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Brief Report
December 2018

Estimated 5-Year Number Needed to Treat to Prevent Cardiovascular Death or Heart Failure Hospitalization With Angiotensin Receptor-Neprilysin Inhibition vs Standard Therapy for Patients With Heart Failure With Reduced Ejection Fraction: An Analysis of Data From the PARADIGM-HF Trial

Author Affiliations
  • 1Division of General Internal Medicine, University of California Los Angeles Medical Center, Los Angeles
  • 2Division of Cardiovascular Medicine, Brigham and Women’s Hospital, Boston, Massachusetts
  • 3British Heart Foundation Cardiovascular Research Centre, University of Glasgow, Glasgow, United Kingdom
  • 4Department of Clinical Sciences, University of Texas Southwestern Medical Center, Dallas
  • 5Medical University of South Carolina and Ralph H. Johnson Veterans Affairs Medical Center, Charleston
  • 6Montreal Heart Institute, University de Montréal, Montreal, Quebec, Canada
  • 7Department of Molecular and Clinical Medicine, University of Gothenburg, Gothenburg, Sweden
  • 8Ahmanson-UCLA Cardiomyopathy Center, University of California Los Angeles Medical Center, Los Angeles
  • 9Associate Editor, JAMA Cardiology
JAMA Cardiol. 2018;3(12):1226-1231. doi:10.1001/jamacardio.2018.3957
Key Points

Question  What is the long-term absolute risk reduction from adding a neprilysin inhibitor to standard therapy, including a renin-angiotensin system blocker, in patients with heart failure with reduced ejection fraction (HFrEF) for cardiovascular death or HF hospitalization and all-cause mortality as quantified by number needed to treat (NNT)?

Findings  In this study, the 5-year estimated NNT for the primary outcome of cardiovascular death or HF hospitalization with angiotensin receptor-neprilysin inhibitor therapy incremental to angiotensin-converting enzyme inhibitor was 14 in the overall cohort and ranged from 12 to 19 among different subpopulations. The 5-year estimated NNT was 21 for all-cause mortality incremental to angiotensin-converting enzyme inhibitor and 11 for all-cause mortality when compared with imputed placebo.

Meaning  The 5-year estimated NNT with adding a neprilysin inhibitor to standard therapy, including a renin-angiotensin system blocker for HFrEF, overall and for clinically relevant subpopulations are comparable with those estimated for other well-established HF therapies, supporting current guideline recommendations for use of angiotensin receptor-neprilysin inhibitor therapy among eligible patients.

Abstract

Importance  The addition of receptor-neprilysin inhibition to standard therapy, including a renin-angiotensin system blocker, has been demonstrated to improve outcomes in patients with heart failure with reduced ejection fraction (HFrEF) compared with standard therapy alone. The long-term absolute risk reduction from angiotensin receptor neprilysin inhibitor (ARNI) therapy, and whether it merits widespread use among diverse subpopulations, has not been well described.

Objective  To calculate estimated 5-year number needed to treat (NNT) values overall and for different subpopulations for the Prospective Comparison of ARNI with Angiotensin-Converting Enzyme Inhibitor (ACEI) to Determine Impact on Global Mortality and Morbidity in Heart Failure (PARADIGM-HF) cohort.

Design, Setting, and Participants  Overall and subpopulation 5-year NNT values were estimated for different end points using data from PARADIGM-HF, a double-blind, randomized trial of sacubitril-valsartan vs enalapril. This multicenter, international study included 8399 men and women with HFrEF (ejection fraction, ≤40%). The study began in December 2009 and ended in March 2014. Analyses began in March 2018.

Interventions  Random assignment to sacubitril-valsartan or enalapril.

Main Outcomes and Measures  Cardiovascular death or HF hospitalization, cardiovascular death, and all-cause mortality.

Results  The final cohort of 8399 individuals included 1832 women (21.8%) and 5544 white individuals (66.0%), with a mean (SD) age of 63.8 (11.4) years. The 5-year estimated NNT for the primary outcome of cardiovascular death or HF hospitalization with ARNI therapy incremental to ACEI therapy in the overall cohort was 14. The 5-year estimated NNT values were calculated for different clinically relevant subpopulations and ranged from 12 to 19. The 5-year estimated NNT for all-cause mortality in the overall cohort with ARNI incremental to ACEI was 21, with values ranging from 16 to 31 among different subgroups. Compared with imputed placebo, the 5-year estimated NNT for all-cause mortality with ARNI was 11. The 5-year estimated NNT values were also calculated for other HFrEF therapies compared with controls from landmark trials for all-cause mortality and were found to be 18 for ACEI, 24 for angiotensin receptor blockers, 8 for β-blockers, 15 for mineralocorticoid antagonists, 14 for implantable cardioverter defibrillator, and 14 for cardiac resynchronization therapy.

Conclusions and Relevance  The 5-year estimated NNT with ARNI therapy incremental to ACEI therapy overall and for clinically relevant subpopulations of patients with HFrEF are comparable with those for well-established HF therapeutics. These data further support guideline recommendations for use of ARNI therapy among eligible patients with HFrEF.

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