Angiotensin Receptor-Neprilysin Inhibition in Acute Myocardial Infarction

Angiotensin Receptor-Neprilysin Inhibition in Acute Myocardial Infarction
Makoto Hang, PharmD, Minnesota Community Care

Background: Sacubitril-valsartan has been shown to reduce the risk of hospitalization and death from cardiovascular causes more effectively than angiotensin-converting enzyme inhibitors (ACE-I) in patients experiencing symptomatic heart failure. However, there is a lack of information regarding the effects of these medications in patients experiencing acute myocardial infarctions (MI). 

Purpose: The objective of this trial was to evaluate the superiority of sacubitril-valsartan versus ACE-I in reducing heart failure events after myocardial infarctions.

Study Design: The study was an international, multicenter, randomized, double-blind, active-comparator trial. All eligible patients were assigned in a 1:1 ratio to receive sacubitril-valsartan 97-103 mg or ramipril 5 mg and were followed for a total of 22 months. Patients included were adults without a history of heart failure, and had a spontaneous myocardial infarction within one-half to seven days before presentation with a reduced left ventricular ejection fraction (LVEF) ≤40%, pulmonary congestion requiring intravenous treatment, or both conditions. Patients also needed to have at least one of eight predetermined risk-augmenting factors (age ≥70 years, diabetes mellitus, previous MI, an estimated glomerular filtration rate [eGFR] <60 mL/min/1.73 m2 of body surface area, atrial fibrillation, LVEF <30%, Killip class III or IV, or ST-segment elevation MI without reperfusion within 24 hours after presentation). Patients were excluded if they were clinically unstable (defined as receiving IV diuretics, vasodilators, vasopressors, or inotropes) within 24 hours before randomization, an eGFR <30 mL/min/1.73m2 , serum potassium >5.2 mmol/L, history of angioedema, or were unable to take an ACE-I or angiotensin receptor blocker (ARB). The use of other ACE-I or ARBs were discontinued at randomization. The primary outcome was death from cardiovascular causes or incidental heart failure, whichever occurred first. Secondary outcomes included hospitalization for heart failure or outpatient episodes of symptomatic heart failure, non-fatal MI, and non-fatal stroke.

Results:  A total of 2,830 patients were assigned to receive sacubitril-valsartan and 2,831 patients were assigned to receive ramipril. The average age of both groups of patients were 64 years, roughly 23% of patients were female, and nearly 75% of patients were identified as white. A total of 338 primary outcome events occurred in patients receiving sacubitril-valsartan whereas a total of 373 primary outcome events occurred in patients receiving ramipril (HR 0.90, [95% CI 0.78-1.04]). Patients receiving sacubitril-valsartan were also more likely to experience hypotensive events (28.3% and 21.9% respectively, P<0.001) but were less likely to experience cough-related side effects (9% and 13.1% respectively, P<0.001) Other adverse events such as elevated serum creatinine and potassium were similar in both trial arms. Serum creatinine ≥ 2.0 mg/dL were 5.7% in the sacubitril-valsartan group and 6.0% in the ramipril group (P 0.60). The percentage of elevated serum potassium levels > 5.5 mmol/L in the sacubitril-valsartan group were 14.2% and 12.8% in the ramipril group (P=0.10). 

Conclusion/Key Point: Overall, the treatment with sacubitril-valsartan did not show statistically significant results compared to ramipril in reducing heart failure events post-MI. Secondary outcomes such as hospitalization for heart failure or outpatient episodes of symptomatic heart failure, death from cardiovascular causes, non-fatal MI, and non-fatal stroke were also not statistically significant when comparing both treatment options. 


  1. Pfeffer MA, Clagget B, Lewis EF, et al. Angiotensin receptor-neprilysin inhibition in acute myocardial infarction. N Engl J Med. 2021;385:1845-55. doi: 10.1056/NEJMoa2104508