Efficacy and Safety of Sacubitril/Valsartan in High-Risk Patients in the PIONEER-HF Trial

Background: In patients stabilized during hospitalization for acute decompensated heart failure (HF), initiation of sacubitril/valsartan compared with enalapril decreased the risk of cardiovascular death or rehospitalization for HF without increasing the risk of adverse events. It is unknown whether potentially high-risk subpopulations have a similar risk-benefit profile. Methods: PIONEER-HF (Comparison of Sacubitril/Valsartan Versus Enalapril on Effect on NT-proBNP [N-terminal pro-B type natriuretic peptide] in Patients Stabilized From an Acute HF Episode) was a multicenter, randomized, double-blind trial of in-hospital initiation of sacubitril/valsartan (n=440) versus enalapril (n=441) in patients stabilized during hospitalization for acute decompensated HF. The composite of cardiovascular death or rehospitalization for HF was adjudicated. Safety outcomes included worsening renal function, symptomatic hypotension, and hyperkalemia. We evaluated heterogeneity in the effect of sacubitril/valsartan on these efficacy and safety outcomes in selected subgroups of clinical concern: patients with baseline systolic blood pressure ≤118 mm Hg (median; n=448), baseline NT-proBNP >2701 pg/mL (median; n=395), estimated glomerular filtration rate 2 (n=455), ≥1 additional hospitalization for HF within the prior year (n=343), admission to the ICU during the index hospitalization (n=96), inotrope use during the index hospitalization (n=68), and severe congestion (n=219). Results: The relative risk reduction in cardiovascular death or rehospitalization for HF with sacubitril/valsartan versus enalapril was consistent across all high-risk subgroups ( P interaction=non-significant [NS] for each). The risks of worsening renal function, symptomatic hypotension, and hyperkalemia with sacubitril/valsartan versus enalapril were also consistent in each high- versus low-risk subgroup ( P interaction=NS for each). Conclusions: In high-risk subpopulations admitted for acute decompensated HF, treatment with sacubitril/valsartan after initial stabilization conferred a consistent reduction in cardiovascular death or rehospitalization for HF and was well tolerated.