PARADIGM-HF Trial: Secondary Analyses Address Unanswered Questions

Pharmacotherapy. 2018 Feb;38(2):284-298. doi: 10.1002/phar.2075.


Our aim was to summarize published secondary analyses of the PARADIGM-HF trial. In the original trial, published in September 2014, sacubitril/valsartan significantly reduced the primary composite outcome of cardiovascular death or heart failure hospitalization compared to enalapril. This summary provides a resource for clinicians to review subsequent analyses of the landmark trial evaluating the benefit of sacubitril/valsartan in various subgroups and providing information regarding optimal use of this new therapy in the broader heart failure population. A full list of publications of the existing PARDADIGM-HF post hoc analyses was obtained and summarized, grouped by focus (e.g., severity of illness, tolerability). Twenty-six publications and one abstract analyzing the PARADIGM-HF trial were reviewed, summarizing the most important results that compared the benefits of sacubitril/valsartan to enalapril, including pertinent subgroup information from each analysis. Key publications evaluated the treatment effect of sacubitril/valsartan based on heart failure severity (i.e., ejection fraction or heart failure risk scores), impact on alternate outcomes, influence of additional therapies, tolerability in patients with comorbidities (i.e., diabetes), long-term benefits, and cost-effectiveness. In addition, nine ongoing phase III and phase IV clinical trials with sacubitril/valsartan were briefly summarized to address potential future uses in more extensive heart failure settings. The benefit of sacubitril/valsartan over enalapril for the primary endpoint in the PARADIGM-HF trial is maintained throughout numerous secondary analyses. Though the subgroups analyzed are based on participants from a single clinical trial, clinicians can more confidently incorporate this novel therapy into practice with expanded knowledge of these existing analyses as well as ongoing prospective trials.

Keywords: cardiovascular death; cost-effectiveness; enalapril; heart failure; hospitalizations; outcomes; sacubitril/valsartan.

Publication types

  • Review

MeSH terms

  • Aminobutyrates / administration & dosage*
  • Aminobutyrates / economics
  • Angiotensin Receptor Antagonists / administration & dosage*
  • Angiotensin Receptor Antagonists / economics
  • Clinical Trials as Topic / methods*
  • Cost-Benefit Analysis / methods
  • Enalapril / administration & dosage
  • Enalapril / economics
  • Heart Failure / drug therapy*
  • Heart Failure / economics
  • Heart Failure / epidemiology
  • Humans
  • Prospective Studies
  • Tetrazoles / administration & dosage*
  • Tetrazoles / economics


  • Aminobutyrates
  • Angiotensin Receptor Antagonists
  • Tetrazoles
  • Enalapril
  • sacubitril-valsartan