title: Importance of Clinical Worsening of Heart Failure Treated in the Outpatient Setting: Evidence From the Prospective Comparison of ARNI With ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure Trial (PARADIGM-HF).
abstract: Many episodes of worsening of heart failure (HF) are treated by increasing oral therapy or temporary intravenous treatment in the community or emergency department (ED), without hospital admission. We studied the frequency and prognostic importance of these episodes of worsening in the Prospective Comparison of ARNI (angiotensin-receptor-neprilysin inhibitor) with ACEI (angiotensin-converting enzyme inhibitor) to Determine Impact on Global Mortality and Morbidity in Heart Failure Trial (PARADIGM-HF).
  
  
  
  Outpatient intensification of HF therapy was added to an expanded composite outcome with ED visits, HF hospitalizations, and cardiovascular deaths. In an examination of first nonfatal events, 361 of 8399 patients (4.3%) had outpatient intensification of HF therapy without a subsequent event (ie, ED visit/HF hospitalizations) within 30 days; 78 of 8399 (1.0%) had an ED visit without previous outpatient intensification of HF therapy or a subsequent event within 30 days; and 1107 of 8399 (13.2%) had HF hospitalizations without a preceding event. The risk of death (in comparison with no-event patients) was similar after each manifestation of worsening: outpatient intensification of HF therapy (hazard ratio, 4.8; 95% confidence interval, 3.9-5.9); ED visit (hazard ratio, 4.5; 95% confidence interval, 3.0-6.7); HF hospitalizations (hazard ratio, 5.9; 95% confidence interval, 5.2-6.6). The expanded composite added 14% more events and shortened time to accrual of a fixed number of events. The benefit of sacubitril/valsartan over enalapril was similar to the primary outcome for the expanded composite (hazard ratio, 0.79; 95% confidence interval, 0.73-0.86) and was consistent across the components of the latter.
  
  
  
  Focusing only on HF hospitalizations underestimates the frequency of worsening and the serious implications of all manifestations of worsening. For clinical trials conducted in an era of heightened efforts to avoid HF hospitalizations, inclusion of episodes of outpatient treatment intensification (and ED visits) in a composite outcome adds an important number of events and shortens the time taken to accrue a target number of end points in an event-driven trial.
  
  
  
  URL: http://www.clinicaltrials.gov. Unique identifier: NCT01035255.
authors.affiliation: From BHF Cardiovascular Research Centre, Institute of Cardiovascular and Medical Sciences, University of Glasgow, United Kingdom (N.O., P.S.J., J.J.V.M.); Novartis Pharmaceutical Corporation, East Hanover, NJ (J.G., M.P.L., A.R.R., V.C.S.); Institut de Cardiologie, Université de Montréal, Canada (J.L.R.); Department of Molecular and Clinical Medicine, University of Gothenburg, Sweden and National Heart and Lung Institute, Imperial College, London, United Kingdom (K.S.); Medical University of South Carolina and RHJ Department of Veterans Administration Medical Center, Charleston, SC (M.R.Z.); Cardiovascular Medicine, Brigham and Women's Hospital, Boston, MA (S.D.S.); and Baylor Heart and Vascular Institute, Baylor University Medical Center, Dallas, TX (M.P.).
authors.forename: Naoki
authors.initials: N
authors.lastname: Okumura
authors.affiliation: From BHF Cardiovascular Research Centre, Institute of Cardiovascular and Medical Sciences, University of Glasgow, United Kingdom (N.O., P.S.J., J.J.V.M.); Novartis Pharmaceutical Corporation, East Hanover, NJ (J.G., M.P.L., A.R.R., V.C.S.); Institut de Cardiologie, Université de Montréal, Canada (J.L.R.); Department of Molecular and Clinical Medicine, University of Gothenburg, Sweden and National Heart and Lung Institute, Imperial College, London, United Kingdom (K.S.); Medical University of South Carolina and RHJ Department of Veterans Administration Medical Center, Charleston, SC (M.R.Z.); Cardiovascular Medicine, Brigham and Women's Hospital, Boston, MA (S.D.S.); and Baylor Heart and Vascular Institute, Baylor University Medical Center, Dallas, TX (M.P.).
