What are the guidelines for using perindopril (Angiotensin-Converting Enzyme Inhibitor) and losartan (Angiotensin II Receptor Blocker) in combination for a patient with resistant hypertension or chronic kidney disease?

Combination of Perindopril and Losartan: Not Recommended

Do not combine perindopril (an ACE inhibitor) with losartan (an ARB) in any patient, as dual RAS blockade increases risks of hypotension, hyperkalemia, and acute kidney injury without providing additional cardiovascular or renal benefits. 1, 2

Evidence Against Combination Therapy

Major Clinical Trial Data

The VA NEPHRON-D trial specifically tested the combination of an ACE inhibitor (lisinopril) with an ARB (losartan) in 1,448 patients with type 2 diabetes and chronic kidney disease. Patients receiving dual therapy experienced no additional benefit for the combined endpoint of GFR decline, end-stage renal disease, or death, but had significantly increased rates of hyperkalemia and acute kidney injury compared to monotherapy. 2

Guideline Consensus

• The 2017 ACC/AHA Hypertension Guidelines explicitly state: "Do not use in combination with ARBs or direct renin inhibitor" for ACE inhibitors, citing increased risk of hyperkalemia, especially in patients with CKD or those on potassium supplements. 1
• The 2019 American Diabetes Association Standards state: "The combined use of ACE inhibitors and ARBs should be avoided" based on two clinical trials showing no benefits on CVD or CKD with higher adverse event rates. 1
• The 2020 ISH Global Guidelines emphasize that dual RAS blockade is "associated with increased risks of hypotension, syncope, hyperkalemia, and changes in renal function (including acute renal failure) compared to monotherapy." 1

Appropriate Monotherapy Selection

For Hypertension with CKD

Choose either perindopril OR losartan as monotherapy, not both. 3

• ACE inhibitors (perindopril) are first-line for patients with CKD and albuminuria ≥300 mg/g creatinine, providing proven renoprotection beyond blood pressure lowering. 1, 3
• ARBs (losartan) are equally effective and should be used when ACE inhibitors cause intolerable cough or angioedema. 1
• Both classes reduce albuminuria progression and cardiovascular events in patients with albuminuria 30-299 mg/g creatinine. 1

Monitoring Requirements for Monotherapy

• Check serum creatinine and potassium within 2-4 weeks of initiating or increasing doses. 3, 4
• Continue therapy unless creatinine rises >30% within 4 weeks of initiation. 3
• Discontinue only for symptomatic hypotension, uncontrolled hyperkalemia despite treatment, or advanced kidney failure (eGFR <15 mL/min/1.73 m²). 3

Appropriate Combination Strategies

If Blood Pressure Remains Uncontrolled on RAS Inhibitor Monotherapy

Add a calcium channel blocker (CCB) or thiazide diuretic, NOT another RAS inhibitor. 1, 5

Preferred Add-On Options:

1. Dihydropyridine CCB (amlodipine, nifedipine): Physiologically synergistic with RAS inhibitors, providing 5-fold greater BP reduction than dose escalation of either agent alone. 5

   • Safe in CKD and specifically recommended for end-stage renal disease with proteinuria. 5
   • Research shows amlodipine combined with losartan reduces proteinuria in CKD patients. 6

2. Thiazide or thiazide-like diuretics (chlorthalidone, indapamide): Maintain efficacy down to eGFR 30 mL/min/1.73 m². 3

   • Perindopril combined with indapamide has proven safety and efficacy in hypertensive patients with chronic renal failure. 7
   • For eGFR <30 mL/min, switch to loop diuretics. 3

3. Mineralocorticoid receptor antagonists (spironolactone, eplerenone): Highly effective for resistant hypertension but require careful monitoring. 3

   • Do not use if serum creatinine ≥2.5 mg/dL (men) or ≥2.0 mg/dL (women), or if potassium ≥5.0 mEq/L. 3

Blood Pressure Targets

• Target systolic BP <130 mmHg and diastolic BP <80 mmHg for most patients with CKD. 1, 5
• For moderate-to-severe CKD (eGFR >30 mL/min/1.73 m²), aim for systolic BP 120-129 mmHg if tolerated. 3, 5

Critical Safety Considerations

Absolute Contraindications for Dual RAS Blockade

• Never combine with aliskiren (direct renin inhibitor) in patients with diabetes or renal impairment (GFR <60 mL/min). 2
• Pregnancy: Both ACE inhibitors and ARBs are absolutely contraindicated. 1, 3, 5

Common Pitfalls to Avoid

• Do not interpret modest creatinine elevations (<30% increase) as treatment failure requiring discontinuation—this often represents beneficial hemodynamic changes. 3, 5
• Do not add a second RAS inhibitor when BP remains elevated—instead, add a CCB or diuretic. 1, 3, 5
• Avoid NSAIDs in patients on RAS inhibitors, as they worsen renal function and attenuate antihypertensive effects. 3, 2