San Francisco Veterans Affairs Medical Center and University of California, San Francisco, San Francisco, CA 94121-1545, USA.
Drug Saf. 2012 Mar 1;35(3):233-44. doi: 10.2165/11594680-000000000-00000.
Adenosine exerts actions in multiple organ systems, and adenosine receptors are a therapeutic target in many development programmes.
The aim of this analysis was to evaluate the safety of rolofylline, an adenosine A(1)-receptor antagonist, in patients with acute heart failure.
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.
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.
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.
腺苷在多个器官系统中发挥作用，腺苷受体是许多开发项目中的治疗靶点。
本分析旨在评估罗氟司特（一种腺苷 A(1)-受体拮抗剂）在急性心力衰竭患者中的安全性。
本研究纳入了因急性心力衰竭伴肾功能受损而住院的患者，评估了罗氟司特的疗效。患者接受静脉输注罗氟司特 30mg 或安慰剂，每天输注 4 小时，持续 3 天。记录从基线到第 7 天和第 14 天的不良事件（AE）和严重不良事件（SAE），并在第 60 天进行临床事件的判定。
共纳入 2033 例患者，2002 例患者接受了研究药物治疗，随机分为罗氟司特组（2:1）和安慰剂组。罗氟司特和安慰剂的特定 AE 或 SAE 风险相似，但除外一些特定的神经系统事件。罗氟司特治疗组的研究者报告癫痫发作发生率为 11%（0.8%），安慰剂组为 0（0.0%）（p=0.02）。在第 60 天，罗氟司特组发生 21 例（1.6%）患者脑卒中，安慰剂组发生 3 例（0.5%）脑卒中，罗氟司特组脑卒中风险更高（风险比 3.49；95%CI 1.04, 11.71；p=0.043）。罗氟司特与脑卒中之间没有时间关系，也没有发现罗氟司特组脑卒中的特定亚型或临床特征可以预测脑卒中。
罗氟司特治疗与癫痫发作率增加相关，这是 A(1)-受体拮抗剂的预期并发症。罗氟司特组意外出现不成比例的脑卒中发生率增加，但未确定明确的时间关系、病因、脑卒中亚型或提示因果关系的相互作用因素。需要进一步研究腺苷调节治疗作为潜在并发症的机制。此外，本研究强调了即使对于急性心力衰竭等治疗期较短的药物，AE 的长期随访也很重要。
