What are the guidelines for using Angiotensin-Converting Enzyme (ACE) inhibitors in patients with hypertension or heart failure, considering their medical history and potential side effects?

ACE Inhibitors: Clinical Guidelines and Practical Implementation

Primary Indications

ACE inhibitors are first-line therapy for heart failure with reduced ejection fraction (HFrEF) and should be initiated in all patients with current or prior symptoms (NYHA class I-IV) unless contraindicated, as they reduce mortality, hospitalizations, and improve quality of life. 1, 2

Specific Patient Populations Requiring ACE Inhibitors:

• Heart failure with reduced ejection fraction (LVEF ≤40-45%): All symptomatic patients regardless of NYHA class 1, 3
• Post-myocardial infarction: Hemodynamically stable patients within 24 hours of acute MI, particularly those with signs of heart failure 1, 2, 4
• Asymptomatic left ventricular systolic dysfunction: To delay or prevent development of symptomatic heart failure 1, 3
• Hypertension: Particularly beneficial in patients with diabetes, chronic kidney disease with albuminuria, or coronary artery disease 5, 2, 4
• Diabetic nephropathy: Especially type 1 diabetes with macroalbuminuria (>300 mg/day), even with normal blood pressure 5, 2
• Chronic kidney disease: Stage 3 or higher, or stage 1-2 with albuminuria 5

Contraindications and Cautions

Absolute Contraindications:

• History of angioedema with previous ACE inhibitor use 2, 4
• Pregnancy or women planning to become pregnant 1, 2, 4
• Bilateral renal artery stenosis 5, 2

Seek Specialist Advice Before Initiating:

• Significant renal dysfunction (creatinine >2.5 mg/dL or >221 μmol/L) 1
• Hyperkalemia (>5.0 mEq/L) 1, 5
• Symptomatic or severe asymptomatic hypotension (systolic BP <90 mmHg) 1, 5

Dosing Strategy

Start Low and Titrate to Target Doses

Begin with low doses and double the dose at minimum 2-week intervals, aiming for target doses proven in clinical trials rather than stopping at initial response. 1, 5, 2

ACE Inhibitor	Starting Dose	Target Dose
Captopril	6.25 mg three times daily	50-100 mg three times daily [1]
Enalapril	2.5 mg twice daily	10-20 mg twice daily [1,3]
Lisinopril	2.5-5.0 mg once daily	30-35 mg once daily [1,3]
Ramipril	2.5 mg once daily	5 mg twice daily or 10 mg once daily [1,5]
Trandolapril	1.0 mg once daily	4 mg once daily [1]

Key Dosing Principles:

• Remember: some ACE inhibitor is better than no ACE inhibitor - if target doses cannot be achieved, use the highest tolerated dose 1, 2
• Higher doses reduce hospitalizations more than lower doses (ATLAS trial evidence) 1
• Abrupt withdrawal should be avoided as it leads to clinical deterioration 1, 5, 2

Monitoring Requirements

Initial and Ongoing Monitoring:

Check serum creatinine, blood urea nitrogen, and potassium within 1-2 weeks of initiation and after each dose increase, then periodically thereafter. 1, 5, 2

• More frequent monitoring required in patients with: preexisting hypotension, hyponatremia, diabetes mellitus, azotemia, or those taking potassium supplements 5, 2
• Monitor blood pressure at each visit 1

Acceptable Laboratory Changes:

An increase in creatinine up to 50% above baseline, or to 3 mg/dL (266 μmol/L), whichever is greater, is acceptable and expected. 1, 5

• Potassium up to 5.5 mEq/L is acceptable 1
• These changes reflect the hemodynamic mechanism of action and do not require dose reduction if asymptomatic 1, 6

Problem-Solving Common Adverse Effects

Hypotension:

Asymptomatic low blood pressure does not require any change in therapy. 1

For symptomatic hypotension:

• Review and reduce/discontinue non-essential vasodilators (nitrates, calcium channel blockers) 1
• If no signs of congestion, consider reducing diuretic dose 1
• If measures fail, seek specialist advice 1

Cough:

ACE inhibitor-induced cough rarely requires treatment discontinuation. 1

• First exclude pulmonary edema as the cause 1
• Cough is common in heart failure patients with smoking-related lung disease 1
• Only discontinue if cough is severe enough to stop sleep AND proven due to ACE inhibitor by withdrawal/rechallenge 1
• Substitute an angiotensin receptor blocker (ARB) only for intolerable cough or angioedema 1, 2, 4

Worsening Renal Function:

If creatinine or potassium rise excessively, first stop nephrotoxic drugs (NSAIDs), non-essential vasodilators, and potassium supplements before reducing ACE inhibitor dose. 1

• If no signs of congestion, reduce diuretic dose 1
• Halve ACE inhibitor dose only if creatinine increases by >50% or to >3 mg/dL (266 μmol/L), or potassium rises to >5.5 mEq/L 1
• Seek specialist advice if potassium rises to 6.0 mEq/L or creatinine increases by 100% or to >4 mg/dL (354 μmol/L) 1
• It is very rarely necessary to stop an ACE inhibitor, and clinical deterioration is likely if withdrawn 1

Hyperkalemia Management:

Use potassium-wasting diuretics or potassium binders rather than stopping the ACE inhibitor. 5

• Stop potassium supplements and potassium-retaining agents (triamterene, amiloride) 1
• Monitor serially until potassium plateaus 1

Special Clinical Situations

Hypertension with Blood Pressure ≥160/100 mmHg:

• Consider initial therapy with two agents: ACE inhibitor plus thiazide diuretic 5

Diabetes with Hypertension:

• ACE inhibitors are first-line therapy, particularly with albuminuria 5, 2

Macroalbuminuria with Normal Blood Pressure:

• Initiate ACE inhibitor and uptitrate to maximally tolerated dose regardless of blood pressure status 5
• Restrict sodium to <2.0 g/day (<90 mmol/day) to maximize efficacy 5
• Accept up to 30% increase in serum creatinine as expected 5
• Counsel patient to hold ACE inhibitor during volume depletion to prevent acute kidney injury 5

Heart Failure Management:

• ACE inhibitors should be used together with beta-blockers unless contraindicated 2, 3
• Recent evidence supports simultaneous initiation of all four foundational medication classes (ACE inhibitor/ARB/ARNI, beta-blocker, mineralocorticoid receptor antagonist, SGLT2 inhibitor) with rapid uptitration within 1 month 3

Critical Clinical Pearls

• Do not combine ACE inhibitors with ARBs or direct renin inhibitors - this increases risk of hyperkalemia, syncope, and acute kidney injury 5
• Angioedema occurs in <1% of patients but is more common in Black patients and women 1, 4
• Dry, persistent cough occurs in up to 20% of patients 2, 4
• ACE inhibitors prevent myocardial infarction in high-risk patients 7
• The renoprotective effects of ACE inhibitors are potentiated by sodium depletion 6
• Patients at greatest risk for renal adverse effects (heart failure, diabetes, chronic renal failure) also derive the greatest benefit and should not have ACE inhibitors withheld 6