What is the best ACE inhibitor (Angiotensin-Converting Enzyme inhibitor) or ARB (Angiotensin Receptor Blocker) for a patient with mildly reduced ejection fraction (EF) and impaired renal function (elevated creatinine)?

Best ACE Inhibitor/ARB for Mildly Reduced EF with Elevated Creatinine

Start with a low-dose ACE inhibitor (such as enalapril 2.5 mg twice daily or lisinopril 2.5 mg daily) or ARB (such as losartan 25 mg daily or candesartan 4 mg daily), accepting an initial creatinine rise up to 30% above baseline within the first 2 months, as this early rise is actually associated with long-term renoprotection and does not predict worse outcomes. 1, 2

Choice of Agent: No Superiority Among ACE Inhibitors or ARBs

• There are no differences among available ACE inhibitors in their effects on symptoms or survival in heart failure with reduced ejection fraction 1
• Both ACE inhibitors and ARBs reduce morbidity and mortality in HFrEF with Class I, Level A evidence 1
• ARBs are specifically indicated if ACE inhibitors cause cough or angioedema 1
• The choice between specific agents should be based on cost (generic availability), dosing convenience, and your familiarity with titration schedules rather than efficacy differences 1

Practical Agents and Dosing in Renal Insufficiency

Starting doses for elevated creatinine:

• Enalapril: 2.5 mg twice daily (target 10-20 mg twice daily) 1
• Lisinopril: 2.5 mg daily (target 20-40 mg daily) 1
• Ramipril: 1.25 mg daily (target 10 mg daily) 1
• Losartan: 25 mg daily (target 150 mg daily) 1
• Candesartan: 4 mg daily (target 32 mg daily) 1

Managing the Expected Creatinine Rise

Accept and monitor an early creatinine increase:

• Expect approximately 25% rise above baseline in patients with preexisting renal insufficiency within the first 2-4 weeks 2
• The rise is typically 15% in the first 2 weeks and an additional 10% in weeks 3-4, then stabilizes 2
• Do NOT discontinue therapy unless creatinine rises >30% above baseline during the first 2 months 2
• This early moderate rise (≤30%) is strongly associated with long-term slowing of renal disease progression 2

Critical monitoring parameters:

• Check creatinine and potassium at baseline, 1-2 weeks, and 4 weeks after initiation or dose changes 1
• Discontinue only if: creatinine doubles, potassium ≥5.5-5.6 mmol/L, or symptomatic hypotension persists despite adjusting other medications 1, 2
• Ensure adequate hydration and normal salt intake to prevent excessive creatinine rise 2

Renal Function Thresholds

Safe to initiate with caution when:

• eGFR ≥30 mL/min/1.73 m² 1
• Creatinine ≤221 µmol/L (≤2.5 mg/dL) 1
• Potassium <5.0-5.5 mmol/L 1

Evidence supports use even in severe renal insufficiency:

• In patients with creatinine >221 µmol/L or creatinine clearance <30 mL/min, RAS antagonist use was associated with 24% lower mortality (HR 0.76) compared to no use 3
• Patients with the most advanced renal insufficiency at baseline show maximum slowing of disease progression with ACE inhibitors/ARBs 2

Dose Titration Strategy

Titrate upward despite stable elevated creatinine:

• Neither high-dose continuation nor up-titration of ACE inhibitors/ARBs was associated with adverse long-term renal function changes in patients with CKD stage III/IV 4
• Conversely, down-titration was NOT associated with improvement in eGFR 4
• Attempt to reach target doses shown to reduce cardiovascular events in clinical trials 1
• If target doses are not tolerated, use intermediate doses rather than discontinuing 1

Common Pitfalls to Avoid

Do not discontinue prematurely:

• The poor outcomes associated with side effects often stem from discontinuing therapy rather than the side effects themselves 1
• Stopping an ACE inhibitor/ARB after hyperkalemia was associated with higher risk of death or cardiovascular events despite reduced recurrent hyperkalemia 1
• Abrupt withdrawal can lead to clinical deterioration 1

Avoid dehydration triggers:

• ARF with ACE inhibitors typically occurs after unexpected dehydration from diuretics or gastrointestinal losses, especially in elderly patients 5
• After resolution of ARF, renal function returns to baseline without long-term sequelae 5
• Monitor for concurrent NSAID use, which increases risk of renal dysfunction 6

Do not combine RAS inhibitors:

• Dual blockade (ACE inhibitor + ARB, or adding either to aldosterone antagonist) increases risks of hypotension, hyperkalemia, and acute renal failure without additional benefit 1, 6

Hyperkalemia Management

• Risk of hyperkalemia is approximately 5 times higher with renal insufficiency (creatinine >1.5 mg/dL) 2
• Concomitant diuretic use reduces hyperkalemia risk by approximately 60% 2
• Consider potassium binders if needed to continue therapy rather than discontinuing 1