The Prospective Comparison of ARNi with ACE inhibitor to Determine Impact on Global Mortality and Morbidity in Heart Failure (PARADIGM-HF) trial, involving NYHA class II–IV HFrEF patients, was terminated early due to a 20% relative risk reduction in the composite outcome of CV mortality or HF hospitalization, and a 16% relative risk reduction in all-cause mortality with ARNi compared with enalapril in addition to standard therapies in HFrEF [48]. The gene discussed is ACE; the disease is hydrops fetalis.