Lastly, although the number of patients in studies of ARNI with chronic HFrEF and NYHA class IV symptoms is limited, sacubitril/valsartan remains indicated in this higher-risk population; the role of sacubitril/ valsartan in more advanced forms of HFrEF continues to be explored (25). 5.1.3. Initiation of an ARNI De Novo Without Prior Exposure to an ACEI or ARB It is possible that a patient may be identi ed who meets all criteria for initiation of an ARNI but has not yet been treated with an ACEI or ARB. Recent data from clinical studies (7 9), along with aggregate clinical experience, suggest that directly initiating an ARNI, rather than a pretreatment period ACEI or ARB, is a safe and effective strategy. In a prospective study comparing the tolera- bility of different initiation strategies of sacubitril/val- sartan (21), patients with de novo HFrEF or those who were naive to ACEIs/ARBs demonstrated no unexpected adverse effects compared with those already taking an ACEI/ARB. In a similar fashion, in an open-label pro- spective study of patients eligible for ARNI therapy, the PROVE-HF study demonstrated tolerability and signi - cant reverse cardiac remodeling among those with de novo HFrEF or those naive to ACEIs/ARBs, in whom an average 12% increase in LVEF by 1 year was noted. These results are also supported by data from studies of acute HFrEF that indicate ef cacy and tolerability for those not previously treated with an ACEI/ARB (9,26). 