BACKGROUND: The American College of Cardiology (ACC) and European Society of Cardiology/European Atherosclerosis Society (ESC/EAS) have recently published recommendations for the use of proprotein convertase subtilisin/kexin-9 (PCSK9) inhibitors in situations of very high risk. We aim to assess in the real world the suitability of PCSK9 inhibitors for acute coronary syndromes.METHODS AND RESULTS: We analyzed a prospective Swiss cohort of 2023 patients hospitalized for acute coronary syndromes between 2009 and 2014 with available data for low-density lipoprotein cholesterol and lipid-lowering therapy at 1 year. Clinical familial hypercholesterolemia was defined using the Dutch Lipid Clinic Network algorithm as unlikely, possible, probable, or definite. We simulated a fixed relative reduction of 24% in low-density lipoprotein cholesterol levels at 1 year in all patients not treated with ezetimibe, irrespective of the low-density lipoprotein cholesterol levels and statin regimen. At 1 year, 94.3% of patients were treated with statin, 5.8% with ezetimibe, and 35.8% of patients had on-target low-density lipoprotein cholesterol levels (<1.8 mmol/L); 25.6% met criteria for possible or probable/definite familial hypercholesterolemia. After a simulation of the lipid-lowering effect of ezetimibe, the proportion of patients who would be eligible for PCSK9 inhibitors at 1 year was 13.4% using American College of Cardiology criteria and 2.7% using European Society of Cardiology/European Atherosclerosis Society criteria. Patients with possible or probable/definite familial hypercholesterolemia were more eligible for PCSK9 inhibitors compared with their non-familial hypercholesterolemia counterparts: 27.6% versus 8.8% according to American College of Cardiology criteria and 6.6% versus 1.8% according to European Society of Cardiology/European Atherosclerosis Society criteria (<0.001).CONCLUSIONS: Recommendations made by the American College of Cardiology guidelines would lead to 5-fold higher eligibility rates for PCSK9 inhibitors compared to the European Society of Cardiology/European Atherosclerosis Society consensus statement in acute coronary syndrome patients.