Association between up-titration of medical therapy and total hospitalizations and mortality in patients with recent worsening heart failure across the ejection fraction spectrum

Background: The role of neurohormonal inhibition in chronic heart failure is well established. There is limited data on the effect of up-titration of renin angiotensin inhibition (RASi) and beta-blockers (BBs) on clinical outcomes of patients with worsening heart failure (HF) across the left ventricular ejection fraction (LVEF) spectrum. Methods and results: We analyzed data from 2345 patients from BIOSTAT-CHF (80.9% LVEF<40%), who completed a 3-month up-titration period after recent worsening of HF. Patients were classified by achieved dose (% of recommended): ≥100%, 50%–99%, 1%–49%, and none. Recurrent event analysis using joint and shared frailty models was used to examine the association between RASi/BBs dose and all-cause and HF hospitalizations. In the 21-months following up-titration, 512 patients died and 879 (37.5%) had ≥1 hospitalization. RASi up-titration was associated, incrementally, with reduced risk of all-cause hospitalization at all achieved dose-levels compared to no treatment [HR (95%CI): ≥100%: 0.60(0.49–0.74), p < 0.001; 50%–99%: 0.56(0.46–0.68), p < 0.001; 1%–49%: 0.71(0.59–0.86), p < 0.001]. This association was consistent up to an LVEF of 49% (p < 0.001), and when considering only HF hospitalizations. Up-titration of BBs was associated with fewer all-cause hospitalizations only when LVEF was <40% (overall p < 0.001), but with more HF hospitalizations when LVEF was ≥50%. Up-titration of both RASi/BBs was associated with lower mortality in LVEF up to 49%. Conclusion: After recent worsening of HF, up-titration of RASi and BBs was associated with a better prognosis in patients with LVEF ≤49%. Up-titration of BBs was associated with a greater risk of HF hospitalization when LVEF was ≥50%