title: The safety of an adenosine A(1)-receptor antagonist, rolofylline, in patients with acute heart failure and renal impairment: findings from PROTECT.
abstract: BACKGROUND
  Adenosine exerts actions in multiple organ systems, and adenosine receptors are a therapeutic target in many development programmes.
  
  
  OBJECTIVE
  The aim of this analysis was to evaluate the safety of rolofylline, an adenosine A(1)-receptor antagonist, in patients with acute heart failure.
  
  
  METHODS
  The effect of rolofylline was investigated in patients hospitalized for acute heart failure with impaired renal function. Intravenous rolofylline 30 mg or placebo was infused over 4 hours daily for up to 3 days. Adverse events (AEs) and serious AEs (SAEs) were recorded from baseline through 7 and 14 days, respectively, and clinical events were adjudicated through 60 days.
  
  
  RESULTS
  Of 2033 patients enrolled, 2002 received study drug randomized 2 : 1 to rolofylline or placebo. Rolofylline and placebo were associated with a similar risk of pre-specified groups of AEs or SAEs, other than selected neurological events. Investigator-reported seizures occurred in 11 (0.8%) rolofylline-treated patients and zero patients receiving placebo (p = 0.02). Stroke occurred in 21 (1.6%) patients assigned to rolofylline compared with 3 (0.5%) placebo-treated patients through 60 days with a greater risk for stroke in the rolofylline group (hazard ratio 3.49; 95% CI 1.04, 11.71; p = 0.043). There was no temporal relation to rolofylline administration and no specific stroke subtype or clinical characteristics that predicted stroke in the rolofylline group.
  
  
  CONCLUSIONS
  Rolofylline treatment was associated with an increased seizure rate, an anticipated complication of A(1)-receptor antagonists. An unanticipated, disproportionate increase in strokes in the rolofylline-treated patients emerged, although no clear temporal relation, aetiology, stroke subtype or interacting factor suggestive of a causal mechanism was identified. Further research into stroke as a potential complication of adenosine-modulating therapies is required. Additionally, this study underscores the value of longer follow-up durations for AEs, even for agents with short treatment periods, such as in acute heart failure.
authors.affiliation: San Francisco Veterans Affairs Medical Center and University of California, San Francisco, San Francisco, CA 94121-1545, USA. john.teerlink@ucsf.edu
authors.forename: John R
authors.initials: JR
authors.lastname: Teerlink
authors.forename: Vicente J
authors.initials: VJ
authors.lastname: Iragui
authors.forename: Jay P
authors.initials: JP
authors.lastname: Mohr
authors.forename: Peter E
authors.initials: PE
authors.lastname: Carson
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Hauptman
authors.forename: David H
authors.initials: DH
authors.lastname: Lovett
authors.forename: Alan B
authors.initials: AB
authors.lastname: Miller
authors.forename: Ileana L
authors.initials: IL
authors.lastname: Piña
authors.forename: Scott
authors.initials: S
authors.lastname: Thomson
authors.forename: Paul D
authors.initials: PD
authors.lastname: Varosy
authors.forename: Michael R
authors.initials: MR
authors.lastname: Zile
authors.forename: John G F
authors.initials: JG
authors.lastname: Cleland
authors.forename: Michael M
authors.initials: MM
authors.lastname: Givertz
authors.forename: Marco
authors.initials: M
authors.lastname: Metra
authors.forename: Piotr
authors.initials: P
authors.lastname: Ponikowski
authors.forename: Adriaan A
authors.initials: AA
authors.lastname: Voors
authors.forename: Beth A
authors.initials: BA
authors.lastname: Davison
authors.forename: Gad
authors.initials: G
authors.lastname: Cotter
authors.forename: Denise
authors.initials: D
authors.lastname: Wolko
authors.forename: Paul
authors.initials: P
authors.lastname: Delucca
authors.forename: Christina M
authors.initials: CM
authors.lastname: Salerno
authors.forename: George A
authors.initials: GA
authors.lastname: Mansoor
authors.forename: Howard
authors.initials: H
authors.lastname: Dittrich
authors.forename: Christopher M
authors.initials: CM
authors.lastname: O'Connor
authors.forename: Barry M
authors.initials: BM
authors.lastname: Massie
mesh_terms: D000208:Acute Disease; D058916:Adenosine A1 Receptor Antagonists / Q000008:administration & dosage / Q000009:adverse effects*; D000368:Aged; D000369:Aged, 80 and over; D005260:Female; D005500:Follow-Up Studies; D006333:Heart Failure / Q000188:drug therapy*; D006760:Hospitalization; D006801:Humans; D008297:Male; D008875:Middle Aged; D051437:Renal Insufficiency / Q000188:drug therapy*; D012307:Risk Factors; D020521:Stroke / Q000139:chemically induced*; D013997:Time Factors; D014970:Xanthines / Q000008:administration & dosage / Q000009:adverse effects*
chemical_list: D058916:Adenosine A1 Receptor Antagonists; D014970:Xanthines; C073525:rolofylline