authors.forename: Pardeep S
authors.initials: PS
authors.lastname: Jhund
authors.affiliation: From BHF Cardiovascular Research Centre, Institute of Cardiovascular and Medical Sciences, University of Glasgow, United Kingdom (N.O., P.S.J., J.J.V.M.); Novartis Pharmaceutical Corporation, East Hanover, NJ (J.G., M.P.L., A.R.R., V.C.S.); Institut de Cardiologie, Université de Montréal, Canada (J.L.R.); Department of Molecular and Clinical Medicine, University of Gothenburg, Sweden and National Heart and Lung Institute, Imperial College, London, United Kingdom (K.S.); Medical University of South Carolina and RHJ Department of Veterans Administration Medical Center, Charleston, SC (M.R.Z.); Cardiovascular Medicine, Brigham and Women's Hospital, Boston, MA (S.D.S.); and Baylor Heart and Vascular Institute, Baylor University Medical Center, Dallas, TX (M.P.).
authors.forename: Jianjian
authors.initials: J
authors.lastname: Gong
authors.affiliation: From BHF Cardiovascular Research Centre, Institute of Cardiovascular and Medical Sciences, University of Glasgow, United Kingdom (N.O., P.S.J., J.J.V.M.); Novartis Pharmaceutical Corporation, East Hanover, NJ (J.G., M.P.L., A.R.R., V.C.S.); Institut de Cardiologie, Université de Montréal, Canada (J.L.R.); Department of Molecular and Clinical Medicine, University of Gothenburg, Sweden and National Heart and Lung Institute, Imperial College, London, United Kingdom (K.S.); Medical University of South Carolina and RHJ Department of Veterans Administration Medical Center, Charleston, SC (M.R.Z.); Cardiovascular Medicine, Brigham and Women's Hospital, Boston, MA (S.D.S.); and Baylor Heart and Vascular Institute, Baylor University Medical Center, Dallas, TX (M.P.).
authors.forename: Martin P
authors.initials: MP
authors.lastname: Lefkowitz
authors.affiliation: From BHF Cardiovascular Research Centre, Institute of Cardiovascular and Medical Sciences, University of Glasgow, United Kingdom (N.O., P.S.J., J.J.V.M.); Novartis Pharmaceutical Corporation, East Hanover, NJ (J.G., M.P.L., A.R.R., V.C.S.); Institut de Cardiologie, Université de Montréal, Canada (J.L.R.); Department of Molecular and Clinical Medicine, University of Gothenburg, Sweden and National Heart and Lung Institute, Imperial College, London, United Kingdom (K.S.); Medical University of South Carolina and RHJ Department of Veterans Administration Medical Center, Charleston, SC (M.R.Z.); Cardiovascular Medicine, Brigham and Women's Hospital, Boston, MA (S.D.S.); and Baylor Heart and Vascular Institute, Baylor University Medical Center, Dallas, TX (M.P.).
authors.forename: Adel R
authors.initials: AR
authors.lastname: Rizkala
authors.affiliation: From BHF Cardiovascular Research Centre, Institute of Cardiovascular and Medical Sciences, University of Glasgow, United Kingdom (N.O., P.S.J., J.J.V.M.); Novartis Pharmaceutical Corporation, East Hanover, NJ (J.G., M.P.L., A.R.R., V.C.S.); Institut de Cardiologie, Université de Montréal, Canada (J.L.R.); Department of Molecular and Clinical Medicine, University of Gothenburg, Sweden and National Heart and Lung Institute, Imperial College, London, United Kingdom (K.S.); Medical University of South Carolina and RHJ Department of Veterans Administration Medical Center, Charleston, SC (M.R.Z.); Cardiovascular Medicine, Brigham and Women's Hospital, Boston, MA (S.D.S.); and Baylor Heart and Vascular Institute, Baylor University Medical Center, Dallas, TX (M.P.).
