What are the potential side effects of Entresto (sacubitril/valsartan) in patients with a history of heart failure or hypertension?

Side Effects of Entresto (Sacubitril/Valsartan)

The most common side effects of Entresto are hypotension (18% of patients), hyperkalemia (12%), cough (9%), dizziness (6%), and renal dysfunction (5%), with symptomatic hypotension and angioedema being the most clinically significant adverse events requiring monitoring. 1

Primary Adverse Reactions from Clinical Trials

Hypotension

• Hypotension is the most frequently reported side effect, occurring in 18% of patients treated with sacubitril/valsartan compared to 12% with enalapril in the PARADIGM-HF trial 1
• Symptomatic hypotension occurred in 11.1% of patients, while asymptomatic hypotension occurred in 16.0% of patients after randomization 2
• In the acute heart failure setting (PIONEER trial), symptomatic hypotension occurred in 15% of patients on sacubitril/valsartan versus 12.7% on placebo 2
• Importantly, the efficacy and safety of sacubitril/valsartan were maintained regardless of the presence or absence of hypotension 2
• Orthostasis was reported in 2.1% of patients on sacubitril/valsartan compared to 1.1% on enalapril 1
• Falls occurred in 1.9% of patients on sacubitril/valsartan versus 1.3% on enalapril 1

Hyperkalemia

• Hyperkalemia occurred in 12% of patients on sacubitril/valsartan compared to 14% on enalapril 1
• Approximately 16% of patients had potassium concentrations greater than 5.5 mEq/L during treatment 1
• The risk is lower than with spironolactone but requires monitoring, especially when combined with potassium-sparing diuretics or supplements 3, 1

Renal Dysfunction

• Renal failure or acute renal failure occurred in 5% of patients on sacubitril/valsartan 1
• Approximately 16% of patients had increases in serum creatinine greater than 50% from baseline 1
• During run-in periods, renal dysfunction was the most common reason for discontinuation (1.7-1.8% of patients) 1

Angioedema

• Angioedema occurred in 0.5% of patients on sacubitril/valsartan compared to 0.2% on enalapril 1
• In Black patients, the incidence was substantially higher at 2.4% with sacubitril/valsartan versus 0.5% with enalapril 1
• This represents a critical safety concern requiring immediate discontinuation if it occurs 1

Respiratory and Neurological Effects

• Cough occurred in 9% of patients on sacubitril/valsartan compared to 13% on enalapril, representing a lower incidence than ACE inhibitors 1
• Dizziness was reported in 6% of patients on sacubitril/valsartan versus 5% on enalapril 1

Laboratory Abnormalities

Hematologic Changes

• Decreases in hemoglobin/hematocrit greater than 20% were observed in approximately 5% of patients in PARADIGM-HF 1
• In PARAGON-HF, approximately 7% of sacubitril/valsartan-treated patients experienced similar decreases 1

Electrolyte and Renal Monitoring

• Approximately 16% of patients had potassium concentrations exceeding 5.5 mEq/L 1
• Serum creatinine increases greater than 50% occurred in approximately 16-17% of patients 1

Discontinuation Rates and Run-In Period Findings

• During the enalapril run-in period, 10.5% of patients discontinued, with 5.6% due to adverse events 1
• During the sacubitril/valsartan run-in period, an additional 10.4% discontinued, with 5.9% due to adverse events 1
• In the double-blind period, 10.7% of sacubitril/valsartan patients discontinued due to adverse events compared to 12.2% on enalapril 1
• In the PIONEER trial, approximately 20% of patients discontinued treatment by 8 weeks, predominantly due to adverse events 2

Special Population Considerations

Patients with Higher LVEF

• In PARAGON-HF (HFpEF patients with LVEF ≥45%), patients with LVEF ≥60% experienced substantially higher treatment-related risks of hypotension 4
• The benefit/risk ratio favors sacubitril/valsartan in patients with LVEF below normal, but not at higher LVEF 4

Elderly Patients

• In the VICTORIA trial, patients older than 75 years experienced more pronounced initial declines in systolic blood pressure with similar medications 2
• Elderly patients (≥75 years) should start with the lowest dose (24/26 mg twice daily) 5

Patients with Renal Dysfunction

• Patients with renal dysfunction (eGFR <60 mL/min/1.73 m²) were observed with more adverse event incidences 6
• Patients with eGFR <30 mL/min/1.73 m² were excluded from PARADIGM-HF, and there is limited evidence for safety in this population 7

Postmarketing Adverse Reactions

• Hypersensitivity reactions including rash, pruritus, and anaphylactic reactions have been reported 1
• These reactions are reported voluntarily, making frequency estimation difficult 1

Drug Interactions Leading to Adverse Effects

• Sacubitril can inhibit OATP1B1, OATP1B3, OAT1, and OAT3 transporters, potentially increasing statin levels 5, 3
• Consider lower doses of atorvastatin, fluvastatin, pitavastatin, pravastatin, rosuvastatin, or simvastatin when combined with sacubitril/valsartan 5
• Concomitant use with potassium-sparing diuretics, potassium supplements, or salt substitutes may lead to hyperkalemia 1

Clinical Context and Management

• Despite these side effects, the overall discontinuation rate was lower with sacubitril/valsartan (10.7%) than with enalapril (12.2%) 1
• Asymptomatic hypotension should not prevent initiation or uptitration, as the drug maintains efficacy regardless of baseline blood pressure 5
• Following documented hypotension, patients had higher risk of cardiovascular death and total HF hospitalizations (adjusted RR: 1.63), emphasizing the need for careful monitoring 4