What is the role of Angiotensin Receptor-Neprilysin Inhibitors (ARNI) such as sacubitril (valsartan) in managing a patient with type 2 diabetes mellitus who has experienced an acute myocardial infarction?

ARNI in Acute Myocardial Infarction

In patients with acute MI complicated by reduced ejection fraction (≤40%) or pulmonary congestion, sacubitril/valsartan does not significantly reduce cardiovascular death or heart failure events compared to ACE inhibitors and should not be routinely preferred over ramipril or other proven ACE inhibitors in the immediate post-MI period. 1

Evidence from the PARADISE-MI Trial

The PARADISE-MI trial directly addressed this question in 5,661 patients with acute MI complicated by left ventricular systolic dysfunction, pulmonary congestion, or both. 1

Key findings:

• Sacubitril/valsartan (97/103 mg twice daily) did not significantly reduce the primary outcome of cardiovascular death or incident heart failure compared to ramipril (5 mg twice daily) over 22 months (11.9% vs 13.2%; HR 0.90,95% CI 0.78-1.04, P=0.17). 1
• Cardiovascular death occurred in 5.9% with sacubitril/valsartan vs 6.7% with ramipril (HR 0.87,95% CI 0.71-1.08, not significant). 1
• All-cause mortality was 7.5% vs 8.5% respectively (HR 0.88,95% CI 0.73-1.05, not significant). 1

Timing and Patient Selection Considerations

When sacubitril/valsartan was initiated:

• Median of 4.4 days after index MI (range 3.0-5.8 days). 2
• FDA labeling indicates valsartan may be initiated as early as 12 hours post-MI, starting at 20 mg twice daily. 3

Patient characteristics in PARADISE-MI:

• 76% had STEMI, 24% had NSTEMI. 2
• Mean LVEF was 37 ± 9%. 4
• 58% were in Killip class ≥II (pulmonary congestion). 4
• 89% underwent coronary reperfusion. 2

Secondary Coronary Outcomes

A prespecified analysis showed modest coronary benefit:

• Sacubitril/valsartan reduced a composite coronary outcome (coronary death, nonfatal MI, hospitalization for angina, or coronary revascularization) by 14% (HR 0.86,95% CI 0.74-0.99, P=0.04). 2
• Individual components were numerically lower but not statistically significant. 2

Special Consideration for Diabetic Patients

In diabetic patients with heart failure after MI:

• A retrospective study of 170 patients with diabetes, AMI, and heart failure with mid-range ejection fraction showed sacubitril/valsartan improved LVEF more than valsartan alone (54.76% vs 49.28%, P<0.001) and reduced readmission rates (7.14% vs 18.60%, P<0.05) over 12 months. 5
• Sacubitril/valsartan reduced HbA1c by an additional 0.13% compared to enalapril (P=0.0023) and decreased new insulin initiation by 29% (HR 0.71, P=0.0052) in diabetic patients with chronic HFrEF. 6

Current Guideline Recommendations

For chronic coronary syndromes with HFrEF:

• The 2024 ESC guidelines recommend sacubitril/valsartan in patients with LVEF ≤35% of ischemic etiology to reduce HF hospitalization and cardiovascular death compared to ACE inhibitors. 7
• Sacubitril/valsartan may decrease myocardial ischemia through reduced LV wall stress and improved coronary circulation. 7

For acute MI specifically:

• The 2022 JACC Heart Failure review notes that PARADISE-MI did not show significant benefit for the primary endpoint, and "future work is needed to better understand the role of angiotensin receptor-neprilysin inhibitors in ACS-HF." 7

Proven Post-MI Therapy

ACE inhibitors remain the standard:

• FDA labeling confirms valsartan (the ARB component of sacubitril/valsartan) is indicated post-MI in clinically stable patients with LV failure or dysfunction to reduce cardiovascular mortality. 3
• The VALIANT trial showed valsartan was non-inferior to captopril for all-cause mortality post-MI (19.9% vs 19.5%, HR 1.001). 3

For patients with diabetes and acute MI:

• 2024 ESC guidelines strongly recommend SGLT2 inhibitors and GLP-1 receptor agonists (Class I, Level A) to reduce cardiovascular events in patients with type 2 diabetes and coronary syndromes, independent of glycemic control. 7

Practical Algorithm for Post-MI Management

Immediate post-MI (first 7 days):

1. Initiate ACE inhibitor (e.g., ramipril 5 mg twice daily) or ARB if ACE-intolerant, starting at low doses. 3, 1
2. Add beta-blocker once acute HF stabilizes. 7
3. Add mineralocorticoid receptor antagonist if LVEF <40% with symptomatic HF or diabetes. 7
4. For diabetic patients, initiate SGLT2 inhibitor with proven CV benefit. 7

After stabilization (weeks to months post-MI):

• If patient develops chronic HFrEF (LVEF ≤40%) and remains symptomatic despite optimal ACE inhibitor, beta-blocker, and MRA therapy, then consider switching ACE inhibitor to sacubitril/valsartan. 7, 8, 9
• Ensure 36-hour washout period when switching from ACE inhibitor to sacubitril/valsartan. 9

Critical Pitfalls to Avoid

Do not:

• Assume sacubitril/valsartan is superior to ACE inhibitors in acute MI based on chronic HFrEF data—PARADISE-MI showed no significant benefit for the primary endpoint. 1
• Initiate sacubitril/valsartan in acute MI expecting better outcomes than ramipril—the evidence does not support this. 7, 1
• Overlook SGLT2 inhibitors in diabetic patients post-MI—these have Class I, Level A recommendations. 7

Common mistake:

• Extrapolating PARADIGM-HF chronic HFrEF benefits to the acute MI setting—the pathophysiology and timing differ substantially. 1