Because angiotensin II is also a substrate for neprilysin, neprilysin inhibitors raise angiotensin levels, which explains the rationale for coadministration of an ARB. Neprilysin inhibitors are not combined with an ACEI due to a higher risk of angioe- dema (15). Sacubitril/valsartan (16,17) was tested among patients with chronic HFrEF in a randomized controlled trial, FIGURE 3 Continued J Maddox et al. FIGURE 3 Continued Maddox et al. J PARADIGM HF (Prospective Comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in HF). The trial enrolled patients with NYHA class II to IV symptoms with an ejection fraction (EF) #40% (modi ed to #35% 1 year into the trial), stable on doses of ACEIs/ARBs, and on other background GDMT. Patients with a history of angioedema, estimated , symptomatic hypotension or systolic blood pressure <100 mm Hg, or current decompensated HF were excluded. The trial began with a sequential run-in period to ensure that every patient who was randomized could tolerate target doses of both sacubitril/valsartan and the compar- ator enalapril. Of the 10,513 candidates screened, 2,079 were not randomized due to inability to achieve target dose therapy on enalapril or sacubitril/valsartan. Most patients enrolled in PARADIGM-HF had NYHA class II to III symptoms (<100 patients with NYHA class IV symptoms). PARADIGM-HF demonstrated an absolute 4.7% reduc- tion in the primary outcome of CV death or HF hospital- ization (hazard ratio: 0.80; 95% con dence interval [CI]: 0.73 to 0.87; p < 0.001) in patients treated with sacubitril/ valsartan versus enalapril. The number of patients who would need to be treated to prevent 1 primary endpoint over 27 months was 21. These differences in outcomes included a 20% reduction in sudden cardiac death. 