What are the potential drug interactions with sacubitril valsartan in a patient with heart failure, possibly with reduced ejection fraction, and comorbid conditions such as hypertension or chronic kidney disease?

Drug Interactions with Sacubitril/Valsartan

Sacubitril/valsartan has clinically significant interactions primarily with ACE inhibitors (contraindicated), aliskiren (contraindicated in diabetes), and statins (requiring dose consideration), while also requiring careful monitoring when combined with potassium-sparing agents, NSAIDs, and lithium. 1, 2

Absolute Contraindications

Critical timing and combination restrictions must be strictly observed:

• ACE inhibitors are absolutely contraindicated with sacubitril/valsartan, requiring a mandatory 36-hour washout period before initiating sacubitril/valsartan to prevent life-threatening angioedema 1, 2
• Aliskiren is contraindicated in patients with diabetes, and should be avoided in patients with eGFR <60 mL/min/1.73 m² 1, 2
• History of angioedema related to previous ACE inhibitor or ARB therapy is an absolute contraindication 1, 2

Statin Interactions Requiring Dose Adjustment

Sacubitril inhibits OATP1B1, OATP1B3, OAT1, and OAT3 transporters, leading to increased statin exposure:

• In phase III studies, coadministration with atorvastatin increased atorvastatin Cmax up to 2-fold and AUC by up to 1.3-fold, though no significant adverse events were reported 1
• Lower doses of atorvastatin, fluvastatin, pitavastatin, pravastatin, rosuvastatin, or simvastatin may be considered when used in combination with sacubitril/valsartan 1
• Despite pharmacokinetic interactions, no dose adjustments are currently mandated in US package labeling, but clinical judgment should guide statin dosing 1
• Monitor patients for statin-related adverse effects (myalgias, elevated creatine kinase, hepatotoxicity) when combining these agents 1

Potassium-Sparing Agents and Hyperkalemia Risk

Combination with mineralocorticoid receptor antagonists and other potassium-affecting drugs requires vigilant monitoring:

• Potassium-sparing diuretics may lead to increased serum potassium when combined with sacubitril/valsartan 2
• Serial measurement of serum potassium is critical, particularly when combined with aldosterone antagonists, with caution when potassium >5.0 mmol/L 3
• Monitor serum electrolytes and renal function routinely, with frequency adjusted based on clinical status and renal function 3
• In the UK HARP-III trial, 32% of patients on sacubitril/valsartan versus 24% on irbesartan developed potassium ≥5.5 mmol/L, though this difference was not statistically significant 4

NSAIDs and Renal Function

NSAIDs may lead to increased risk of renal impairment when combined with sacubitril/valsartan 2:

• The combination can precipitate acute kidney injury through dual inhibition of renal protective mechanisms
• Monitor renal function closely when NSAIDs cannot be avoided
• Consider temporarily discontinuing sacubitril/valsartan in settings of reduced oral intake or fluid losses 1

Lithium Toxicity Risk

Increased risk of lithium toxicity exists with sacubitril/valsartan 2:

• Monitor lithium levels closely when coadministered
• Watch for signs of lithium toxicity (tremor, confusion, polyuria)
• Dose adjustments of lithium may be necessary

Loop Diuretics (Furosemide)

Sacubitril/valsartan reduces furosemide exposure but clinical impact is minimal:

• Coadministration decreased furosemide Cmax by 50% and AUC by 28%, with 24-hour urinary excretion reduced by 26% 5
• Despite pharmacokinetic changes, 0-24 hour diuresis was reduced by only 0.2% and natriuresis by 15% 5
• Post-hoc analysis of PARADIGM-HF showed median furosemide dose remained similar at baseline and study end 5
• In noncongested patients, empiric modest lowering of loop diuretic doses may mitigate hypotensive effects of sacubitril/valsartan 1

Drugs Without Significant Interactions

The following medications showed no clinically significant interactions in dedicated studies 2:

• Furosemide, warfarin, digoxin, carvedilol
• Levonorgestrel/ethinyl estradiol (oral contraceptives)
• Amlodipine, omeprazole, hydrochlorothiazide
• Metformin, sildenafil

Monitoring Strategy for Drug Interactions

Implement systematic monitoring at each clinical encounter:

• Blood pressure monitoring is essential, as sacubitril/valsartan may exert more pronounced BP effects than ACE inhibitors/ARBs alone 1, 3
• Renal function (serum creatinine, eGFR) should be monitored routinely, especially with aldosterone antagonists or NSAIDs 3
• Serum potassium requires serial measurement, particularly with MRAs or potassium-sparing diuretics 3
• Review all medications at each encounter and during care transitions to identify interactions early 1

Special Populations and Interaction Considerations

Chronic kidney disease patients require particular attention:

• In patients with CKD (eGFR 20-60 mL/min/1.73 m²), sacubitril/valsartan showed similar effects on kidney function compared to irbesartan over 12 months 4
• Even in end-stage kidney disease, serum potassium did not increase significantly with sacubitril/valsartan 6
• Severe renal impairment (eGFR <30 mL/min/1.73 m²) requires reduced starting dose of 24/26 mg twice daily 1

Common Pitfalls to Avoid

• Never initiate sacubitril/valsartan within 36 hours of the last ACE inhibitor dose - this is the most critical drug interaction to prevent angioedema 1, 2
• Do not automatically reduce statin doses without clinical indication, but remain vigilant for myopathy symptoms 1
• Avoid discontinuing sacubitril/valsartan for asymptomatic hyperkalemia or mild creatinine elevation without attempting management strategies first 3
• Do not overlook the enhanced natriuretic effect when adjusting diuretic doses 1, 5