Prospective ARNI versus ACE Inhibitor Trial to Determine Superiority in Reducing Heart Failure Events After MI - PARADISE-MI

Contribution To Literature:

Highlighted text has been updated as of March 6, 2024.

The PARADISE-MI trial showed that sacubitril/valsartan did not reduce the primary endpoint in a contemporary enriched AMI population, compared with ramipril.


The goal of the trial was to assess the efficacy and safety of sacubitril/valsartan compared with ramipril in a contemporary acute myocardial infarction (AMI) population.

Study Design

Eligible patients were randomized in a 1:1 fashion to either sacubitril/valsartan (target dose 97/103 mg BID) (n = 2,830) or ramipril (target 5 mg BID) (n = 2,831).

  • Total number of patients: 5,661
  • Duration of follow-up: 23 months
  • Mean patient age: 64 years
  • Percentage female: 24%

Inclusion criteria:

  • Presentation with AMI
  • Left ventricular ejection fraction (LVEF) ≤40% with or without pulmonary congestion
  • Plus one of the following: age ≥70 years, atrial fibrillation, estimated glomerular filtration rate (eGFR) <60, diabetes mellitus, prior MI, LVEF <30%, Killip class ≥III, ST-segment elevation MI (STEMI) without reperfusion

Exclusion criteria:

  • Prior heart failure (HF)
  • Clinical instability
  • eGFR <30

Other salient features/characteristics:

  • White race: 76%
  • Prior MI: 16%
  • Diabetes mellitus: 43%
  • Index presentation: STEMI, 76%

Principal Findings:

The primary outcome of cardiovascular (CV) death, first HF hospitalization, or outpatient HF for sacubitril/valsartan vs. ramipril, was: 11.9% vs. 13.2% (p = 0.17).

  • CV death: 5.9% vs. 6.7% (p = 0.20)
  • HF hospitalization: 6% vs. 6.9% (p = 0.17)

Secondary outcomes for sacubitril/valsartan vs. ramipril:

  • CV death/MI/stroke: 11.1% vs. 12.3% (p = 0.18)
  • All-cause mortality: 7.5% vs. 8.5% (p = 0.16)
  • Total HF hospitalization, outpatient HF events, and CV mortality: 8.4 vs. 10.1/100 patient-years (PY) (p = 0.02)
  • Hypotension: 28.4% vs. 22.0% (p < 0.05)

Analysis done using win ratio analysis: More serious events were given higher priority. The analysis also included positive events that were not confirmed by the clinical endpoint committee. Total win ratio of sacubitril/valsartan vs. ramipril was 1.17 (95% confidence interval [CI] 1.03-1.33, p = 0.015).

Effect on coronary events:

  • Death from coronary heart disease (CHD), nonfatal MI, angina, coronary revascularization for sacubitril/valsartan vs. ramipril: 6.9 vs. 8.1 events/100 PY (p = 0.04)
  • CHD death or MI: 3.1 vs. 3.6 events/100 PY (p = 0.18)
  • MI: 2.2% vs. 2.6% events/100 PY (p = 0.27)
  • Coronary revascularization: 4.6% vs. 5.4% events/100 PY (p = 0.09)

Effect based on type of AMI: 75.8% had STEMI; the remainder had NSTEMI. Following adjustment for potential confounders, a borderline significant increase in the risk for the primary endpoint was noted in the NSTEMI versus STEMI group (adjusted hazard ratio [HR], 1.19; 95% CI, 1.00-1.41; p = 0.05). Event rates of reinfarction, coronary revascularization, and all-cause mortality were higher among NSTEMI patients. The primary composite outcome occurred at similar rates in patients randomized to sacubitril/valsartan versus ramipril in STEMI (10% vs. 12%; HR, 0.87; 95% CI, 0.73-1.04; p = 0.13) and NSTEMI patients (17% vs. 17%; HR, 0.97; 95% CI, 0.75-1.25; p = 0.80) (p-interaction = 0.53). Similar patterns were found for secondary endpoints (CV death, HF hospitalization, outpatient HF, all-cause death, and a composite of CV death, nonfatal MI, or stroke) with comparable risk estimates for either treatment arms in both types of AMI.


The results of this trial indicate that the combination sacubitril/valsartan did not reduce the primary endpoint in a contemporary enriched AMI population, compared with ramipril. Rates were numerically lower in the sacubitril/valsartan arm, and the composite endpoint that included all HF events, not just the first one, showed a benefit with sacubitril/valsartan. Similarly, there was a reduction noted among recurrent coronary events primarily due to a reduction in coronary revascularization. These are interesting findings, and add to the available data with angiotensin receptor-neprilysin inhibitors (ARNIs). Event rates were higher among NSTEMI versus STEMI patients, but effects of sacubitril/valsartan compared with ramipril were similar irrespective of type of AMI. Some of these findings are hypothesis generating and deserve further study.


Mann DL, Nicolas J, Claggett B, et al. Angiotensin Receptor-Neprilysin Inhibition in Patients With STEMI vs NSTEMI. J Am Coll Cardiol 2024;83:904-14.

Editorial Comment: Udell JA, Armstrong DW. Targeting the Natriuretic Peptide System to Improve Outcomes: PARADISE Lost or Found. J Am Coll Cardiol 2024;83:915-7.

Mehran R, Steg PG, Pfeffer MA, et al. The Effects of Angiotensin Receptor-Neprilysin Inhibition on Major Coronary Events in Patients With Acute Myocardial Infarction: Insights From the PARADISE-MI Trial. Circulation 2022;146:1749-57.

Presented by Dr. Otavio Berwanger at the European Society of Cardiology Congress (ESC 2022), Barcelona, Spain, August 29, 2022.

Presented by Dr. Marc Pfeffer at the American College of Cardiology Virtual Annual Scientific Session (ACC 2021), May 15, 2021.

Study Design Paper: Jering KS, Claggett B, Pfeffer MA, et al. Prospective ARNI vs. ACE inhibitor trial to DetermIne Superiority in reducing heart failure Events after Myocardial Infarction (PARADISEā€MI): design and baseline characteristics. Eur J Heart Fail 2021;23:1040-8.

Clinical Topics: Acute Coronary Syndromes, Heart Failure and Cardiomyopathies, ACS and Cardiac Biomarkers, Acute Heart Failure, Heart Failure and Cardiac Biomarkers

Keywords: ACC21, Acute Coronary Syndrome, ESC22, Heart Failure, Neprilysin, Ramipril

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