Common Side Effects of Entresto
The most common side effects of Entresto (sacubitril/valsartan) are hypotension (low blood pressure), hyperkalemia (elevated potassium), kidney problems, and angioedema (swelling of face, lips, tongue, throat), with hypotension being the most frequently reported adverse event. 1
Primary Side Effects from FDA Labeling
The FDA-approved drug label explicitly identifies these key adverse events 1:
Serious Side Effects Requiring Immediate Attention:
- Angioedema: Swelling of face, lips, tongue, and throat that may cause trouble breathing and death. This risk is significantly higher in Black patients and those with prior angioedema history. Get emergency help immediately if this occurs.
- Hypotension (Low Blood Pressure): Most common when combined with diuretics ("water pills"). Presents as dizziness, lightheadedness, or extreme fatigue.
- Kidney Problems: Requires monitoring of kidney function during treatment; may necessitate dose reduction or temporary discontinuation.
- Hyperkalemia: Elevated potassium levels requiring regular blood monitoring.
Clinical Trial and Real-World Data
Frequency of Common Side Effects:
From the PARADIGM-HF trial and subsequent guidelines 2:
- Symptomatic hypotension: 14.0% (compared to 9.2% with enalapril)
- Angioedema: Numerically higher but not statistically significant versus ACE inhibitors
- Hyperkalemia and renal dysfunction: Actually less common than with ACE inhibitors
Recent real-world data from hospitalized patients 3 showed:
- Acute kidney injury: 14.02% (most common)
- Hypotension: 9.35%
- Hyperkalemia: 8.9%
- Angioedema: 0.44% (rare but serious)
- Overall discontinuation rate: 18.1%
Additional Adverse Events from Post-Marketing Surveillance:
A comprehensive FAERS database analysis 4 identified:
- Hypotension had the highest incidence (n=10,338) with strong signal intensity
- Throat clearing showed highest signal intensity (though less common)
- Uncommon but notable signals: cardiac dysfunction, memory impairment, paroxysmal nocturnal dyspnea
Important Clinical Considerations
Monitoring Requirements:
You must check these parameters regularly during Entresto therapy 2, 1:
- Blood pressure (watch for symptomatic hypotension)
- Serum potassium levels (risk of hyperkalemia)
- Renal function (serum creatinine, eGFR)
- Signs of angioedema (especially in first weeks of therapy)
Dose Adjustments for Side Effects:
- Severe renal impairment (eGFR <30): Start at 24/26 mg twice daily 2
- Moderate hepatic impairment (Child-Pugh B): Start at 24/26 mg twice daily 2
- If hypotension occurs: Consider reducing diuretic dose first before stopping Entresto
Critical Pitfalls to Avoid:
- Do NOT use within 36 hours of ACE inhibitor - significantly increases angioedema risk 1
- Black patients have higher angioedema risk - counsel appropriately and monitor closely 1
- Patients with diabetes on aliskiren - contraindicated combination 1
- Pregnancy - can cause fetal harm or death; absolute contraindication 1
Special Populations:
Patients with CKD 5: Despite concerns, recent data shows Entresto actually improved mean eGFR by 5.90% over 12 months, though 5.10% experienced worsening renal function requiring monitoring.
Patients with diabetes 3: Had worse safety outcomes and higher 30-day readmission rates - monitor these patients more intensively.
Comparative Safety Profile
Compared to ACE inhibitors/ARBs 6, 7:
- More common: Hypotension
- Less common: Renal dysfunction, hyperkalemia, cough
- Similar: Overall serious adverse event rates
The hypotension risk, while higher, is generally manageable and should not prevent use in appropriate candidates, as the mortality and morbidity benefits substantially outweigh this risk 2, 7.