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Circulation. 2022;145:e895–e1032. DOI: 10.1161/CIR.0000000000001063 May 3, 2022 e929 CLINICAL STATEMENTS AND GUIDELINES

HFrEF with NYHA class II or III symptoms and they tolerate an ACEi or ARB, they should be switched to an ARNi because of improvement in morbidity and mortality.1–5 An ARNi is recommended as de novo treatment in hospitalized patients with acute HF before discharge given improvement in health status, reduction in the prognostic biomarker NT-proBNP, and improvement of LV remodeling parameters compared with ACEi/ARB. Although data are limited, the use of an ARNi may be efficacious as de novo treatment in patients with symptomatic chronic HFrEF to simplify management. ARB may be used as an alternative to ACEi in the setting of intolerable cough, or as alternatives to ACEi and ARNi in patients with a history of angioedema. If patients are switched from an ACEi to an ARNi or vice versa, there should be at least 36 hours between ACEi and ARNi doses.

Recommendation-Specific Supportive Text

1.	 An ARNi is composed of an ARB and an inhibitor of neprilysin, an enzyme that degrades natriuretic peptides, bradykinin, adrenomedullin, and other vasoactive peptides. In PARADIGM-HF (Prospective Comparison of ARNi with ACEi to Determine Impact on Global Mortality and Morbidity in Heart Failure), an RCT that compared the first approved ARNi, sacubitril-valsartan, with enalapril in symptomatic patients with HFrEF tolerating an adequate dose of either ACEi or ARB, sacubitril-valsartan significantly reduced the composite endpoint of cardiovascular death or HF hospitalization by 20% relative to enalapril.1 The benefit was observed to a similar extent for death and HF hospitalization and was consistent across prespecified subgroups.1 Use of an ARNi is more frequently associated with symptomatic hypotension and a comparable incidence of angioedema when compared with enalapril.1 Sacubitril-valsartan has been approved for patients with symptomatic HF. HF effects and potential off-target effects may be complex with inhibition of the neprilysin enzyme, which has multiple biological targets. Trial data have included ACEi/ARB-naïve patients before ARNi initiation (53% in the PIONEER-HF [Comparison of Sacubitril-Valsartan versus Enalapril on Effect on NT-proBNP in Patients Stabilized from an Acute Heart Failure Episode] trial and 24% in the TRANSITION [Comparison of Pre- and Post-discharge Initiation of Sacubitril/ Valsartan Therapy in HFrEF Patients After an Acute Decompensation Event] trial) and have shown similar efficacy and safety in treatmentnaïve patients.2,3 The PIONEER-HF trial showed that ARNi reduced NT-proBNP levels in patients hospitalized for acute decompensated HF without increased rates of adverse events (worsening renal function, hyperkalemia, symptomatic hypotension, angioedema) when compared with enalapril.3 Additional outcome analyses suggested reduction in all-cause mortality and rehospitalization for HF but were only hypothesis-generating as exploratory study endpoints. In the open-label TRANSITION trial, patients with HFrEF hospitalized with worsening HF were randomized to start ARNi either before or after discharge.2 Safety outcomes were similar for both arms, suggesting that early initiation may simplify management (rather than initiating and uptitrating ACEi first and then switching to ARNi).2 ARNi should be initiated de novo in patients hospitalized with acute HFrEF before discharge in the absence of contraindications. ARNi may be initiated de novo in patients with chronic symptomatic HFrEF to simplify management, although data are limited. The PARADISE-MI (Prospective ARNi vs ACE Inhibitor Trial to DetermIne Superiority in Reducing Heart Failure Events After MI) trial40 will provide information on whether sacubitril-valsartan will significantly reduce the rate of cardiovascular death, HF hospitalization or outpatient HF requiring treatment in patients after acute MI, with LVEF ≤40% and/or pulmonary congestion, and 1 of 8 additional risk-enhancing factors like AF, previous MI, diabetes, compared with the ACEi ramipril; and whether the safety and tolerability of sacubitril-valsartan was comparable to that of ramipril. Thus, at the present time, the efficacy of ARNi in patients with LV dysfunction, and HF in the early post-MI period, remains uncertain. 2.	 ACEi reduce morbidity and mortality in HFrEF. RCTs clearly establish the benefits of ACE inhibition in patients with mild, moderate, or severe symptoms of HF and in patients with or without CAD.6–11 Data suggest that there are no differences among available ACEi in their effects on symptoms or survival.12 ACEi should be started at low doses and titrated upward to doses shown to reduce the risk of cardiovascular events in clinical trials. ACEi can produce angioedema and should be given with caution to patients with low systemic blood pressures, renal insufficiency, or elevated serum potassium (>5.0 mEq/L). If maximal doses are not tolerated, intermediate doses should be tried; abrupt withdrawal of ACE inhibition can lead to clinical deterioration and should be avoided. Although the use of an ARNi in lieu of an ACEi for HFrEF has been found to be superior, for those patients for whom ARNi is inappropriate, continued use of an ACEi for all classes of HFrEF remains strongly advised. 3.	 ARB have been shown to reduce mortality and HF hospitalizations in patients with HFrEF in large RCTs.14–16 Long-term treatment with ARB in patients with HFrEF produces hemodynamic,

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