Original Research Articles

Drug Safety

, Volume 35, Issue 3, pp 233-244

First online:

The Safety of an Adenosine A1-Receptor Antagonist, Rolofylline, in Patients with Acute Heart Failure and Renal Impairment

Findings from PROTECT
  • John R. TeerlinkAffiliated withSan Francisco Veterans Affairs Medical Center and University of California, San Francisco Email author 
  • , Vicente J. IraguiAffiliated withUniversity of California, San Diego
  • , Jay P. MohrAffiliated withColumbia University College of Physicians and Surgeons
  • , Peter E. CarsonAffiliated withWashington DC Veterans Affairs Medical Center and Georgetown University
  • , Paul J. HauptmanAffiliated withSt Louis University School of Medicine
  • , David H. LovettAffiliated withSan Francisco Veterans Affairs Medical Center and University of California, San Francisco
  • , Alan B. MillerAffiliated withUniversity of Florida Health Science Center, Jacksonville
  • , Ileana L. PiñaAffiliated withCleveland Veterans Affairs Medical Center and Case Western Reserve University
  • , Scott ThomsonAffiliated withSan Diego Veterans Affairs Medical Center University of California, San Diego
    • , Paul D. VarosyAffiliated withVeterans Affairs Eastern Colorado Health Care System and University of Colorado Denver
    • , Michael R. ZileAffiliated withRHJ Department of Veterans Affairs Medical Center and Medical University of South Carolina
    • , John G. F. ClelandAffiliated withUniversity of Hull
    • , Michael M. GivertzAffiliated withBrigham and Women’s Hospital
    • , Marco MetraAffiliated withUniversity of Brescia
    • , Piotr PonikowskiAffiliated withMedical University, Clinical Military Hospital
    • , Adriaan A. VoorsAffiliated withUniversity Medical Center Groningen
    • , Beth A. DavisonAffiliated withMomentum Research, Inc.
    • , Gad CotterAffiliated withMomentum Research, Inc.
    • , Denise WolkoAffiliated withMerck Research Laboratories
    • , Paul DeLuccaAffiliated withMerck Research Laboratories
    • , Christina M. SalernoAffiliated withMerck Research Laboratories
    • , George A. MansoorAffiliated withNovaCardia, Inc.
    • , Howard DittrichAffiliated withDuke University Medical Center
    • , Christopher M. O’ConnorAffiliated withSan Francisco Veterans Affairs Medical Center and University of California, San Francisco
    • , Barry M. Massie

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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 A1-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 A1-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.

Trial Registration: ClinicalTrials.gov identifiers NCT00328692 and NCT00354458.