What head‑to‑head trial compared an ACE inhibitor (e.g., lisinopril) with an ARB (e.g., losartan) in heart‑failure patients and what were the results?

Head-to-Head Trial: ACE Inhibitor vs ARB in Heart Failure

The ELITE II trial directly compared losartan (ARB) with captopril (ACE inhibitor) in 3,152 elderly heart failure patients and found no significant difference in all-cause mortality, though captopril showed a trend toward better outcomes and losartan was better tolerated with fewer discontinuations due to adverse effects. 1

Key Trial Results

ELITE II (Definitive Study)

The ELITE II Losartan Heart Failure Survival Study was designed to confirm findings from the smaller ELITE I trial and enrolled patients aged ≥60 years with NYHA class II-IV heart failure and ejection fraction ≤40%. 1

Primary outcomes showed:

• All-cause mortality: 11.7% vs 10.4% annual mortality rate for losartan vs captopril (hazard ratio 1.13,95% CI 0.95-1.35, p=0.16) - not statistically significant 1
• Sudden death or resuscitated arrest: 9.0% vs 7.3% (hazard ratio 1.25,95% CI 0.98-1.60, p=0.08) - favoring captopril but not significant 1
• Tolerability: Significantly fewer losartan patients discontinued due to adverse effects (9.7% vs 14.7%, p<0.001), particularly cough (0.3% vs 2.7%) 1

ELITE I (Preliminary Study)

The original ELITE study in 722 elderly patients (≥65 years) surprisingly showed lower mortality with losartan (4.8% vs 8.7%, risk reduction 46%, p=0.035), but this was a secondary endpoint in a trial primarily designed to assess renal safety. 2 This unexpected finding prompted the larger ELITE II trial, which failed to confirm the mortality benefit. 1

Current Guideline Recommendations

ACE inhibitors and ARBs are considered equivalent first-line options for renin-angiotensin system inhibition in heart failure with reduced ejection fraction (HFrEF), with ARBs reserved primarily for ACE inhibitor-intolerant patients. 3

Specific Indications for ARB Use:

• Intolerable cough from ACE inhibitors 3
• History of angioedema with ACE inhibitors (use with caution, as cross-reactivity can occur) 3
• Alternative when both ACE inhibitors and ARNI (angiotensin receptor-neprilysin inhibitor) are contraindicated 3

Important Caveats:

• Both drug classes reduce morbidity and mortality in HFrEF when compared to placebo 3
• ARNI (sacubitril-valsartan) has now superseded both ACE inhibitors and ARBs as the preferred renin-angiotensin system inhibitor in patients with chronic symptomatic HFrEF NYHA class II-III who tolerate these medications 3
• Cost-effectiveness analyses show both ACE inhibitors and ARBs provide high economic value due to generic availability 3

Clinical Algorithm for Drug Selection

For newly diagnosed HFrEF patients:

1. Start with ARNI (sacubitril-valsartan) if patient is hemodynamically stable and has no contraindications 3
2. If ARNI unavailable or contraindicated, use ACE inhibitor as first choice 3
3. Use ARB only if ACE inhibitor causes intolerable cough or angioedema 3

For patients already on ACE inhibitor or ARB:

• Switch to ARNI if NYHA class II-III symptoms persist and patient tolerates current therapy 3
• Allow ≥36 hours washout period when switching from ACE inhibitor to ARNI to avoid angioedema risk 3

Safety Considerations

Common adverse effects requiring monitoring:

• Hypotension (more common with ACE inhibitors in acute MI patients) 4
• Hyperkalemia (occurred in 2.2% hypertension, 4.8% heart failure patients on lisinopril) 4
• Renal dysfunction (reversible increases in BUN/creatinine in ~2% with ACE inhibitors alone, 11.6% with concomitant diuretics) 4
• Cough is significantly more common with ACE inhibitors (2.7% captopril vs 0.3% losartan in ELITE II) 1
• Angioedema risk exists with both classes but is lower with ARBs 3

The bottom line: While ELITE II demonstrated equivalent mortality outcomes between losartan and captopril, the current standard of care has evolved beyond this comparison, with ARNI now representing the preferred renin-angiotensin system inhibitor for most HFrEF patients. 3