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). In a pre- speci ed subanalysis from PIONEER-HF, patients with de novo HF who underwent in-hospital initiation of an ARNI had a greater reduction in natriuretic peptide concentra- tions, a comparable safety pro le, and a signi cant improvement in early clinical outcomes compared with those on enalapril (23); such improvement in early clin- ical outcomes would be lost in a scenario of ACEI/ARB pre-treatment. Because of this totality of data, a direct-to-ARNI approach is now recommended. When de novo initiation of ARNI is performed, close follow-up and serial assess- ments (blood pressure, electrolytes, and renal function) should be considered, and any such usage should consider concerns regarding the risk of angioedema or hypotension (Figures 2 and 3, Tables 1 to 4). When making a recommendation to initiate an ARNI (either as a switch or as de novo treatment), the Writing Committee recommends the decision occurs within a Dose Adjustments of Sacubitril/Valsartan for Speci c Patient Populations Population Initial Dose High-dose ACEI > Enalapril 10-mg total daily dose or therapeutically equivalent dose of another ACEI twice daily High-dose ARB > Valsartan 160-mg total daily dose or therapeutically equivalent dose of another ARB De novo initiation of ARNI 24/26 mg twice daily Low- or medium-dose ACEI # Enalapril 10-mg total daily dose or therapeutically equivalent dose of another ACEI Low- or medium-dose ARB # Valsartan 160-mg total daily dose or therapeutically equivalent dose of another ARB ACEI/ARB naive Severe renal impairment* ) Moderate hepatic impairment (Child-Pugh Class B) Elderly (age $75 years) *This population was not studied in the PARADIGM-HF trial. The statement is consistent with FDA-approved labeling indications. 