When to initiate Angiotensin-Receptor Neprilysin Inhibitor (ARNI) or Angiotensin-Converting Enzyme (ACE) inhibitors in patients with heart failure and chronic kidney disease (CKD)?

Initiation of ARNI or ACE Inhibitors in Heart Failure with CKD

ACE inhibitors should be initiated in all patients with heart failure and reduced ejection fraction (HFrEF), including those with chronic kidney disease (CKD), starting with low doses and carefully titrating upward while monitoring renal function and electrolytes. 1

Patient Selection and Timing

• ACE inhibitors are recommended as first-line therapy for all patients with HFrEF (EF <40-45%), with or without symptoms 1, 2
• For patients with CKD and heart failure:
  • Start ACE inhibitors in all patients unless contraindicated
  • Contraindications include:
    • Previous life-threatening reactions (angioedema)
    • Pregnancy
    • Bilateral renal artery stenosis
    • Potassium >5.0 mEq/L
    • Severe hypotension (systolic BP <80 mmHg)

Dosing Protocol in CKD

Initial Dosing

• For patients with normal to moderate renal impairment (GFR >30 mL/min):
  • Start with standard low doses (e.g., enalapril 2.5 mg daily, lisinopril 2.5-5 mg daily) 1, 3
• For patients with severe renal impairment (GFR <30 mL/min):
  • Start with reduced doses (e.g., enalapril 2.5 mg every other day) 3
  • For heart failure with severe renal impairment or hyponatremia, start with 2.5 mg daily under close supervision 3

Titration Strategy

1. Start with low dose
2. Check renal function and electrolytes after 5-7 days 1
3. If tolerated, double the dose at 2-week intervals 1
4. Aim for target doses proven effective in clinical trials (e.g., enalapril 10-20 mg twice daily, lisinopril 20-35 mg daily) 1
5. If target doses cannot be achieved, maintain the highest tolerated dose 1

Monitoring Protocol

Before Initiation

• Assess baseline renal function and electrolytes
• Review and adjust diuretic dosing
• Consider withholding diuretics for 24 hours before starting ACE inhibitor to avoid excessive volume depletion 1

After Initiation

• Check blood pressure, renal function, and electrolytes:
  • 1-2 weeks after initiation
  • 1-2 weeks after each dose increment
  • At 3 months
  • Every 6 months thereafter 1
• More frequent monitoring for patients with:
  • Pre-existing renal dysfunction
  • Diabetes mellitus
  • Hyponatremia
  • Concomitant potassium-sparing diuretics 1

Management of Adverse Effects

Worsening Renal Function

• Small increases in creatinine are expected and acceptable:
  • Up to 50% increase from baseline
  • Or up to 3 mg/dL (266 μmol/L), whichever is greater 1
• If greater increases occur:
  • Stop nephrotoxic drugs (NSAIDs)
  • Consider reducing diuretic dose if no congestion
  • If creatinine increases by >100% or >4 mg/dL, seek specialist advice 1

Hyperkalemia

• Potassium up to 5.5 mmol/L is generally acceptable
• If potassium >6.0 mmol/L:
  • Reduce/stop potassium supplements or potassium-sparing diuretics
  • Consider specialist advice 1

ARNI Considerations in CKD

• ARNIs (sacubitril/valsartan) can be used in patients with CKD, including advanced stages (eGFR <30 mL/min/1.73m²) with careful monitoring 4
• For patients with moderate renal impairment, start with half the usual dose 5
• Recent evidence suggests ARNIs can be effective in advanced CKD (stages 4-5) with careful monitoring of potassium and renal function 4

Common Pitfalls and Cautions

1. Excessive diuresis before ACE inhibitor initiation - can lead to severe hypotension and acute kidney injury

   • Solution: Consider reducing or withholding diuretics 24 hours before starting ACE inhibitor 1, 6

2. Failure to monitor renal function - may miss progressive renal deterioration

   • Solution: Implement structured monitoring protocol as outlined above

3. Abrupt withdrawal - can lead to clinical deterioration

   • Solution: If stopping is necessary, taper gradually when possible 1

4. Drug interactions - NSAIDs can reduce efficacy and worsen renal function

   • Solution: Avoid NSAIDs and COX-2 inhibitors in these patients 1, 2

5. Dual RAAS blockade - combining ACE inhibitors with ARBs increases adverse effects

   • Solution: Avoid dual RAAS blockade in CKD patients 7

By following these guidelines, clinicians can safely initiate and optimize ACE inhibitor or ARNI therapy in patients with heart failure and CKD, improving outcomes while minimizing risks of adverse effects.