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
The Safety of an Adenosine A(1)-Receptor Antagonist, Rolofylline, in Patients with Acute Heart Failure and Renal Impairment: Findings from PROTECT / Teerlink, Jr; Iragui, Vj; Mohr, Jp; Carson, Pe; Hauptman, Pj; Lovett, Dh; Miller, Ab; Piña, Il; Thomson, S; Varosy, Pd; Zile, Mr; Cleland, Jg; Givertz, Mm; Metra, Marco; Ponikowski, P; Voors, Aa; Davison, Ba; Cotter, G; Wolko, D; Delucca, P; Salerno, Cm; Mansoor, Ga; Dittrich, H; O'Connor, Cm; Massie, Bm. - In: DRUG SAFETY. - ISSN 0114-5916. - 35:3(2012), pp. 233-244.
The Safety of an Adenosine A(1)-Receptor Antagonist, Rolofylline, in Patients with Acute Heart Failure and Renal Impairment: Findings from PROTECT
METRA, Marco;
2012-01-01
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 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 failureI documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
