What are the recommended indications, initial dosing, titration schedule, monitoring parameters, contraindications, adverse effects, and alternative therapy for ACE inhibitors in adult patients?

ACE Inhibitors: Clinical Management Guide

Primary Indications

ACE inhibitors are first-line therapy for patients with reduced left ventricular ejection fraction (LVEF <40-45%), with or without symptoms, to reduce mortality, hospitalizations, and delay disease progression. 1

Established Indications with Mortality Benefit:

• Heart failure with reduced ejection fraction (HFrEF): All patients with LVEF <40-45%, regardless of symptom status 1
• Post-myocardial infarction: Initiate within 24 hours in patients with anterior MI, heart failure, or LVEF ≤0.40 1
• Asymptomatic left ventricular dysfunction: Prevents progression to symptomatic heart failure and reduces risk of MI and sudden death 1
• Hypertension with high cardiovascular risk: Target BP <130/80 mmHg in patients with known CVD or 10-year ASCVD risk ≥10% 1
• Diabetic kidney disease: All patients with diabetes, hypertension, and chronic kidney disease 1
• Post-MI with diabetes or CKD: Continue indefinitely regardless of LVEF 1

Initial Dosing and Titration

Starting Doses (Choose One Agent):

Always start at the lowest dose and uptitrate to target doses proven effective in clinical trials, not based on symptomatic improvement alone. 1

Agent	Initial Dose	Target Dose	Frequency
Lisinopril	2.5-5 mg	20-40 mg	Once daily [1,2,3]
Ramipril	1.25-2.5 mg	10 mg	Once daily [1,2]
Enalapril	2.5 mg	10-20 mg	Twice daily [1,2]
Captopril	6.25 mg	50 mg	Three times daily [1,2]
Trandolapril	1 mg	4 mg	Once daily [1,2]
Perindopril	2 mg	8-16 mg	Once daily [1,2]
Fosinopril	5-10 mg	40 mg	Once daily [1,2]

Titration Schedule:

• Double the dose every 1-2 weeks if tolerated, monitoring BP and renal function before each increase 1
• Target the maximum evidence-based dose from clinical trials, not intermediate doses 1
• Higher doses reduce heart failure hospitalizations more effectively than low doses 2
• Avoid intravenous ACE inhibitors in acute heart failure; oral therapy is preferred after initial stabilization 1

Special Dosing Considerations:

• With fluid retention: Combine with diuretics from initiation 1
• Without fluid retention: ACE inhibitor monotherapy is appropriate 1
• Renal impairment: Use caution when creatinine >2.5 mg/dL or potassium >5.0 mEq/L 2
• Ramipril in CKD: Start 1.25 mg daily if creatinine clearance <40 mL/min 1

Monitoring Parameters

Baseline Assessment:

• Serum creatinine and potassium 1
• Blood pressure 1
• Volume status 1

Follow-Up Monitoring Schedule:

Check renal function and potassium at specific intervals, not just "periodically." 1

• 1-2 weeks after initiation 1
• 1-2 weeks after each dose increase 1
• Every 3-6 months during stable therapy 1
• More frequently in patients with baseline renal dysfunction or electrolyte abnormalities 1
• During any hospitalization 1
• When adding other nephrotoxic agents (aldosterone antagonists, ARBs, NSAIDs) 1

Acceptable Changes During Titration:

• Creatinine increase up to 30% from baseline is acceptable and may predict better long-term renal protection 4
• Systolic BP decrease to 90-100 mmHg is tolerable; discontinue if drops further 1
• Small increases in creatinine are expected and represent the trade-off for long-term renoprotection 4

Absolute Contraindications

Do not prescribe ACE inhibitors in these situations: 1

• Bilateral renal artery stenosis (Class III, Level A) 1
• History of angioedema with previous ACE inhibitor use (Class III, Level A) 1
• Pregnancy 1
• Current ARNI therapy (sacubitril/valsartan) - risk of angioedema 1

Relative Contraindications Requiring Caution:

• Hypotension or shock 1
• Severe volume depletion - correct first 4
• Serum potassium >5.0 mEq/L 2
• Serum creatinine >2.5 mg/dL - use with intensive monitoring 2
• Aortic stenosis - use cautiously with close monitoring 1

Adverse Effects and Management

Common Adverse Effects:

• Dry cough (5-10% of patients): Switch to ARB if intolerable 1
• Hypotension: Most common in volume-depleted patients; reduce diuretics or slow titration 1
• Hyperkalemia: Monitor closely, especially with concurrent aldosterone antagonists or potassium supplements 1
• Acute kidney injury: Usually reversible; most common with bilateral renal artery stenosis or severe volume depletion 4
• Angioedema (rare but serious): Discontinue immediately and never rechallenge 1

Managing Renal Function Decline:

A modest creatinine rise (up to 30%) at initiation predicts better long-term outcomes and should not prompt discontinuation. 4

• If creatinine increases >30%: Reduce dose, check for volume depletion, review concurrent nephrotoxic drugs 4
• If acute renal failure develops: Discontinue temporarily, correct volume status, restart at lower dose when stable 4
• Sodium depletion potentiates both benefits and risks: Adjust sodium intake and diuretics accordingly 4

Alternative Therapy

When to Use ARBs Instead:

ARBs are equivalent alternatives for patients who cannot tolerate ACE inhibitors. 1

• Intolerable cough (Class I, Level A) 1
• Angioedema (Class I, Level A) 1
• Post-MI with LVEF <0.40 and ACE inhibitor intolerance 1

ARB Dosing (If ACE Inhibitor Not Tolerated):

Agent	Initial Dose	Target Dose
Losartan	25-50 mg daily	50-100 mg daily [1]
Valsartan	80 mg daily	160-320 mg daily [1]
Candesartan	16 mg daily	32 mg daily [1]

When to Consider ARNI (Sacubitril/Valsartan):

• Symptomatic HFrEF (NYHA class II-III) already tolerating ACE inhibitor or ARB - superior to enalapril for reducing cardiovascular death and heart failure hospitalization 1
• Never combine with ACE inhibitors - increased angioedema risk 1

Common Pitfalls to Avoid

• Undertitration: Most patients receive suboptimal doses; always target trial-proven doses 1
• Stopping for small creatinine increases: Up to 30% rise is acceptable and beneficial long-term 4
• Avoiding in advanced disease: Patients with NYHA class III-IV benefit most despite higher risk 5
• Using symptom improvement as titration endpoint: Uptitrate to target dose regardless of symptoms 1
• Combining ACE inhibitor with ARNI: Contraindicated due to angioedema risk 1
• Inadequate monitoring: Must check renal function 1-2 weeks after each dose change 1
• Concurrent NSAIDs: Significantly increase risk of renal dysfunction 1