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

• Published in: Drug safety 2012-03, Vol.35 (3), p.233-244
• Main Authors: Teerlink, John R., Iragui, Vicente J., Mohr, Jay P., Carson, Peter E., Hauptman, Paul J., Lovett, David H., Miller, Alan B., Piña, Ileana L., Thomson, Scott, Varosy, Paul D., Zile, Michael R., Cleland, John G. F., Givertz, Michael M., Metra, Marco, Ponikowski, Piotr, Voors, Adriaan A., Davison, Beth A., Cotter, Gad, Wolko, Denise, DeLucca, Paul, Salerno, Christina M., Mansoor, George A., Dittrich, Howard, O’Connor, Christopher M., Massie, Barry M.
• Format: Article
• Language: English
• Subjects: Biological and medical sciences; Clinical trial. Drug monitoring; Drug Safety and Pharmacovigilance; Drug toxicity and drugs side effects treatment; General pharmacology; Medical sciences; Medicine; Medicine & Public Health; Miscellaneous (drug allergy, mutagens, teratogens...); Original Research Articles; Pharmacology. Drug treatments; Pharmacology/Toxicology
• ISSN: 0114-5916; 1179-1942
• DOI: 10.2165/11594680-000000000-00000

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. Trial Registration: ClinicalTrials.gov identifiers NCT00328692 and NCT00354458.