 1
• Monitor blood pressure closely during initiation and titration, and consider reducing diuretic doses in non-congested patients due to enhanced natriuresis. 1

Regarding bradycardia:

• Bradycardia itself is not a contraindication to sacubitril/valsartan, as the medication does not directly affect heart rate (unlike beta-blockers). 1
• However, ensure hemodynamic stability before initiation. 1

Dosing Strategy

• Initial dose: 24/26 mg twice daily for elderly patients (≥75 years), those with severe renal impairment, or moderate hepatic impairment. 1
• Titration: Double the dose every 2-4 weeks as tolerated, targeting 97/103 mg twice daily if possible. 1
• Monitoring: Check renal function and electrolytes within 1-2 weeks after initiation and with each dose increase. 1

Critical Safety Precautions

• Mandatory 36-hour washout period when transitioning from ACE inhibitors to avoid angioedema; no washout needed from ARBs. 1
• Hypotension is the most common side effect—sacubitril/valsartan increases hypotension risk compared to valsartan alone (OR 1.67,95% CI 1.27-2.19). 2
• No increased risk of hyperkalemia or worsening renal function compared to ARB monotherapy. 2

Evidence Limitations

• The benefit in HFpEF is modest and limited to specific subgroups, unlike the robust mortality benefit seen in HFrEF. 1, 2
• Meta-analysis shows improvement in quality of life measures (KCCQ score mean difference 1.13, NYHA class improvement OR 1.32) and composite outcomes (hospitalization/CV death RR 0.86), but no mortality benefit in the overall HFpEF population. 2