title: Comparing LCZ696 with enalapril according to baseline risk using the MAGGIC and EMPHASIS-HF risk scores: an analysis of mortality and morbidity in PARADIGM-HF.
abstract: BACKGROUND
  Although most patients in the PARADIGM-HF (Prospective Comparison of ARNI With ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure) trial had mild symptoms, there is a poor correlation between reported functional limitation and prognosis in heart failure.
  
  
  OBJECTIVE
  The aim of this study was to examine the spectrum of risk in PARADIGM-HF and the effect of LCZ696 across that spectrum.
  
  
  METHODS
  This study analyzed rates of the primary composite outcome of cardiovascular death or heart failure hospitalization, its components, and all-cause mortality using the MAGGIC (Meta-Analysis Global Group in Chronic Heart Failure) and EMPHASIS-HF (Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure) risk scores to categorize patients. The authors determined whether risk, on the basis of these scores, modified the treatment effect of LCZ696.
  
  
  RESULTS
  The complete MAGGIC risk score was available for 8,375 of the 8,399 patients in PARADIGM-HF. The median MAGGIC score was 20 (IQR: 16 to 24). An increase of 1 point was associated with a 6% increased risk for the primary endpoint (p < 0.001) and a 7% increased risk for cardiovascular death (p < 0.001). The benefit of LCZ696 over enalapril for the primary endpoint was similar across the spectrum of risk (p = 0.159). Treating 100 patients for 2 years with LCZ696 instead of enalapril led to 7 fewer patients in the highest quintile of risk experiencing primary outcomes, compared with 3 in the lowest quintile. Analyses using the EMPHASIS-HF risk score gave similar findings.
  
  
  CONCLUSIONS
  Although most PARADIGM-HF patients had mild symptoms, many were at high risk for adverse outcomes and obtained a large absolute benefit from LCZ696, compared with enalapril, over a relatively short treatment period. LCZ696's benefit was consistent across the spectrum of risk. (PARADIGM-HF trial [Prospective Comparison of ARNI With ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure]; NCT01035255).
authors.affiliation: BHF Cardiovascular Research Centre, University of Glasgow, Glasgow, United Kingdom.
authors.forename: Joanne
authors.initials: J
authors.lastname: Simpson
authors.affiliation: BHF Cardiovascular Research Centre, University of Glasgow, Glasgow, United Kingdom.
authors.forename: Pardeep S
authors.initials: PS
authors.lastname: Jhund
authors.affiliation: Department of Cardiology, Porto Medical School, São João Hospital, Porto, Portugal.
authors.forename: Jose
authors.initials: J
authors.lastname: Silva Cardoso
authors.affiliation: Instituto DAMIC, Cordoba National University, Córdoba, Argentina.
authors.forename: Felipe
authors.initials: F
authors.lastname: Martinez
authors.affiliation: Meander Medical Center, Amersfoort and WCN-Dutch Network for Cardiovascular Research, Utrecht, the Netherlands.
authors.forename: Arend
authors.initials: A
authors.lastname: Mosterd
authors.affiliation: Heart Institute, University of São Paulo, São Paulo, Brazil.
authors.forename: Felix
authors.initials: F
authors.lastname: Ramires
authors.affiliation: Novartis Pharmaceutical Corporation, East Hanover, New Jersey.
authors.forename: Adel R
authors.initials: AR
authors.lastname: Rizkala
authors.affiliation: Cardiology, Heart Failure and Heart Transplantation Unit, Azienda Ospedaliera Papa Giovanni XXIII, Bergamo, Italy.
authors.forename: Michele
authors.initials: M
authors.lastname: Senni
authors.affiliation: University of Leicester, Department of Cardiovascular Sciences and NIHR Cardiovascular, Biomedical Research Unit, Glenfield Hospital, Leicester, United Kingdom.
authors.forename: Iain
authors.initials: I
authors.lastname: Squire
authors.affiliation: Novartis Pharmaceutical Corporation, East Hanover, New Jersey.
authors.forename: Jianjian
authors.initials: J
authors.lastname: Gong
authors.affiliation: Novartis Pharmaceutical Corporation, East Hanover, New Jersey.
authors.forename: Martin P
authors.initials: MP
authors.lastname: Lefkowitz
authors.affiliation: Novartis Pharmaceutical Corporation, East Hanover, New Jersey.
authors.forename: Victor C
authors.initials: VC
authors.lastname: Shi
authors.affiliation: Cardiovascular Medicine, Brigham and Women's Hospital, Boston, Massachusetts.
authors.forename: Akshay S
authors.initials: AS
authors.lastname: Desai
authors.affiliation: Institut de Cardiologie, Université de Montréal, Montréal, Québec, Canada.
authors.forename: Jean L
authors.initials: JL
authors.lastname: Rouleau
authors.affiliation: Department of Molecular and Clinical Medicine, University of Gothenburg, Gothenburg, Sweden.
authors.forename: Karl
authors.initials: K
authors.lastname: Swedberg
authors.affiliation: Medical University of South Carolina and RHJ Department of Veterans Administration Medical Center, Charleston, South Carolina.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Zile
authors.affiliation: BHF Cardiovascular Research Centre, University of Glasgow, Glasgow, United Kingdom. Electronic address: john.mcmurray@glasgow.ac.uk.
authors.forename: John J V
authors.initials: JJV
authors.lastname: McMurray
authors.affiliation: Department of Clinical Sciences, University of Texas Southwestern Medical Center, Dallas, Texas.
authors.forename: Milton
authors.initials: M
authors.lastname: Packer
authors.affiliation: Cardiovascular Medicine, Brigham and Women's Hospital, Boston, Massachusetts.
authors.forename: Scott D
authors.initials: SD
authors.lastname: Solomon
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000613:Aminobutyrates / Q000627:therapeutic use*; D057911:Angiotensin Receptor Antagonists / Q000627:therapeutic use; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000627:therapeutic use; D001713:Biphenyl Compounds; D004338:Drug Combinations; D004656:Enalapril / Q000627:therapeutic use*; D005260:Female; D014943:Global Health; D006333:Heart Failure / Q000188:drug therapy* / Q000453:epidemiology; D006801:Humans; D008297:Male; D008875:Middle Aged; D009017:Morbidity / Q000639:trends; D015260:Neprilysin / Q000037:antagonists & inhibitors; D011379:Prognosis; D011446:Prospective Studies; D018570:Risk Assessment / Q000379:methods*; D015996:Survival Rate / Q000639:trends; D013777:Tetrazoles / Q000627:therapeutic use*; D000068756:Valsartan; D055815:Young Adult
chemical_list: D000613:Aminobutyrates; D057911:Angiotensin Receptor Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors; D001713:Biphenyl Compounds; D004338:Drug Combinations; D013777:Tetrazoles; D004656:Enalapril; D000068756:Valsartan; D015260:Neprilysin; C549068:sacubitril and valsartan sodium hydrate drug combination
keywords: angiotensin receptor neprilysin inhibitor; prognostic model; risk score; survival