Prognostic importance of heart rate, and effect of sacubitril/valsartan according to heart rate, in PARADIGM-HF.

Background: Heart rate (HR) has emerged as an important prognostic marker in heart failure with reduced ejection fraction (HF-REF). Whether it is independently predictive of natriuretic peptides is unknown. We evaluated the prognostic importance of HR in the Prospective comparison of ARNI with ACEI to Determine Impact on Global Mortality and morbidity in Heart Failure trial (PARADIGM-HF) and examined the effect of sacubitril/valsartan (LCZ696), compared with enalapril, according to HR in this trial. Purpose: To examine the prognostic importance of HR in conjunction with natriuretic peptides in HF-REF and the effect of sacubitril/valsartan compared with enalapril according to baseline HR in patients with HF-REF. Methods: Baseline HR was added to a multivariable predictive model including age, sex, renal function, LVEF, prior myocardial infarction and HF hospitalization, as well as NT pro BNP. We estimated the risk of the primary composite endpoint (cardiovascular death or heart failure hospitalization) and all-cause death according to HR considered as either a categorical or continuous variable. We also examined the effect of randomized treatment according to HR. Results: HR data were available in 8399 PARADIGM-HF patients. HR was not an independent predictor of outcome in patients with atrial fibrillation (n=2223). The relationship between HR (tertiles) and outcome in patients with sinus rhythm is shown in the table. In these patients, each 10 bpm increase in HR was associated with an 8 (3-14%)% increase in adjusted risk of death from any cause and 8 (3-12%) increase risk of the primary composite endpoint. The effect of sacubitril/valsartan compared with enalapril was consistent for all outcomes across HR tertiles and when HR was considered as a continuous variable. In patients with a HR ≥70 bpm in sinus rhythm, the sacubitril/valsartan vs. enalapril hazard ratios for the primary endpoint and all-cause mortality were 0.79 (0.69-0.90) and 0.82 (0.70-0.95), respectively. Conclusions: HR is adds incremental prognostic information to other prognostic variables, including NT proBNP. LCZ696 is equally effective, irrespective of HR (and whether the rhythm is sinus or atrial fibrillation/flutter).