Objectives: The aims of this study were i) to examine the incidence, risk factors and subsequent mortality after high-risk acute myocardial infarction (AMI) and ii) compare the effects of sacubitril/valsartan with the ACE inhibitor ramipril across heart failure (HF) risk categories. Background: The contemporary risk of developing HF following AMI in the coronary reperfusion era is not well documented. Methods: We analyzed the 5661 patients enrolled in the PARADISE-MI trial which compared sacubitril-valsartan to ramipril after AMI. Patients were required to have acute pulmonary congestion and/or left ventricular systolic dysfunction at the time of AMI, but no history of HF. We analyzed a composite outcome of first occurrence of investigator-reported HF hospitalization or outpatient development of HF. Results: During a median follow up of 22 months, 734 patients (13%) developed a first episode of HF, of which 496 (68%) were a hospitalization and 238 (32%) an outpatient HF episode. Only 74 patients (10%) experienced another AMI prior to developing HF. Independent predictors for the development of HF were a lower baseline left ventricular ejection fraction (LVEF), pulmonary congestion, diabetes, older age, higher heart rate, previous MI, and renal dysfunction. A risk-score showed an exponential increased risk of developing HF with a higher score (Figure 1). The relative effect of sacubitril/valsartan compared to ramipril was similar across the HF risk spectrum (p-value for interaction=0.14). The hazard ratio for cardiovascular mortality after outpatient development of HF (in comparison to no event) was 3.9 (95% CI 2.5-6.2) and after an HF hospitalization was 10.0 (95% CI 7.8-12.8). Conclusion: New onset HF after high-risk AMI was common and resulted in a 10-fold higher cardiovascular mortality than no HF. Sacubitril/valsartan, compared to ramipril, showed similar efficacy across the HF risk spectrum.