Table 7.2. Recommendations for the use of sacubitril-valsartan in HFrEF patients.

Recommendations	Class	LE	Comment	Table 2018	Ref.
Sacubitril-valsartan, instead of ACEI/ARB, for symptomatic LV dysfunction, patients with optimal medical therapy for HF with triple therapy to reduce morbidity and mortality.	I	B	2018 recommendation remains current.	Item 7.4 (page 458)	See 2018
Sacubitril-valsartan, as initial treatment for symptomatic chronic HF, may be considered instead of ACEI or ARB.	IIa	C	NEW: Analysis of subgroups of randomized and non-randomized trials have found it safe for patients without prior use of ACEI/ARB.	New	84,92,93
Sacubitril-valsartan, instead of ACEI/ARB, may be considered for hospitalized patients with decompensated HF.	IIa	B	NEW: Randomized trial using surrogate endpoint (reduction of biomarkers) supports the new recommendation.	New	84,92,94
The PARADIGM-HF trial investigated the effects on morbidity and mortality in HFrEF patients of attenuating the deleterious effects of angiotensin II associated with enhancing the protective effect of endogenous natriuretic peptides through the inhibition of neprilysin (an enzyme responsible for the degradation of BNP) using a new medication class, the angiotensin II receptor-neprilysin inhibitor (ARNI), of which the molecule currently available is sacubitril-valsartan, as compared to enalapril.83 The trial included 8,442 patients with symptomatic outpatient HFrEF in an optimized clinical therapy regimen with persistent LVEF ≤ 40%, elevated plasma natriuretic peptide levels, and estimated creatinine clearance ≥ 30 mL/min/1.73 m2. In this population, sacubitril-valsartan was associated with a 21% decrease in hospitalizations for worsening HF, 20% decrease in cardiovascular death, 20% decrease in sudden death, and 16% decrease in overall mortality when compared to enalapril. Based on the results from the PARADIGM-HF trial, we recommend replacing ACEI/ARB with sacubitril-valsartan in HFrEF patients whose symptoms persist even after the use of optimized doses of neurohormonal blockers. More recently, the PIONEER-HF (Angiotensin–Neprilysin Inhibition in Acute Decompensated Heart Failure) trial compared sacubitril-valsartan (n = 440) to enalapril (n = 441) in patients hospitalized for decompensated HF, where the primary outcome was the time-averaged proportional change in the NT-proBNP concentration from baseline through weeks 4 and 8.84 The results show a significant decrease in NT-proBNP, higher with sacubitril-valsartan than with enalapril, and the reduction was already noticeable after the first week of treatment, regardless of prior HF history and/or use of ACEIs or ARBs.94 The side effects were similar for both groups, including hypercalcemia, renal dysfunction, and hypotension. In an open analysis, at the end of 8 weeks (PIONEER-HF extended) where all patients received sacubitril-valsartan for an additional 4 weeks, there was a significant decrease in NT-proBNP in the enalapril group after initiating sacubitril-valsartan use.92 Another prospective observational study, the TRANSITION (Initiation of sacubitril/valsartan in haemodynamically stabilised heart failure patients in hospital or early after discharge) Trial,93 initiated sacubitril-valsartan in 1,002 hemodynamically stabilized HF patients in hospital or early after discharge and found it to be safe and well tolerated, with half of patients reaching the target dose within 10 weeks and few adverse events.93 These results suggest that the use of sacubitril-valsartan is safe in hemodynamically stabilized patients with acute HF; extrapolating the results of the PARADIGM-HF trial, sacubitril-valsartan may be considered for treatment of patients hospitalized for decompensated HF instead of ACEI/ARB. The results from these recent trials also indicate the safety and tolerability of initiating treatment with sacubitril-valsartan instead of ACEIs/ARBs in HFrEF patients, which made up 34% of the sample in the PIONEER-HF trial and 29 of patients in the TRANSITION trial.84,92,93 Taken as a whole, these data suggest initiating sacubitril-valsartan for patients with no prior treatment with ACEIs/ARBs and during episodes of HF decompensation is reasonably safe. Long-term and outcome data on this form of intervention, including mortality rates, are not yet available.

ACEI: angiotensin-converting enzyme II inhibitors; ARB: angiotensin II receptor blockers; ARNI: angiotensin II receptor-neprilysin inhibitors; HF: heart failure; HFrEF: heart failure with reduced ejection fraction; HR: heart rate; LV: left ventricle; LVEF: left ventricular ejection fraction; RAAS: renin-angiotensin-aldosterone system.