Angiotensin Receptor Neprilysin Inhibition Compared With Enalapril on the Risk of Clinical Progression in Surviving Patients With Heart Failure

Abstract

Packer et al Angiotensin Neprilysin Inhibition in Heart Failure 55Background-Clinical trials in heart failure have focused on the improvement in symptoms or decreases in the risk of death and other cardiovascular events. Little is known about the effect of drugs on the risk of clinical deterioration in surviving patients. Methods and Results-We compared the angiotensin-neprilysin inhibitor LCZ696 (400 mg daily) with the angiotensinconverting enzyme inhibitor enalapril (20 mg daily) in 8399 patients with heart failure and reduced ejection fraction in a double-blind trial. The analyses focused on prespecified measures of nonfatal clinical deterioration. In comparison with the enalapril group, fewer LCZ696-treated patients required intensification of medical treatment for heart failure (520 versus 604; hazard ratio, 0.84; 95% confidence interval, 0.74-0.94; P=0.003) or an emergency department visit for worsening heart failure (hazard ratio, 0.66; 95% confidence interval, 0.52-0.85; P=0.001). The patients in the LCZ696 group had 23% fewer hospitalizations for worsening heart failure (851 versus 1079; P<0.001) and were less likely to require intensive care (768 versus 879; 18% rate reduction, P=0.005), to receive intravenous positive inotropic agents (31% risk reduction, P<0.001), and to have implantation of a heart failure device or cardiac transplantation (22% risk reduction, P=0.07). The reduction in heart failure hospitalization with LCZ696 was evident within the first 30 days after randomization. Worsening of symptom scores in surviving patients was consistently more common in the enalapril group. LCZ696 led to an early and sustained reduction in biomarkers of myocardial wall stress and injury (N-terminal pro-Btype natriuretic peptide and troponin) versus enalapril. Conclusions-Angiotensin-neprilysin inhibition prevents the clinical progression of surviving patients with heart failure more effectively than angiotensin-converting enzyme inhibition. Clinical Trial Registration-URL: http://www.clinicaltrials.gov. Unique identifier: NCT01035255. (Circulation. 2015;131:54-61.

Insights into implementation of sacubitril/valsartan into clinical practice

“…The use of sacubitril/valsartan has convincingly proven its benefit in reducing heart failure hospitalization and cardiovascular mortality in selected patients with HFrEF 1, 8, 9. Despite the firm evidence of benefit, several factors could interfere with drug prescription in clinical practice.…”

Serum Neprilysin and Recurrent Admissions in Patients With Heart Failure

“…Recent initiatives have advocated a more comprehensive portrayal of the natural course of HF by analyzing all hospitalizations that occur during follow‐up 5, 6, 7, 16, 17. Furthermore, recent HF trials have reported the effect of interventions on repeated events 18, 19. For example, the ongoing multinational trial PARAGON‐HF, which was designed to evaluate the effect of sacubitril/valsartan in patients with HF and preserved ejection fraction, selected as a primary end point the cumulative number of a composite of cardiovascular deaths and HF admissions (first and recurrent) (trial no.…”

Rationale and design of TRANSITION: a randomized trial of pre‐discharge vs. post‐discharge initiation of sacubitril/valsartan

“…In addition to a mortality benefit, sacubitril/valsartan was also superior to enalapril in reducing symptoms and physical limitations associated with HF, as assessed by the Kansas City Cardiomyopathy Questionnaire. Fewer patients on sacubitril/valsartan experienced a worsening of NYHA functional class (≥1 class) from baseline to 8 months after starting treatment compared with those on enalapril (5.4% vs. 7.0%, P  = 0.004) 41. Sacubitril/valsartan was associated with a reduction in clinical progression in terms of worsening HF, hospital admissions, and recurrent readmissions,38, 41 an effect that was particularly marked in patients previously hospitalized for HF 42.…”