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 Management

Primary Indications

ACE inhibitors are first-line therapy for heart failure with reduced ejection fraction (HFrEF) and hypertension, with proven mortality reduction and should be initiated in all eligible patients unless contraindicated. 1, 2

Heart Failure

• Use ACE inhibitors in all patients with NYHA class I-IV heart failure with reduced ejection fraction to reduce mortality, hospitalizations, and improve quality of life 1
• ACE inhibitors are first-line treatment alongside beta-blockers for symptomatic CHF 1
• Benefits extend to patients with asymptomatic left ventricular systolic dysfunction, preventing progression to symptomatic heart failure 1
• Post-myocardial infarction patients with left ventricular dysfunction benefit from ACE inhibitor therapy with increased survival 1

Hypertension

• ACE inhibitors are recommended as first-line therapy for hypertension, particularly in patients with diabetes, chronic kidney disease with albuminuria, or coronary artery disease 3, 2, 4
• For blood pressure ≥160/100 mmHg, initiate dual therapy with an ACE inhibitor plus thiazide diuretic 3
• Lowering blood pressure reduces fatal and non-fatal cardiovascular events, primarily strokes and myocardial infarctions 4

Diabetic Nephropathy and Chronic Kidney Disease

• ACE inhibitors are first-line therapy for patients with macroalbuminuria (≥300 mg/day), even with normal blood pressure 3
• Use in chronic kidney disease stage 3 or higher, or stage 1-2 with albuminuria, to slow kidney disease progression 3, 2

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Dosing Strategy

Initial Dosing and Titration

Start with low doses and titrate upward at 2-week intervals to target doses proven in clinical trials, as higher doses reduce death and hospitalization more than lower doses. 1, 3

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

1, 3, 2

• Double the dose at minimum 2-week intervals if tolerated 1
• Aim for target doses; if not tolerated, use the highest tolerated dose—some ACE inhibitor is better than none 1
• For macroalbuminuria, uptitrate to maximally tolerated doses regardless of blood pressure 3

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Monitoring Requirements

Initial and Ongoing Monitoring

Check serum creatinine and potassium within 1-2 weeks of initiation and after each dose increase, then periodically thereafter. 3, 2, 5

• More frequent monitoring required in patients with preexisting hypotension, hyponatremia, diabetes, azotemia, or those taking potassium supplements 3, 2
• Monitor blood pressure at each visit 1
• For proteinuric patients, monitor urine albumin excretion periodically to assess treatment response 3

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Contraindications

Absolute Contraindications

• History of angioedema with previous ACE inhibitor use 3, 2
• Pregnancy or women planning to become pregnant 3, 2, 4
• Bilateral renal artery stenosis 3, 2

Relative Contraindications (Seek Specialist Advice)

• Significant renal dysfunction (creatinine >2.5 mg/dL or >221 μmol/L) 1
• Hyperkalemia (>5.0 mEq/L) 1, 3
• Symptomatic or severe asymptomatic hypotension (systolic BP <90 mmHg) 1, 3

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Managing Common Side Effects

Hypotension

Asymptomatic low blood pressure does not require treatment discontinuation or dose adjustment. 1

• If symptomatic hypotension occurs, discontinue non-essential vasodilators (nitrates, calcium channel blockers) 1, 5
• If no signs of congestion, reduce diuretic dose 1, 5
• If these measures fail, seek specialist advice 1

Cough

• ACE inhibitor-induced cough occurs in up to 20% of patients but rarely requires discontinuation 1, 2, 4
• Exclude pulmonary edema when new or worsening cough develops 1
• If cough is severe (e.g., preventing sleep) and proven due to ACE inhibitor (recurs after withdrawal and rechallenge), substitute an angiotensin receptor blocker 1, 2

Renal Function 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

Management Algorithm for Rising Creatinine:

1. Discontinue nephrotoxic medications: NSAIDs, non-essential vasodilators (calcium channel blockers, nitrates), potassium supplements, potassium-retaining agents (triamterene, amiloride) 1, 5
2. Reduce diuretic dose if no signs of congestion 1, 5
3. If creatinine rises >50% or >3 mg/dL despite above measures: Halve the ACE inhibitor dose and recheck blood chemistry in 1-2 weeks 1, 5
4. If creatinine increases by 100% or to >4 mg/dL (354 μmol/L): Seek specialist advice 1, 5
5. Monitor serially until creatinine plateaus 1, 5

It is very rarely necessary to stop an ACE inhibitor; clinical deterioration is likely if treatment is withdrawn. 1, 5

Hyperkalemia

Potassium up to 5.5 mEq/L is acceptable; aggressive management allows ACE inhibitor continuation in most cases. 1, 3

Management Algorithm for Rising Potassium:

1. Potassium 5.0-5.5 mEq/L: Continue ACE inhibitor, stop potassium supplements and potassium-retaining agents 1
2. Potassium 5.5-5.9 mEq/L: Stop potassium supplements and potassium-retaining agents, reduce diuretic dose if no congestion, continue ACE inhibitor 5
3. Potassium ≥6.0 mEq/L: Stop potassium supplements and potassium-retaining agents, seek specialist advice before stopping ACE inhibitor 1, 5
4. Consider potassium-wasting diuretics or potassium binders rather than stopping ACE inhibitor 3

Angioedema

• Occurs in <1% of patients, more frequently in Black patients and women 1, 2
• Potentially life-threatening; ACE inhibitors are absolutely contraindicated in patients with prior angioedema 1, 3, 2

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Critical Clinical Pearls

Drug Interactions and Combinations

• Do not combine ACE inhibitors with ARBs or direct renin inhibitors due to increased risk of hyperkalemia, syncope, and acute kidney injury 3
• ACE inhibitors can be used with beta-blockers (recommended in heart failure), diuretics, and other antihypertensives 1, 2

Special Considerations

• Abrupt withdrawal should be avoided as it leads to clinical deterioration in heart failure patients 1, 2
• Sodium restriction (<2.0 g/day) maximizes ACE inhibitor efficacy, particularly for proteinuria 3
• Counsel patients to hold ACE inhibitors during volume depletion (e.g., vomiting, diarrhea) to prevent acute kidney injury 3
• In heart failure, use ACE inhibitors together with beta-blockers unless contraindicated 2

When ACE Inhibitors Cannot Be Used

• Substitute an angiotensin receptor blocker (ARB) for patients intolerant to ACE inhibitors due to cough or angioedema 1, 2
• ARBs reduce mortality and heart failure hospitalizations similarly to ACE inhibitors 1

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Patient Counseling

• Explain that treatment improves symptoms, prevents worsening of heart failure, and increases survival 1
• Symptoms improve within a few weeks to a few months 1
• Advise patients to report dizziness, symptomatic hypotension, or troublesome cough 1
• Inform diabetic patients on insulin or oral antidiabetic agents about potential hypoglycemia risk 4