title: Risk-based evaluation of efficacy of rolofylline in patients hospitalized with acute heart failure - Post-hoc analysis of the PROTECT trial.
abstract: BACKGROUND
  The selective adenosine A1 receptor antagonist rolofylline showed a neutral overall result on clinical outcomes in the PROTECT trial. However, we hypothesized that response to rolofylline treatment could be influenced by underlying clinical risk.
  
  
  METHODS
  We performed a post-hoc analysis of the PROTECT trial - a large, double-blind, randomized, placebo-controlled trial that enrolled 2033 patients. Baseline risk of 180-day all-cause mortality was estimated using a previously published 8-item model. Evaluation of efficacy of rolofylline across subpopulations defined based on estimated risk of mortality was performed using subpopulation treatment effect pattern plot (STEPP) analysis. Findings were validated in an independent cohort of acute heart failure patients.
  
  
  RESULTS
  Median estimated risk of mortality was 13.0%, IQR [8.0%-23.0%] and was comparable between the rolofylline and placebo arms. In low to intermediate risk subgroups of patients, rolofylline was associated with a higher rate of 180-day all-cause mortality (11.9% in the rolofylline versus 8.4% in the placebo arms, p=0.050). In the high risk subgroup of patients, particularly those with estimated risk of mortality between 20% and 30%, 180-day all-cause mortality rate was markedly lower in the rolofylline arm (18.4% in the rolofylline versus 34.0% in the placebo arms, p=0.003). The trend towards potential harm with rolofylline treatment in the low to intermediate risk subpopulations and significant benefit in high risk patients was also observed in the validation cohort.
  
  
  CONCLUSIONS
  Our findings suggest that selective adenosine A1 receptor antagonism could be harmful in low risk acute heart failure patients, while it might significantly benefit higher risk patients.
authors: Department of Cardiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands; Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors: Biniyam G
authors: BG
authors: Demissei
authors: Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors: Douwe
authors: D
authors: Postmus
authors: Department of Cardiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors: Licette C Y
authors: LCY
authors: Liu
authors: Imperial College, London, UK.
authors: John G
authors: JG
authors: Cleland
authors: Inova Heart and Vascular Institute, Falls Church, VA, USA.
authors: Christopher M
authors: CM
authors: O'Connor
authors: University of Brescia, Brescia, Italy.
authors: Marco
authors: M
authors: Metra
authors: Medical University, Clinical Military Hospital, Wroclaw, Poland.
authors: Piotr
authors: P
authors: Ponikowski
authors: University of California at San Francisco and San Francisco Veterans Affairs Medical Center, San Francisco, CA, USA.
authors: John R
authors: JR
authors: Teerlink
authors: Momentum Research, Durham, NC, USA.
authors: Gad
authors: G
authors: Cotter
authors: Momentum Research, Durham, NC, USA.
authors: Beth A
authors: BA
authors: Davison
authors: Momentum Research, Durham, NC, USA.
authors: Christopher
authors: C
authors: Edwards
authors: Brigham and Women's Hospital, Boston, MA, USA.
authors: Michael M
authors: MM
authors: Givertz
authors: Merck Research Laboratories, Rahway, NJ, USA.
authors: Daniel M
authors: DM
authors: Bloomfield
authors: Abboud Cardiovascular Research Center, University of Iowa Carver College of Medicine, Iowa, USA.
authors: Howard C
authors: HC
authors: Dittrich
authors: Department of Cardiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands. Electronic address: a.a.voors@umcg.nl.
authors: Adriaan A
authors: AA
authors: Voors
authors: Department of Cardiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands; Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors: Hans L
authors: HL
authors: Hillege
mesh_terms: D000208:Acute Disease; D058916:Adenosine A1 Receptor Antagonists / Q000008:administration & dosage; D000368:Aged; D004232:Diuretics / Q000008:administration & dosage; D004311:Double-Blind Method; D005260:Female; D006333:Heart Failure / Q000175:diagnosis / Q000188:drug therapy / Q000401:mortality; D006760:Hospitalization / Q000706:statistics & numerical data; D006801:Humans; D008297:Male; D008875:Middle Aged; D062072:Patient Acuity; D020011:Protective Agents / Q000008:administration & dosage; D015203:Reproducibility of Results; D018570:Risk Assessment / Q000379:methods; D016896:Treatment Outcome; D014970:Xanthines / Q000008:administration & dosage*
chemical_list: D058916:Adenosine A1 Receptor Antagonists; D004232:Diuretics; D020011:Protective Agents; D014970:Xanthines; C073525:rolofylline
keywords: Acute heart failure; Heterogeneity of treatment effect; Multivariable risk; Rolofylline; STEPP; Subgroup analysis