For heart failure guideline‑directed medical therapy, should I start an angiotensin‑converting enzyme inhibitor (ACE inhibitor) or an angiotensin receptor blocker (ARB)?

ACE Inhibitor vs ARB in Heart Failure GDMT

Start with an ACE inhibitor as first-line therapy for heart failure with reduced ejection fraction (HFrEF), but strongly consider transitioning to an ARNI (sacubitril-valsartan) as soon as the patient is stable and tolerating therapy, as ARNI provides superior mortality and morbidity reduction compared to ACE inhibitors. 1

Primary Recommendation Framework

First-Line Therapy Hierarchy

• ACE inhibitors remain the traditional first-line renin-angiotensin system (RAS) inhibitor for newly diagnosed HFrEF patients, with established mortality reduction of 17% in pivotal trials 1
• However, ARNI (sacubitril-valsartan) is now recommended as the preferred agent once patients are stabilized, as it provides an additional 16% relative risk reduction in all-cause mortality beyond ACE inhibitor therapy 1
• ARBs should be reserved as alternatives specifically for patients who cannot tolerate ACE inhibitors due to intolerable cough or who have a history of angioedema with ACE inhibitors 1

When to Use Each Agent

ACE Inhibitors (enalapril, lisinopril, ramipril):

• Initial therapy in newly diagnosed HFrEF patients 1
• Patients with cost or access barriers to ARNI 1
• Starting doses: enalapril 2.5 mg twice daily, lisinopril 2.5-5 mg daily, ramipril 1.25 mg daily 1
• Target doses: enalapril 10-20 mg twice daily, lisinopril 20-40 mg daily, ramipril 10 mg daily 1

ARBs (candesartan, losartan, valsartan):

• Only when ACE inhibitors cause intolerable cough (not for other side effects like hypotension or renal dysfunction, which occur with ARBs too) 1
• Patients with documented angioedema history on ACE inhibitors 1
• ARBs do NOT provide superior outcomes compared to ACE inhibitors—they are therapeutically equivalent alternatives, not upgrades 1, 2, 3
• Starting doses: candesartan 4-8 mg daily, losartan 25-50 mg daily, valsartan 40 mg twice daily 1

ARNI (sacubitril-valsartan):

• Preferred agent for chronic symptomatic HFrEF (NYHA class II-III) once patients tolerate ACE inhibitor or ARB 1
• Can be initiated de novo in hospitalized patients before discharge 1
• May be initiated de novo in chronic HFrEF to simplify management, though data are more limited 1
• Provides 20% reduction in cardiovascular death or HF hospitalization compared to enalapril 1
• Starting dose: 24/26 mg to 49/51 mg twice daily; target dose: 97/103 mg twice daily 1

Critical Safety Considerations

Angioedema Risk

• ARNI is absolutely contraindicated in patients with any history of angioedema (Class 3: Harm recommendation) 1
• ACE inhibitors are absolutely contraindicated in patients with any history of angioedema (Class 3: Harm recommendation) 1
• ARBs are the only RAS inhibitor option for patients with prior angioedema 1

Washout Period

• Mandatory 36-hour washout period between stopping ACE inhibitor and starting ARNI (Class 3: Harm recommendation) 1
• This prevents the combined neprilysin and ACE inhibition that dramatically increases angioedema risk 1
• Never administer ARNI concomitantly with ACE inhibitor 1

Practical Implementation Strategy

Optimal Sequencing

1. Initiate ACE inhibitor at low dose in newly diagnosed HFrEF patients 1
2. Uptitrate ACE inhibitor to target or maximally tolerated dose over weeks 1
3. Transition to ARNI once patient is stable on ACE inhibitor therapy (typically within weeks to months) 1
4. Alternative: Initiate ARNI de novo in hospitalized patients before discharge or in chronic HFrEF to simplify management 1

Why Not Start with ARB?

• ARBs offer no mortality or morbidity advantage over ACE inhibitors in head-to-head trials (ELITE II showed equivalence, not superiority) 2, 3
• ARBs have the same side effect profile as ACE inhibitors (hypotension, hyperkalemia, renal dysfunction) except for cough 1, 4
• The only valid reason to choose ARB over ACE inhibitor is intolerable cough 1, 3
• Since ARNI contains an ARB component (valsartan), starting with ACE inhibitor allows assessment of RAS inhibitor tolerance before committing to the more expensive ARNI 1

Comparative Efficacy Data

Number Needed to Treat (Standardized to 12 months)

• ACE inhibitor or ARB: NNT = 77 to prevent one death 1
• ARNI (incremental benefit beyond ACE inhibitor): NNT = 80 to prevent one additional death 1
• Beta-blocker: NNT = 28 (for comparison—emphasizes importance of comprehensive GDMT) 1
• MRA: NNT = 18 (for comparison) 1

Key Clinical Trial Evidence

• PARADIGM-HF demonstrated ARNI superiority over enalapril with 20% reduction in cardiovascular death or HF hospitalization 1
• PIONEER-HF showed ARNI can be safely initiated in hospitalized patients with similar adverse event rates to enalapril 1
• Recent real-world data (2025) confirms superior outcomes with sacubitril-valsartan versus ACE inhibitor/ARB across 6- and 12-month follow-up in patients with EF ≤60% 5

Common Pitfalls to Avoid

• Do not use ARB as first-line therapy instead of ACE inhibitor unless there is documented ACE inhibitor intolerance 1, 3
• Do not delay transition to ARNI in stable patients who tolerate ACE inhibitor/ARB—this represents underutilization of superior therapy 1, 6
• Do not combine ACE inhibitor + ARB routinely—combination therapy has not shown survival benefit and increases adverse events 3
• Do not forget the 36-hour washout when switching from ACE inhibitor to ARNI 1
• Do not use ARNI in patients with angioedema history regardless of which agent caused it 1

Economic Value Consideration

• ARNI provides high economic value (Value Statement: High Value A) when used instead of ACE inhibitor in chronic symptomatic HFrEF despite higher acquisition costs 1
• This reflects reduced hospitalizations and improved outcomes that offset medication costs 1