What is the recommended use and dosing of Angiotensin-Converting Enzyme Inhibitors (ACEIs) for treating hypertension and heart failure?

ACE Inhibitor Use and Dosing in Hypertension and Heart Failure

ACE inhibitors should be prescribed to all patients with heart failure due to left ventricular systolic dysfunction (LVEF <35-40%) and are recommended as alternative first-line therapy for hypertension, with preference given to agents proven to reduce morbidity and mortality in clinical trials: captopril, enalapril, lisinopril, perindopril, ramipril, and trandolapril. 1

Selection of ACE Inhibitors

Prioritize ACE inhibitors with proven mortality benefit in large-scale trials rather than agents lacking such evidence, as these studies have clearly defined effective doses for modifying disease natural history. 1 While all ACE inhibitors appear similarly effective for blood pressure control, evidence-based agents should be preferred for cardiovascular protection. 1, 2

The six ACE inhibitors with demonstrated mortality reduction in heart failure or post-MI populations are:

• Captopril 1
• Enalapril 1
• Lisinopril 1
• Perindopril 1
• Ramipril 1
• Trandolapril 1

Dosing Strategy

Heart Failure

Start low and titrate to target doses used in clinical trials, as higher doses reduce hospitalization risk more effectively than low doses, though mortality benefits are similar. 1

ACE Inhibitor	Starting Dose	Target Dose
Captopril	6.25 mg three times daily	50 mg three times daily
Enalapril	2.5 mg twice daily	10-20 mg twice daily
Lisinopril	2.5-5 mg once daily	30-35 mg once daily
Ramipril	1.25-2.5 mg once daily	10 mg once daily
Trandolapril	1 mg once daily	4 mg once daily

For patients with hyponatremia (serum sodium <130 mEq/L), start at 2.5 mg daily. 4

Hypertension

For hypertension, initiate lisinopril at 10 mg once daily and titrate to 20-40 mg once daily based on blood pressure response. 3, 4 The usual maintenance range is 20-40 mg daily, though doses up to 80 mg have been used without additional benefit. 4

If blood pressure remains uncontrolled on ACE inhibitor monotherapy, add a low-dose diuretic (hydrochlorothiazide 12.5 mg) rather than increasing ACE inhibitor dose beyond target. 4

Titration Protocol

Double the dose at intervals of not less than 2 weeks if the previous dose is well tolerated. 1 This gradual up-titration minimizes adverse effects while achieving therapeutic benefit. 1

Aim for target doses demonstrated in clinical trials, but if not tolerated, maintain the highest tolerated dose—some ACE inhibitor is better than no ACE inhibitor. 1 Intermediate doses show only small differences in efficacy compared to high doses. 1

Do not delay beta-blocker initiation due to failure to reach target ACE inhibitor doses, as both medications provide independent mortality benefits. 1

Monitoring Requirements

Check renal function and serum potassium within 1-2 weeks of initiation and periodically thereafter, especially in patients with:

• Pre-existing hypotension 1
• Hyponatremia 1
• Diabetes mellitus 1
• Azotemia 1
• Concurrent potassium supplements 1

An increase in creatinine up to 50% above baseline or to 3 mg/dL (266 μmol/L), whichever is greater, is acceptable. 1 If creatinine or potassium rise excessively, stop nephrotoxic drugs (NSAIDs, potassium supplements) and reduce diuretics if no congestion is present before reducing ACE inhibitor dose. 1

Fluid Management

Ensure appropriate diuretic dosing before and during ACE inhibitor therapy, as fluid retention blunts therapeutic effects while fluid depletion potentiates adverse effects. 1 Most patients (85-90%) tolerate long-term ACE inhibitor therapy when fluid balance is properly managed. 1

Minimize sodium retention or depletion during long-term treatment, as changes in salt and water balance can exaggerate or attenuate cardiovascular and renal effects. 1

Renal Dosing Adjustments

For creatinine clearance >30 mL/min, no dose adjustment is required. 4

For creatinine clearance 10-30 mL/min, reduce initial dose by 50%:

• Hypertension: 5 mg daily 4
• Heart failure: 2.5 mg daily 4
• Post-MI: 2.5 mg daily 4

For hemodialysis or creatinine clearance <10 mL/min, start at 2.5 mg once daily. 4

Common Pitfalls and Management

Hypotension

Asymptomatic low blood pressure requires no intervention. 1 For symptomatic hypotension, first reduce or eliminate non-essential vasodilators (nitrates, calcium channel blockers), then reduce diuretics if no congestion is present, before adjusting ACE inhibitor dose. 1

Cough

ACE inhibitor-induced cough rarely requires discontinuation. 1 Exclude pulmonary edema as the cause before attributing cough to the ACE inhibitor. 1 Only if cough is persistent and severely troublesome (preventing sleep) should substitution with an ARB be considered. 1

Angioedema

Angioedema occurs in <1% of patients but is life-threatening—permanently avoid all ACE inhibitors if this occurs. 1 Exercise extreme caution when substituting an ARB, as angioedema has been reported with ARBs in patients with prior ACE inhibitor-related angioedema. 1

Critical Contraindications

Absolute contraindications:

• History of angioedema with any ACE inhibitor 1
• Life-threatening adverse reactions (anuric renal failure) 1
• Pregnancy 4

Seek specialist advice before initiating in:

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

Long-Term Maintenance

Continue ACE inhibitor therapy indefinitely to reduce death and hospitalization risk, even if symptoms do not improve, as clinical responses may require weeks to months to become apparent. 1 Symptomatic improvement within 48 hours occurs in some patients, but delayed responses are common. 1

Never abruptly withdraw ACE inhibitor therapy, as this can lead to clinical deterioration—only discontinue for life-threatening complications. 1

Avoid NSAIDs during ACE inhibitor therapy, as they block favorable effects and enhance adverse effects in heart failure patients. 1