In‐Hospital or Out‐of‐Hospital Initiation of Sacubitril/Valsartan Versus Valsartan in Patients With Mildly Reduced or Preserved Ejection Fraction After A Worsening Heart Failure Event: The PARAGLIDE‐HF Trial

Background Efficacy and tolerability of sacubitril/valsartan (Sac/Val) is not well characterized in heart failure (HF) with ejection fraction >40% initiated in‐hospital. Thus, this prespecified PARAGLIDE‐HF (Prospective Comparison of ARNI With ARB Given Following Stabilization In Decompensated HFpEF) analysis assessed the effects of Sac/Val versus valsartan (Val) by location of initiation in HF with ejection fraction >40% and recent worsening HF. Methods and Results This analysis of the double‐blind, randomized controlled trial assessed patients by in‐hospital and out‐of‐hospital (≤30 days of worsening HF) initiation. The primary end point was time‐averaged proportional change in NT‐proBNP (N‐terminal pro‐B‐type natriuretic peptide) from baseline through weeks 4 and 8. A secondary hierarchical outcome consisted of cardiovascular death, HF hospitalizations, urgent HF visits, and NT‐proBNP change. Safety end points were symptomatic hypotension, hyperkalemia, and worsening renal function. Overall, 324 (70%, 162 Sac/Val, 162 Val) were initiated in‐hospital and 142 (71 Sac/Val, 71 Val) out‐of‐hospital. There was no evidence of a statistically significant differential treatment benefit of Sac/Val versus Val on NT‐proBNP change by location of initiation (in‐hospital, 0.86 [95% CI, 0.70–1.05] and out‐of‐hospital, 0.87 [95% CI, 0.70–1.09]; P interaction =0.99). The win ratio for the hierarchical outcome was 1.09 (95% CI, 0.82–1.45; P =0.57) for in‐hospital and 1.43 (95% CI, 0.91–2.26; P =0.12) for out‐of‐hospital. For the safety end points of symptomatic hypotension, hyperkalemia, and worsening renal function, no statistically significant differences in tolerability were seen between in‐hospital and out‐hospital initiation ( P interaction >0.1). Conclusions Sac/Val provided consistent benefit compared with Val, whether initiated in‐hospital or out‐of‐hospital in HF with ejection fraction >40% with a recent worsening HF event, demonstrating an opportunity to improve postdischarge outcomes by initiating Sac/Val during hospitalization.