What is the preferred initial treatment with Angiotensin-Converting Enzyme (ACE) inhibitors or Angiotensin Receptor Blockers (ARBs) in patients with heart failure?

ACE Inhibitors vs ARBs in Heart Failure

ACE inhibitors are the preferred initial treatment for heart failure with reduced ejection fraction and should be used as first-line therapy unless contraindicated or not tolerated. 1

Primary Recommendation

ACE inhibitors remain the established first-line therapy for all patients with reduced left ventricular systolic function (ejection fraction <40-45%), whether symptomatic or asymptomatic, based on Class I, Level A evidence demonstrating improved survival, reduced hospitalizations, and improved functional capacity. 1

When to Use ACE Inhibitors (First-Line)

• All patients with symptomatic heart failure and reduced ejection fraction should receive ACE inhibitors unless contraindicated 1
• Asymptomatic patients with documented left ventricular systolic dysfunction should be treated with ACE inhibitors to delay or prevent development of heart failure and reduce risk of myocardial infarction and sudden death 1
• Post-myocardial infarction patients with signs or symptoms of heart failure (even if transient) should receive ACE inhibitors to improve survival and reduce reinfarctions 1

When to Use ARBs Instead

ARBs serve as an alternative, not a superior option, and should be used in specific circumstances:

• ACE inhibitor intolerance (primarily cough or angioedema): ARBs are recommended as an effective alternative to improve morbidity and mortality (Class I, Level B evidence) 1
• True ACE inhibitor contraindications: bilateral renal artery stenosis or previous angioedema with ACE inhibitor therapy 1

The 2013 ACC/AHA guidelines note that ARBs are reasonable as first-line alternatives to ACE inhibitors, especially for patients already taking ARBs for other indications, but this represents a weaker recommendation (Class IIa, Level A) compared to ACE inhibitors. 1

Evidence Comparison

Efficacy Evidence

ARBs and ACE inhibitors appear to have similar efficacy on mortality and morbidity in heart failure (Class IIa, Level B evidence), but this equivalence does not establish superiority. 1

The key distinction is that ACE inhibitors have overwhelming evidence from multiple large-scale trials demonstrating mortality reduction, while ARB evidence is less persuasive and based primarily on non-inferiority comparisons. 2, 3, 4

Side Effect Profile

• Cough occurs significantly more frequently with ACE inhibitors (7.9%) compared to ARBs (2.6%) or placebo (1.5%) 5
• In a trial limited to patients with previous ACE inhibitor-induced cough, cough recurred in 69% with lisinopril versus only 20% with valsartan 5
• Angioedema appears less frequent with ARBs than ACE inhibitors, though it can still occur 1, 5
• Renal dysfunction and hyperkalemia risks are similar between both drug classes 1, 6, 5

Dosing Strategy

ACE Inhibitor Titration

Target the doses proven effective in clinical trials, not just symptomatic improvement (Class I, Level A evidence): 1

• Start at low doses and uptitrate to target maintenance doses
• Monitor renal function and electrolytes before initiation, 1-2 weeks after each dose increment, and at 3-6 month intervals 1
• Use proven agents: captopril, enalapril, lisinopril, or ramipril 2

ARB Initiation and Monitoring

Follow similar procedures as ACE inhibitors for initiation and monitoring 1

Common Pitfalls to Avoid

• Do not substitute ARBs for ACE inhibitors based solely on theoretical advantages of more complete angiotensin II blockade—clinical outcomes do not support superiority 3, 7
• Do not underdose ACE inhibitors—uptitrate to target doses from clinical trials, not just until symptoms improve 1
• Do not use ARBs as first-line therapy without justification—they should be reserved for ACE inhibitor intolerance or contraindication 4, 8
• Do not assume ARBs eliminate all ACE inhibitor side effects—renal dysfunction and hyperkalemia occur with both classes 1, 6, 5

Combination Therapy Consideration

Adding ARBs to ACE inhibitors may improve symptoms and reduce heart failure hospitalizations (Class I, Level B evidence), but concerns about negative interactions with beta-blockers have been raised and subsequently refuted in recent studies. 1 This combination should be considered only in patients remaining symptomatic despite maximal ACE inhibitor therapy, particularly those unable to tolerate beta-blockers. 8