What alternative treatment options are available for a patient with heart failure with reduced ejection fraction who cannot take Entresto (sacubitril/valsartan)?

Alternative Treatments for Heart Failure with Reduced Ejection Fraction When Entresto Cannot Be Used

If a patient with HFrEF cannot take Entresto (sacubitril/valsartan), the best alternative is an ACE inhibitor (such as enalapril) or an ARB (angiotensin receptor blocker), combined with the other three foundational medication classes: beta-blockers, mineralocorticoid receptor antagonists (MRAs), and SGLT2 inhibitors. 1, 2

First-Line Alternative: ACE Inhibitors

ACE inhibitors remain highly effective alternatives to Entresto, with enalapril demonstrating an 11% reduction in all-cause mortality and 30% reduction in heart failure hospitalization in landmark trials. 3

• Enalapril is FDA-approved for symptomatic heart failure and has a 30-year track record of safety and efficacy 3, 4
• Start enalapril at 2.5 mg twice daily and titrate to target dose of 10-20 mg twice daily over 2-4 weeks 3
• Enalapril provides mortality reduction that does not depend on digitalis being present 3
• This medication is generic and relatively inexpensive compared to newer agents 4

Complete Quadruple Therapy Without Entresto

The 2022 AHA/ACC/HFSA guidelines now recommend four foundational medication classes for HFrEF, and three of these can be used even when Entresto is contraindicated. 1, 2

The Four Pillars (with ACEi replacing ARNI):

1. ACE Inhibitor or ARB (replacing Entresto)

   • ACE inhibitors and ARBs reduce mortality by at least 20% 2
   • Never combine ACE inhibitor with ARB due to increased risk of renal dysfunction and hyperkalemia 2

2. Beta-Blockers (carvedilol, metoprolol succinate, or bisoprolol)

   • Reduce mortality by at least 20% and decrease sudden cardiac death 2
   • Start at low doses in clinically stable patients and gradually up-titrate to maximum tolerated dose 2

3. Mineralocorticoid Receptor Antagonists (spironolactone or eplerenone)

   • Recommended for all symptomatic patients with LVEF ≤35% 2
   • Provide at least 20% mortality reduction and reduce sudden cardiac death 2
   • Require monitoring of renal function and serum potassium levels 2
   • Can be used if eGFR >30 ml/min/1.73 m² 2

4. SGLT2 Inhibitors (dapagliflozin or empagliflozin)

   • Reduce cardiovascular death and HF hospitalization regardless of diabetes status 1, 2
   • Have minimal blood pressure effect, making them ideal first agents 2
   • Can be used if eGFR ≥30 ml/min/1.73 m² for empagliflozin, or ≥20 ml/min/1.73 m² for dapagliflozin 2

Initiation Strategy Without Entresto

Start all four medication classes simultaneously as soon as possible after diagnosis, beginning with SGLT2 inhibitor and MRA first since they have minimal blood pressure effects. 2

• Up-titrate one drug at a time every 1-2 weeks using small increments until target or maximally tolerated dose is achieved 2
• For patients with low blood pressure, start SGLT2 inhibitor and MRA first, then add beta-blocker or very low-dose ACE inhibitor 2
• Loop diuretics are essential for congestion control but do not reduce mortality 2

Additional Therapies for Specific Subgroups

For self-identified Black patients with NYHA class III-IV symptoms despite optimal therapy, add hydralazine/isosorbide dinitrate. 2

• Starting dose: hydralazine 25 mg three times daily + isosorbide dinitrate 20 mg three times daily 2
• This combination can prolong survival but may be inferior to ACE inhibitors for mortality 2

For patients with heart rate ≥70 bpm in sinus rhythm despite maximally tolerated beta-blocker, consider ivabradine. 2

• Starting dose: 2.5-5 mg twice daily 2
• Survival benefit is modest or negligible in the broad HFrEF population 2

Common Reasons Entresto Cannot Be Used and Alternatives

History of Angioedema with ACE Inhibitors or ARBs

• Use ARB as alternative if angioedema was with ACE inhibitor only 2
• If angioedema occurred with both classes, focus on optimizing the other three pillars (beta-blocker, MRA, SGLT2i) and consider hydralazine/isosorbide dinitrate 2

Severe Renal Impairment

• ACE inhibitors can still be used with dose adjustment 3
• Enalapril is contraindicated only in severe renal failure (creatinine >2.5 mg/dL) 3
• Modest increases in creatinine (up to 30% above baseline) are acceptable and should not prompt discontinuation 2

Hypotension

• Do not withhold therapy for asymptomatic low blood pressure with adequate perfusion 2
• Start SGLT2 inhibitor and MRA first as they have minimal blood pressure effects 2
• SGLT2 inhibitors cause the smallest average BP decrease (only -1.50 mmHg in patients with baseline SBP 95-110 mmHg) 2

Hyperkalemia

• Address reversible causes first before discontinuing RAAS inhibitors 2
• Consider potassium binders like patiromer rather than discontinuing life-saving medications 2
• Discontinuation of RAAS inhibitors after hyperkalemia was associated with two to fourfold higher risk of subsequent adverse events 2

Critical Contraindications to Avoid

• Never combine ACE inhibitor with ARB and MRA (triple combination) due to hyperkalemia and renal dysfunction risk 2
• Avoid diltiazem or verapamil in HFrEF as they increase risk of worsening heart failure and hospitalization 2
• Avoid non-evidence-based beta-blockers 2

Monitoring Requirements

• Check blood pressure, renal function, and electrolytes at 1-2 weeks after initiation and with each dose increment 2
• More frequent monitoring in elderly patients and those with chronic kidney disease 2
• Potassium levels require close monitoring with MRAs 2

Common Pitfalls to Avoid

• Delaying initiation of all four medication classes - start simultaneously, not sequentially 2
• Accepting suboptimal doses - target doses provide maximum mortality benefit 2
• Stopping medications for asymptomatic hypotension - adverse events occur in 75-85% of HFrEF patients regardless of treatment 2
• Inadequate monitoring - regular follow-up prevents unnecessary discontinuation 2