Is losartan (Angiotensin II Receptor Blocker) more effective than lisinopril (Angiotensin-Converting Enzyme inhibitor) for treating heart failure with reduced ejection fraction (HFrEF)?

Lisinopril is Preferred Over Losartan for Heart Failure with Reduced Ejection Fraction

ACE inhibitors like lisinopril are the superior first-line choice over ARBs like losartan for treating heart failure with reduced ejection fraction (HFrEF), based on stronger mortality evidence and head-to-head trial data. 1

Evidence Hierarchy for Renin-Angiotensin System Inhibition

ACE inhibitors remain the gold standard for initial therapy in HFrEF:

• ACE inhibitors (including lisinopril) have Class I, Level A evidence for reducing mortality and morbidity in HFrEF, established through landmark trials like CONSENSUS and SOLVD that demonstrated 16-27% relative risk reductions in mortality 1

• Losartan specifically failed to demonstrate non-inferiority to captopril in the OPTIMAAL trial and was shown to be less effective than captopril in the ELITE II study 1

• ARBs are recommended primarily as alternatives for patients who are ACE inhibitor-intolerant (typically due to cough or angioedema), not as first-line therapy 1

Direct Comparison Data

The critical evidence against losartan comes from head-to-head trials:

• ELITE II demonstrated that losartan 50 mg daily was NOT as effective as captopril 50 mg three times daily for mortality reduction in elderly HF patients 1

• The HEAAL trial subsequently showed that higher-dose losartan (150 mg daily) was superior to standard-dose losartan (50 mg daily), with a 10% relative risk reduction in death or HF hospitalization, but this still doesn't establish superiority over ACE inhibitors 1, 2

• OPTIMAAL trial confirmed losartan 50 mg once daily did not demonstrate non-inferiority compared with captopril in post-MI patients with HF 1

When ARBs Are Appropriate

ARBs have a defined but secondary role:

• Use ARBs (including losartan) only when ACE inhibitors are not tolerated due to cough or angioedema 1

• The CHARM-Alternative trial showed candesartan reduced cardiovascular or HF hospitalization by 23% in ACE inhibitor-intolerant patients, establishing ARBs as effective alternatives 1

• Valsartan demonstrated non-inferiority to captopril in the VALIANT trial, but losartan did not achieve this benchmark 1

Dosing Considerations Matter

Both drug classes require adequate dosing for maximum benefit:

• Lisinopril should be titrated to high doses (32.5-35 mg daily) based on the ATLAS trial, which showed 12% lower risk of death or hospitalization and 24% fewer HF hospitalizations compared to low doses (2.5-5 mg daily) 1, 3

• If losartan must be used, target 150 mg daily rather than the standard 50 mg dose based on HEAAL trial data showing superior outcomes with higher dosing 1, 2

Current Guideline Recommendations

The treatment algorithm is clear and hierarchical:

• First-line therapy: ACE inhibitor (like lisinopril) + beta-blocker 1

• Second-line: Add mineralocorticoid receptor antagonist if symptoms persist 1

• Third-line: Consider switching ACE inhibitor to ARNI (sacubitril/valsartan) for further mortality reduction, which provides 20% risk reduction compared to ACE inhibitors 1, 4

• ARBs are reserved for ACE inhibitor intolerance, not as equivalent alternatives 1

Practical Implementation

When initiating therapy in a newly diagnosed HFrEF patient:

• Start lisinopril 2.5-5 mg daily, checking renal function and potassium within 1-2 weeks 1

• Titrate every 2-4 weeks toward target dose of 20-35 mg daily as tolerated 1, 3

• Monitor for hypotension, worsening renal function (creatinine increase <0.5 mg/dL is acceptable), and hyperkalemia 1, 5

• Only switch to losartan if intolerable cough or angioedema develops with ACE inhibitor therapy 1

• If using losartan, start at 50 mg daily and titrate to 150 mg daily for maximum benefit 1, 2

Common Pitfalls to Avoid

• Do not use losartan as first-line therapy when ACE inhibitors are tolerated—this contradicts guideline recommendations and trial evidence 1

• Do not accept suboptimal dosing—both ATLAS (for lisinopril) and HEAAL (for losartan) demonstrated dose-dependent benefits 1, 3, 2

• Do not discontinue ACE inhibitors during HF hospitalization without compelling contraindications—withdrawal is associated with 92% higher 30-day mortality and 35% higher 1-year mortality 5

• Asymptomatic hypotension or mild creatinine elevation (<0.5 mg/dL increase) should not prompt discontinuation 1, 5

The evidence unequivocally supports lisinopril (and ACE inhibitors generally) over losartan for HFrEF treatment, with ARBs reserved exclusively for ACE inhibitor-intolerant patients. 1