The safety of an adenosine A(1)-receptor antagonist, rolofylline, in patients with acute heart failure and renal impairment: findings from PROTECT.


Journal Article

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.

Full Text

Duke Authors

Cited Authors

  • Teerlink, JR; Iragui, VJ; Mohr, JP; Carson, PE; Hauptman, PJ; Lovett, DH; Miller, AB; Piña, IL; Thomson, S; Varosy, PD; Zile, MR; Cleland, JGF; Givertz, MM; Metra, M; Ponikowski, P; Voors, AA; Davison, BA; Cotter, G; Wolko, D; Delucca, P; Salerno, CM; Mansoor, GA; Dittrich, H; O'Connor, CM; Massie, BM

Published Date

  • March 1, 2012

Published In

Volume / Issue

  • 35 / 3

Start / End Page

  • 233 - 244

PubMed ID

  • 22339573

Pubmed Central ID

  • 22339573

Electronic International Standard Serial Number (EISSN)

  • 1179-1942

Digital Object Identifier (DOI)

  • 10.2165/11594680-000000000-00000


  • eng

Conference Location

  • New Zealand