authors.forename: Jean L
authors.initials: JL
authors.lastname: Rouleau
authors.affiliation: From BHF Cardiovascular Research Centre, Institute of Cardiovascular and Medical Sciences, University of Glasgow, United Kingdom (N.O., P.S.J., J.J.V.M.); Novartis Pharmaceutical Corporation, East Hanover, NJ (J.G., M.P.L., A.R.R., V.C.S.); Institut de Cardiologie, Université de Montréal, Canada (J.L.R.); Department of Molecular and Clinical Medicine, University of Gothenburg, Sweden and National Heart and Lung Institute, Imperial College, London, United Kingdom (K.S.); Medical University of South Carolina and RHJ Department of Veterans Administration Medical Center, Charleston, SC (M.R.Z.); Cardiovascular Medicine, Brigham and Women's Hospital, Boston, MA (S.D.S.); and Baylor Heart and Vascular Institute, Baylor University Medical Center, Dallas, TX (M.P.).
authors.forename: Victor C
authors.initials: VC
authors.lastname: Shi
authors.affiliation: From BHF Cardiovascular Research Centre, Institute of Cardiovascular and Medical Sciences, University of Glasgow, United Kingdom (N.O., P.S.J., J.J.V.M.); Novartis Pharmaceutical Corporation, East Hanover, NJ (J.G., M.P.L., A.R.R., V.C.S.); Institut de Cardiologie, Université de Montréal, Canada (J.L.R.); Department of Molecular and Clinical Medicine, University of Gothenburg, Sweden and National Heart and Lung Institute, Imperial College, London, United Kingdom (K.S.); Medical University of South Carolina and RHJ Department of Veterans Administration Medical Center, Charleston, SC (M.R.Z.); Cardiovascular Medicine, Brigham and Women's Hospital, Boston, MA (S.D.S.); and Baylor Heart and Vascular Institute, Baylor University Medical Center, Dallas, TX (M.P.).
authors.forename: Karl
authors.initials: K
authors.lastname: Swedberg
authors.affiliation: From BHF Cardiovascular Research Centre, Institute of Cardiovascular and Medical Sciences, University of Glasgow, United Kingdom (N.O., P.S.J., J.J.V.M.); Novartis Pharmaceutical Corporation, East Hanover, NJ (J.G., M.P.L., A.R.R., V.C.S.); Institut de Cardiologie, Université de Montréal, Canada (J.L.R.); Department of Molecular and Clinical Medicine, University of Gothenburg, Sweden and National Heart and Lung Institute, Imperial College, London, United Kingdom (K.S.); Medical University of South Carolina and RHJ Department of Veterans Administration Medical Center, Charleston, SC (M.R.Z.); Cardiovascular Medicine, Brigham and Women's Hospital, Boston, MA (S.D.S.); and Baylor Heart and Vascular Institute, Baylor University Medical Center, Dallas, TX (M.P.).
authors.forename: Michael R
authors.initials: MR
authors.lastname: Zile
authors.affiliation: From BHF Cardiovascular Research Centre, Institute of Cardiovascular and Medical Sciences, University of Glasgow, United Kingdom (N.O., P.S.J., J.J.V.M.); Novartis Pharmaceutical Corporation, East Hanover, NJ (J.G., M.P.L., A.R.R., V.C.S.); Institut de Cardiologie, Université de Montréal, Canada (J.L.R.); Department of Molecular and Clinical Medicine, University of Gothenburg, Sweden and National Heart and Lung Institute, Imperial College, London, United Kingdom (K.S.); Medical University of South Carolina and RHJ Department of Veterans Administration Medical Center, Charleston, SC (M.R.Z.); Cardiovascular Medicine, Brigham and Women's Hospital, Boston, MA (S.D.S.); and Baylor Heart and Vascular Institute, Baylor University Medical Center, Dallas, TX (M.P.).
