What is the role of sacubitril/valsartan (angiotensin receptor-neprilysin inhibitor) in treating resistant hypertension and chronic kidney disease (CKD)?

Role of Sacubitril/Valsartan in Resistant Hypertension and CKD

Sacubitril/valsartan is not currently recommended as a first-line treatment for resistant hypertension in CKD patients, but should be considered in specific cases where patients have comorbid heart failure or when conventional antihypertensive therapies have failed to achieve blood pressure targets. 1

Current Treatment Recommendations for Hypertension in CKD

• For patients with CKD and hypertension, blood pressure should be lowered if ≥140/90 mmHg and treated to a target of <130/80 mmHg (<140/80 mmHg in elderly patients) 1
• RAS inhibitors (ACE inhibitors or ARBs) are recommended as first-line therapy in CKD because they reduce albuminuria in addition to providing BP control 1
• CCBs and diuretics (loop diuretics if eGFR <30 ml/min/1.73m²) can be added to the treatment regimen for better BP control 1
• Regular monitoring of eGFR, microalbuminuria, and blood electrolytes is essential during treatment 1

Evidence for Sacubitril/Valsartan in Resistant Hypertension and CKD

• Sacubitril/valsartan has BP-lowering properties but lacks supportive evidence from cardiovascular outcomes trials for routine use in hypertension without heart failure 1
• In the UK HARP-III trial, sacubitril/valsartan showed similar effects on kidney function and albuminuria compared to irbesartan in CKD patients, but demonstrated additional benefits of lowering blood pressure and cardiac biomarkers 2
• Recent research indicates that compared to thiazide diuretics, sacubitril/valsartan resulted in greater BP reduction and more favorable changes in uric acid, HbA1c, and eGFR in patients with CKD 3
• A meta-analysis found that sacubitril/valsartan significantly increased eGFR and decreased blood pressure and NT-proBNP in patients with heart failure and CKD compared to RAS inhibitors alone 4

Specific Considerations for Use in Resistant Hypertension with CKD

• Sacubitril/valsartan may be particularly beneficial in patients with both resistant hypertension and heart failure (especially HFrEF) 1
• In patients with CKD, sacubitril/valsartan has been shown to provide stability in CKD progression after 6 months of treatment 5
• The medication has demonstrated superior BP reduction compared to thiazide diuretics with less annual decline in eGFR in CKD patients 3
• Careful monitoring is required due to potential risks of hypotension and hyperkalemia, particularly in patients with advanced CKD 6

Treatment Algorithm for Resistant Hypertension in CKD

1. Start with lifestyle modifications and optimize first-line therapies:

   • RAS inhibitor (ACE inhibitor or ARB) 1
   • Calcium channel blocker 1
   • Diuretic (thiazide or loop diuretic depending on eGFR) 1

2. If BP remains uncontrolled despite optimal doses of three agents:

   • Consider adding a mineralocorticoid receptor antagonist (MRA) like spironolactone (with careful monitoring of potassium) 1

3. Consider sacubitril/valsartan in the following scenarios:

   • When the patient has comorbid heart failure with reduced ejection fraction 1
   • When conventional therapies have failed to achieve BP targets 1
   • When there is evidence of elevated cardiac biomarkers suggesting subclinical cardiac damage 2, 4

4. When initiating sacubitril/valsartan:

   • Start with lower doses and titrate gradually 5
   • Monitor renal function, blood pressure, and electrolytes closely 6
   • Discontinue previous ACE inhibitor therapy at least 36 hours before starting sacubitril/valsartan to reduce risk of angioedema 1

Potential Benefits and Limitations

Benefits:

• Provides additional BP reduction beyond conventional therapies 3, 4
• May slow the decline in eGFR compared to thiazide diuretics 3
• Reduces cardiac biomarkers (troponin I and NT-proBNP) suggesting potential cardiovascular protection 2, 4

Limitations:

• Limited long-term outcome data specifically in resistant hypertension without heart failure 1
• Potential for hypotension, especially in volume-depleted patients 6
• Higher cost compared to conventional antihypertensive medications
• Not yet included in major hypertension guidelines as a primary treatment for resistant hypertension without heart failure 1