Background:
The aim of this analysis was to examine the effect of the angiotensin receptor neprilysin inhibitor (ARNI) sacubitril/valsartan (LCZ696), compared with enalapril, on progressive worsening over time in patients with heart failure and reduced ejection fraction (HF-REF) enrolled in the Prospective comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidly in Heart Failure trial (PARADIGM-HF).
Methods:
In PARADIGM-HF, 4212 patients were randomized to enalapril and 4187 to sacubitril/valsartan. The primary outcome was the composite of cardiovascular (CV) death or hospitalization for heart failure (HF). To make a more comprehensive evaluation of HF worsening over time, we analysed the broader composite of CV death, HF hospitalization, emergency department visit for HF or intensification of therapy for HF (as time-to-first event) using the Kaplan-Meier (KM) method.
Results:
At baseline, 71% of patients were in NYHA functional class II and 24% in class III. Their mean LVEF was 27% and 93% were treated with a beta-blocker and 56% with a mineralocorticoid receptor antagonist. The median duration of follow-up was 27 months. The 1, 2 and 3 year KM rates for the composite outcome in the enalapril group were 16.5 (95% CI 15.5, 17.7)%, 27.6 (26.2, 29.1) and 34.8 (33.1-36.6)%, respectively. The corresponding rates in the sacubitril/valsartan group were 13.4 (12.4, 14.5), 22.1 (20.8, 23.4) and 29.5 (27.9, 31.2)%, respectively. Overall 1275 enalapril treated and 1038 sacubitril/valsartan treated patients had an event, giving a hazard ratio 0.79 (95% CI 0.73, 0.86), p<0.0001. Over the course of the trial, 55 fewer patients per 1000 treated with sacubitril/valsartan, compared with enalapril, experienced worsening (number needed to treat = 18).
Conclusions:
Even in patients with predominantly mild symptoms, well treated with evidence-based pharmacological therapy, worsening of HF over time was common, with more than a third of patients exhibiting progression within 3 years. The ARNI sacubitril/valsartan led to clinically important relative and absolute reductions in progressive worsening, compared with enalapril.
The angiotensin receptor neprilysin inhibitor LCZ696 improves systolic cardiac function compared to angiotensin converting enzyme inhibition (ACEi) in a rat model of myocardial infarction
