Drug Safety

, Volume 35, Issue 3, pp 233–244

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

Findings from PROTECT
  • John R. Teerlink
  • Vicente J. Iragui
  • Jay P. Mohr
  • Peter E. Carson
  • Paul J. Hauptman
  • David H. Lovett
  • Alan B. Miller
  • Ileana L. Piña
  • Scott Thomson
  • Paul D. Varosy
  • Michael R. Zile
  • John G. F. Cleland
  • Michael M. Givertz
  • Marco Metra
  • Piotr Ponikowski
  • Adriaan A. Voors
  • Beth A. Davison
  • Gad Cotter
  • Denise Wolko
  • Paul DeLucca
  • Christina M. Salerno
  • George A. Mansoor
  • Howard Dittrich
  • Christopher M. O’Connor
  • Barry M. Massie
Original Research Articles

DOI: 10.2165/11594680-000000000-00000

Cite this article as:
Teerlink, J.R., Iragui, V.J., Mohr, J.P. et al. Drug Saf (2012) 35: 233. doi:10.2165/11594680-000000000-00000

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 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.

Copyright information

© Adis Data Information BV. 2012

Authors and Affiliations

  • John R. Teerlink
    • 1
  • Vicente J. Iragui
    • 2
  • Jay P. Mohr
    • 3
  • Peter E. Carson
    • 4
  • Paul J. Hauptman
    • 5
  • David H. Lovett
    • 1
  • Alan B. Miller
    • 6
  • Ileana L. Piña
    • 7
  • Scott Thomson
    • 8
  • Paul D. Varosy
    • 9
  • Michael R. Zile
    • 10
  • John G. F. Cleland
    • 11
  • Michael M. Givertz
    • 12
  • Marco Metra
    • 13
  • Piotr Ponikowski
    • 14
  • Adriaan A. Voors
    • 15
  • Beth A. Davison
    • 16
  • Gad Cotter
    • 16
  • Denise Wolko
    • 17
  • Paul DeLucca
    • 17
  • Christina M. Salerno
    • 18
  • George A. Mansoor
    • 19
  • Howard Dittrich
    • 20
  • Christopher M. O’Connor
    • 1
  • Barry M. Massie
  1. 1.San Francisco Veterans Affairs Medical Center and University of California, San FranciscoSan FranciscoUSA
  2. 2.University of California, San DiegoSan DiegoUSA
  3. 3.Columbia University College of Physicians and SurgeonsNew YorkUSA
  4. 4.Washington DC Veterans Affairs Medical Center and Georgetown UniversityUSA
  5. 5.St Louis University School of MedicineSt LouisUSA
  6. 6.University of Florida Health Science Center, JacksonvilleJacksonvilleUSA
  7. 7.Cleveland Veterans Affairs Medical Center and Case Western Reserve UniversityClevelandUSA
  8. 8.San Diego Veterans Affairs Medical Center University of California, San DiegoSan DiegoUSA
  9. 9.Veterans Affairs Eastern Colorado Health Care System and University of Colorado DenverDenverUSA
  10. 10.RHJ Department of Veterans Affairs Medical Center and Medical University of South CarolinaCharlestonUSA
  11. 11.University of HullKingston Upon HullUK
  12. 12.Brigham and Women’s HospitalBostonUSA
  13. 13.University of BresciaBresciaItaly
  14. 14.Medical University, Clinical Military HospitalWroclawPoland
  15. 15.University Medical Center GroningenGroningenthe Netherlands
  16. 16.Momentum Research, Inc.DurhamUSA
  17. 17.Merck Research LaboratoriesNorth WalesUSA
  18. 18.Merck Research LaboratoriesRahwayUSA
  19. 19.NovaCardia, Inc.San DiegoUSA
  20. 20.Duke University Medical CenterDurhamUSA
  21. 21.San Francisco Veterans Affairs Medical Center, Section of CardiologySan FranciscoUSA

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