Sodium-hydrogen exchange inhibition by cariporide to reduce the risk of ischemic cardiac events in patients undergoing coronary artery bypass grafting: Results of the EXPEDITION study
Sodium-hydrogen exchange inhibition by cariporide to reduce the risk of ischemic cardiac events in patients undergoing coronary artery bypass grafting: Results of the EXPEDITION study
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DOI：
10.1016/j.athoracsur.2007.10.054
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发表时间：
2008-04-01
影响因子：
4.6
通讯作者：
Weisel, Richard D.
中科院分区：
文献类型：
--
作者：
Mentzer, Robert M.;Bartels, Claus;Weisel, Richard D.
背景。 EXPEDITION 研究探讨了卡立泊来抑制钠氢交换异构体 1 (NHE-1) 在预防冠状动脉搭桥手术患者死亡或心肌梗死 (MI) 方面的有效性和安全性。前提是抑制 NHE-1 限制细胞内 Na 积累，从而限制 Na/Ca 交换器介导的钙超载，从而减少梗塞面积。方法。高危冠状动脉搭桥手术患者 (n = 5,761) 被随机分配接受静脉注射卡立泊利（术前 1 小时负荷剂量 180 毫克，然后 24 小时内每小时 40 毫克，随后 24 小时内每小时 20 毫克）或安慰剂。在第 5 天评估死亡或 MI 的主要复合终点，并对患者进行长达 6 个月的随访。 结果。第 5 天时，死亡或 MI 的发生率从安慰剂组的 20.3% 降低到治疗组的 16.6% (p = 0.0002)。矛盾的是，单独的心肌梗死发生率从安慰剂组的 18.9% 下降到治疗组的 14.4% (p = 0.000005)，而单独的死亡率从安慰剂组的 1.5% 增加到卡立泊来德的 2.2% (p = 0.02)。死亡率的增加与脑血管事件的增加有关。与 6 个月时维持的有益效果不同，6 个月时死亡率的差异并不显着。结论。 EXPEDITION 研究是第一个 III 期心肌保护试验，其中实现了主要终点并证明了概念。由于与脑血管事件增加相关的死亡率增加，卡立泊利不太可能用于临床。研究结果表明，钠氢交换异构体-1 抑制有望成为一类新型药物，可显着减轻与缺血再灌注损伤相关的心肌损伤。
Background. The EXPEDITION study addressed the efficacy and safety of inhibiting the sodium hydrogen exchanger isoform-1 (NHE-1) by cariporide in the prevention of death or myocardial infarction (MI) in patients undergoing coronary artery bypass graft surgery. The premise was that inhibition of NHE-1 limits intracellcular Na accumulation and thereby limits Na/Ca-exchanger mediated calcium overload to reduce infarct size.Methods. High-risk coronary artery bypass graft surgery patients (n = 5,761) were randomly allocated to receive either intravenous cariporide (180 mg in a 1-hour preoperative loading dose, then 40 mg per hour over 24 hours and 20 mg per hour over the subsequent 24 hours) or placebo. The primary composite endpoint of death or MI was assessed at 5 days, and patients were followed for as long as 6 months.Results. At 5 days, the incidence of death or MI was reduced from 20.3% in the placebo group to 16.6% in the treatment group (p = 0.0002). Paradoxically, MI alone declined from 18.9% in the placebo group to 14.4% in the treatment group (p = 0.000005), while mortality alone increased from 1.5% in the placebo group to 2.2% with cariporide (p = 0.02). The increase in mortality was associated with an increase in cerebrovascular events. Unlike the salutary effects that were maintained at 6 months, the difference in mortality at 6 months was not significant.Conclusions. The EXPEDITION study is the first phase III myocardial protection trial in which the primary endpoint was achieved and proof of concept demonstrated. As a result of increased mortality associated with an increase in cerebrovascular events, it is unlikely that cariporide will be used clinically. The findings suggest that sodium hydrogen exchanger isoform-1 inhibition holds promise for a new class of drugs that could significantly reduce myocardial injury associated with ischemia-reperfusion injury.