University of California at San Francisco and San Francisco Veterans Affairs Medical Center, San Francisco, CA 94121, USA.
N Engl J Med. 2010 Oct 7;363(15):1419-28. doi: 10.1056/NEJMoa0912613.
Worsening renal function, which is associated with adverse outcomes, often develops in patients with acute heart failure. Experimental and clinical studies suggest that counterregulatory responses mediated by adenosine may be involved. We tested the hypothesis that the use of rolofylline, an adenosine A1-receptor antagonist, would improve dyspnea, reduce the risk of worsening renal function, and lead to a more favorable clinical course in patients with acute heart failure.
We conducted a multicenter, double-blind, placebo-controlled trial involving patients hospitalized for acute heart failure with impaired renal function. Within 24 hours after presentation, 2033 patients were randomly assigned, in a 2:1 ratio, to receive daily intravenous rolofylline (30 mg) or placebo for up to 3 days. The primary end point was treatment success, treatment failure, or no change in the patient's clinical condition; this end point was defined according to survival, heart-failure status, and changes in renal function. Secondary end points were the post-treatment development of persistent renal impairment and the 60-day rate of death or readmission for cardiovascular or renal causes.
Rolofylline, as compared with placebo, did not provide a benefit with respect to the primary end point (odds ratio, 0.92; 95% confidence interval, 0.78 to 1.09; P=0.35). Persistent renal impairment developed in 15.0% of patients in the rolofylline group and in 13.7% of patients in the placebo group (P=0.44). By 60 days, death or readmission for cardiovascular or renal causes had occurred in similar proportions of patients assigned to rolofylline and placebo (30.7% and 31.9%, respectively; P=0.86). Adverse-event rates were similar overall; however, only patients in the rolofylline group had seizures, a known potential adverse effect of A1-receptor antagonists.
Rolofylline did not have a favorable effect with respect to the primary clinical composite end point, nor did it improve renal function or 60-day outcomes. It does not show promise in the treatment of acute heart failure with renal dysfunction. (Funded by NovaCardia, a subsidiary of Merck; ClinicalTrials.gov numbers, NCT00328692 and NCT00354458.).
肾功能恶化与不良结局相关，常发生于急性心力衰竭患者。实验和临床研究表明，腺苷介导的代偿反应可能与此相关。我们检验了如下假说：使用罗氟司特（一种腺苷 A1 受体拮抗剂）可改善呼吸困难，降低肾功能恶化风险，并改善急性心力衰竭患者的临床转归。
我们开展了一项多中心、双盲、安慰剂对照试验，纳入因急性心力衰竭合并肾功能受损而住院的患者。入组后 24 小时内，2033 例患者按 2:1 的比例随机分组，接受每日静脉滴注罗氟司特（30mg）或安慰剂，疗程最多 3 天。主要终点为治疗成功、治疗失败或患者临床状况无变化；该终点定义为存活、心力衰竭状态和肾功能变化。次要终点为治疗后持续性肾功能损害的发生和 60 天内因心血管或肾脏原因死亡或再入院的发生率。
与安慰剂相比，罗氟司特在主要终点方面无获益（比值比，0.92；95%置信区间，0.78 至 1.09；P=0.35）。罗氟司特组 15.0%的患者和安慰剂组 13.7%的患者发生持续性肾功能损害（P=0.44）。60 天时，罗氟司特组和安慰剂组因心血管或肾脏原因死亡或再入院的患者比例相似（分别为 30.7%和 31.9%；P=0.86）。总体而言，不良事件发生率相似；但只有罗氟司特组的患者出现了癫痫，这是已知的 A1 受体拮抗剂的潜在不良作用。
罗氟司特在主要临床复合终点方面没有获益，也没有改善肾功能或 60 天结局。它在治疗急性心力衰竭合并肾功能障碍方面没有前景。（由 Merck 的子公司 NovaCardia 资助；ClinicalTrials.gov 编号，NCT00328692 和 NCT00354458。）