authors.forename: Scott D
authors.initials: SD
authors.lastname: Solomon
authors.affiliation: From BHF Cardiovascular Research Centre, Institute of Cardiovascular and Medical Sciences, University of Glasgow, United Kingdom (N.O., P.S.J., J.J.V.M.); Novartis Pharmaceutical Corporation, East Hanover, NJ (J.G., M.P.L., A.R.R., V.C.S.); Institut de Cardiologie, Université de Montréal, Canada (J.L.R.); Department of Molecular and Clinical Medicine, University of Gothenburg, Sweden and National Heart and Lung Institute, Imperial College, London, United Kingdom (K.S.); Medical University of South Carolina and RHJ Department of Veterans Administration Medical Center, Charleston, SC (M.R.Z.); Cardiovascular Medicine, Brigham and Women's Hospital, Boston, MA (S.D.S.); and Baylor Heart and Vascular Institute, Baylor University Medical Center, Dallas, TX (M.P.).
authors.forename: Milton
authors.initials: M
authors.lastname: Packer
authors.affiliation: From BHF Cardiovascular Research Centre, Institute of Cardiovascular and Medical Sciences, University of Glasgow, United Kingdom (N.O., P.S.J., J.J.V.M.); Novartis Pharmaceutical Corporation, East Hanover, NJ (J.G., M.P.L., A.R.R., V.C.S.); Institut de Cardiologie, Université de Montréal, Canada (J.L.R.); Department of Molecular and Clinical Medicine, University of Gothenburg, Sweden and National Heart and Lung Institute, Imperial College, London, United Kingdom (K.S.); Medical University of South Carolina and RHJ Department of Veterans Administration Medical Center, Charleston, SC (M.R.Z.); Cardiovascular Medicine, Brigham and Women's Hospital, Boston, MA (S.D.S.); and Baylor Heart and Vascular Institute, Baylor University Medical Center, Dallas, TX (M.P.). john.mcmurray@glasgow.ac.uk.
authors.forename: John J V
authors.initials: JJ
authors.lastname: McMurray
mesh_terms: D000368:Aged; D000553:Ambulatory Care; D000613:Aminobutyrates / Q000009:adverse effects / Q000627:therapeutic use*; D047228:Angiotensin II Type 1 Receptor Blockers / Q000009:adverse effects / Q000627:therapeutic use*; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000009:adverse effects / Q000627:therapeutic use*; D001713:Biphenyl Compounds; D018450:Disease Progression; D004311:Double-Blind Method; D004338:Drug Combinations; D004656:Enalapril / Q000009:adverse effects / Q000627:therapeutic use*; D023381:Endpoint Determination; D005260:Female; D006333:Heart Failure / Q000175:diagnosis / Q000401:mortality / Q000503:physiopathology / Q000628:therapy*; D006760:Hospitalization; D006801:Humans; D008297:Male; D008875:Middle Aged; D015260:Neprilysin / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011446:Prospective Studies; D011480:Protease Inhibitors / Q000009:adverse effects / Q000627:therapeutic use*; D012107:Research Design; D018570:Risk Assessment; D012307:Risk Factors; D013777:Tetrazoles / Q000009:adverse effects / Q000627:therapeutic use*; D013997:Time Factors; D016896:Treatment Outcome; D000068756:Valsartan
chemical_list: D000613:Aminobutyrates; D047228:Angiotensin II Type 1 Receptor Blockers; D000806:Angiotensin-Converting Enzyme Inhibitors; D001713:Biphenyl Compounds; D004338:Drug Combinations; D011480:Protease Inhibitors; D013777:Tetrazoles; D004656:Enalapril; D000068756:Valsartan; D015260:Neprilysin; C549068:sacubitril and valsartan sodium hydrate drug combination
keywords: emergency service, hospital; heart failure; hospitalization; mortality; neprilysin; sacubitril/valsartan