PARADIGM-HF - angiotensin receptor neprilysin inhibition (ARNI) versus enalapril in reduced ejection fraction heart failure (HFrEF)

PARADIGM-HF - Angiotensin-Neprilysin Inhibition versus Enalapril in Heart Failure

• compared the angiotensin receptor-neprilysin inhibitor LCZ696 with enalapril in patients who had heart failure with a reduced ejection fraction. In previous studies, enalapril improved survival in such patients
  
  
• methodology:
  • double-blind trial, we randomly assigned 8442 patients with class II, III, or IV heart failure and an ejection fraction of 40% or less to receive either LCZ696 (at a dose of 200 mg twice daily) or enalapril (at a dose of 10 mg twice daily), in addition to recommended therapy
    • primary outcome was a composite of death from cardiovascular causes or hospitalization for heart failure, but the trial was designed to detect a difference in the rates of death from cardiovascular causes
  • inclusion:
    • age >=18 years, NYHA class II, III, or IV symptoms at screening, ejection fraction <= 40% (amended to <=35% December 15th, 2010), plasma B-type natriuretic peptide (BNP) >= 150pg/mL (or N-terminal pro-BNP [NT] proBNP] >=600pg/mL) at screening or hospitalized for HF in the past year and BNP >= 100pg/mL (or NT proBNP >=.400pg/mL)
    • treatment with a stable dose of an ACEI or ARB (equivalent to enalapril>=10mg/day) and beta blocker (unless CI or not tolerated) for >=4 weeks prior to screening was permitted. Use of an aldosterone antagonist >=4 weeks prior to screening was encouraged
      
      
• results:
  • trial was stopped early, according to prespecified rules, after a median follow-up of 27 months, because the boundary for an overwhelming benefit with LCZ696 had been crossed
    • at the time of study closure, the primary outcome had occurred in 914 patients (21.8%) in the LCZ696 group and 1117 patients (26.5%) in the enalapril group (hazard ratio in the LCZ696 group, 0.80; 95% confidence interval [CI], 0.73 to 0.87; P<0.001)
    • a total of 711 patients (17.0%) receiving LCZ696 and 835 patients (19.8%) receiving enalapril died (hazard ratio for death from any cause, 0.84; 95% CI, 0.76 to 0.93; P<0.001); of these patients, 558 (13.3%) and 693 (16.5%), respectively, died from cardiovascular causes (hazard ratio, 0.80; 95% CI, 0.71 to 0.89; P<0.001)
    • compared with enalapril, LCZ696 also reduced the risk of hospitalization for heart failure by 21% (P<0.001) and decreased the symptoms and physical limitations of heart failure (P=0.001)
    • LCZ696 group had higher proportions of patients with hypotension and nonserious angioedema but lower proportions with renal impairment, hyperkalemia, and cough than the enalapril group
      
      
• conclusion:
  • In PARADIGM-HF, clinically stable patients with heart failure (HF) on conventional HF therapy and who were treated with LCZ696 had:
    • a lower risk of cardiovascular death and 1st hospitalization for worsening HF (ARR 4.7%, NNT=21/2.25 years),
    • but - more symptomatic hypotension (ARI 4.8%, NNH=21; SBP<90mmHg ARI 1.3%, NNH=77) and non-serious angioedema (n=19 vs 10, NS)

Reference:

• McMurray J, et al. Angiotensin-neprilysin inhibition versus enalapril in heart failure. N Engl J Med 2014;371(11):993-1004