Which renin‑angiotensin‑aldosterone system inhibitor should be started after an acute myocardial infarction: an angiotensin‑converting enzyme inhibitor or an angiotensin receptor neprilysin inhibitor (e.g., sacubitril/valsartan)?

ACE Inhibitor Should Be Started First After Acute MI

Start an ACE inhibitor (not ARNI) as the first-line RAAS inhibitor after acute myocardial infarction. The 2025 ACC/AHA/ACEP/NAEMSP/SCAI guidelines explicitly recommend ACE inhibitors for patients with AMI, particularly those with LVEF ≤40%, anterior STEMI, or heart failure symptoms 1. ARNI (sacubitril/valsartan) has not demonstrated superiority over ACE inhibitors in the acute post-MI setting and carries increased risk of symptomatic hypotension.

Evidence-Based Rationale

ACE Inhibitors Are Guideline-Recommended for Post-MI

The 2025 guidelines provide Class 1 recommendations for ACE inhibitors in acute MI patients with:

• LVEF ≤40% 1
• Anterior STEMI 1
• Heart failure symptoms 1

ACE inhibitors reduce all-cause mortality, major adverse cardiovascular events, and nonfatal cardiac failure in this population 1. The benefit is greatest in patients with hypertension, diabetes, and anterior STEMI 1.

ARNI Failed to Show Superiority in Acute MI

The PARADISE-MI trial directly compared sacubitril/valsartan to ramipril in 5,661 patients with acute MI complicated by reduced LVEF, pulmonary congestion, or both 2. Sacubitril/valsartan did not significantly reduce the primary outcome of cardiovascular death or incident heart failure (11.9% vs 13.2%; HR 0.90,95% CI 0.78-1.04, P=0.17) 2.

Critical safety concern: Symptomatic hypotension occurred in 28.3% of ARNI patients versus 21.9% with ACE inhibitor 3. This 6.4% absolute increase in hypotension is clinically significant in the acute post-MI period when hemodynamic stability is paramount.

ARNI Is Reserved for Established Heart Failure

The 2022 AHA/ACC/HFSA heart failure guidelines clearly state that ARNI efficacy in patients with LV dysfunction and HF in the early post-MI period remains uncertain 4. ARNI is indicated for:

• Chronic symptomatic HFrEF (not acute MI) 4
• Patients already tolerating adequate doses of ACE inhibitor or ARB 4

The FDA labeling for sacubitril/valsartan is for chronic heart failure, not acute MI 5.

Clinical Algorithm for Post-MI RAAS Inhibition

Within 24 hours of STEMI:

1. Start ACE inhibitor at low dose in patients with:

   • LVEF ≤40%
   • Anterior MI location
   • Heart failure symptoms
   • Diabetes or hypertension

2. Titrate ACE inhibitor upward to target doses proven in clinical trials 1

3. Monitor for hypotension, renal dysfunction, and hyperkalemia (K+ >5.0 mEq/L) 1

Consider ARNI transition only if:

• Patient develops chronic symptomatic HFrEF after the acute phase
• Patient is stable and tolerating ACE inhibitor
• At least 36-hour washout period from ACE inhibitor 5
• No contraindications (hypotension, severe renal impairment)

Important Caveats

Do not use ARNI in acute MI based on the negative PARADISE-MI trial and increased hypotension risk. The mixed design of prevention and treatment in PARADISE-MI, combined with the 28.3% hypotension rate, supports a "careful approach with ACE inhibitors as first choice in the first week(s) after myocardial infarction" 3.

ARB is the alternative only if ACE inhibitor causes intolerable cough or angioedema 1. The VALIANT trial showed ARBs are noninferior to ACE inhibitors for mortality in post-MI patients with LV dysfunction 1.

Never combine ACE inhibitor + ARB in acute MI—this increases adverse events without added benefit 1.

While some observational data suggest ARNI may reduce ventricular remodeling 6, this does not translate to improved mortality or heart failure outcomes in the acute MI setting per the definitive PARADISE-MI randomized trial 2. Prioritize proven mortality benefit with ACE inhibitors over surrogate endpoints.