The safety of an adenosine A1-receptor antagonist, rolofylline, in patients with acute heart failure and renal impairment: Findings from PROTECT

Teerlink, J. R. et al. (2012) The safety of an adenosine A1-receptor antagonist, rolofylline, in patients with acute heart failure and renal impairment: Findings from PROTECT. Drug Safety, 35(3), pp. 233-244. (doi: 10.2165/11594680-000000000-00000) (PMID:22339573)

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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.

Item Type:Articles
Glasgow Author(s) Enlighten ID:Cleland, Professor John
Authors: Teerlink, J. R., Iragui, V. J., Mohr, J. P., Carson, P. E., Hauptman, P. J., Lovett, D. H., Miller, A. B., Piña, I. L., Thomson, S., Varosy, P. D., Zile, M. R., Cleland, J. G.F., Givertz, M. M., Metra, M., Ponikowski, P., Voors, A. A., Davison, B. A., Cotter, G., Wolko, D., DeLucca, P., Salerno, C. M., Mansoor, G. A., Dittrich, H., O’Connor, C. M., and Massie, B. M.
College/School:College of Medical Veterinary and Life Sciences > Institute of Health and Wellbeing > Robertson Centre
Journal Name:Drug Safety
Publisher:Adis Data Information
ISSN (Online):1179-1942
Published Online:06 November 2012

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