Effect of Selepressin vs Placebo on Ventilator- and Vasopressor-Free Days in Patients With Septic Shock: The SEPSIS-ACT Randomized Clinical Trial
Effect of Selepressin vs Placebo on Ventilator- and Vasopressor-Free Days in Patients With Septic Shock: The SEPSIS-ACT Randomized Clinical Trial
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DOI：
10.1001/jama.2019.14607
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发表时间：
2019-10-15
影响因子：
120.7
通讯作者：
Angus, Derek C.
中科院分区：
文献类型：
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作者：
Laterre, Pierre-Francois;Berry, Scott M.;Angus, Derek C.
要点问题对于接受去甲肾上腺素治疗的感染性休克成人，与安慰剂相比，使用选择性加压素 V1a 受体激动剂选择性加压素 V1a 受体激动剂是否可以改善患者的预后（定义为增加不使用通气和加压药物的存活天数）？结果在这项纳入 828 名需要去甲肾上腺素的感染性休克患者的随机临床试验中，与安慰剂相比，使用选择性加压素治疗导致 30 天内不使用呼吸机和血管加压药的天数分别为 15.0 天和 14.4 天，这一差异不具有统计学意义。意义 选择性加压素治疗对于改善无呼吸机和无血管加压药的天数并不能有效。 重要性 去甲肾上腺素是治疗感染性休克的一线血管加压药，但并不总是有效，并且具有重要的儿茶酚胺能不良反应。 Selepressin 是一种选择性加压素 V1a 受体激动剂，是一种非儿茶酚胺能血管加压药，可减轻脓毒症引起的血管舒张、血管渗漏和水肿，且副作用较少。目的测试选择性加压素是否可以改善感染性休克的预后。设计、设置和参与者一项适应性 2b/3 期随机临床试验，包括 2 个部分，其中包括需要超过 5 μg/min 去甲肾上腺素的感染性休克成年患者 (n=868)。第 1 部分使用贝叶斯算法来调整选择性静压素给药方案的随机概率，并触发向第 2 部分的过渡，第 2 部分将效果最佳的方案与安慰剂进行比较。该试验于 2015 年 7 月至 2017 年 8 月在比利时、丹麦、法国、荷兰和美国的 63 家医院进行，随访于 2018 年 5 月完成。 干预措施 随机分配至 3 种抗抑郁素给药方案中的 1 种（起始输注速率为 1.7、2.5 和 3.5 ng/kg/min；n=585）或安慰剂(n=283)，所有药物均根据血流动力学参数以连续输注方式滴定。主要结果和措施主要终点是开始研究药物后 30 天内不使用呼吸机和升压药的天数（死亡数为零天）。关键的次要终点是 90 天死亡率、无肾脏替代治疗天数和无 ICU 天数。结果 在 868 名随机患者中，828 名患者接受了研究药物（平均年龄 66.3 岁；341 名女性 [41.2%]），构成主要分析队列，其中 562 名患者接受了 3 种抗抑郁素治疗方案中的一种，266 名患者接受了安慰剂，817 名患者（98.7%）完成了试验。该试验在第 1 部分结束时因无效而停止。中位研究药物持续时间为 37.8 小时（IQR，17.8-72.4）。主要终点（无呼吸机和升压药天数：选择性加压素组和安慰剂组分别为 15.0 与 14.5；差异为 0.6 [95% CI，-1.3 至 2.4]；P=.30）或关键次要终点（90 天死亡率，40.6% 与 39.4%；差异为 1.1% [95% CI， -6.5% 至 8.8%]；P=.77；无肾脏替代治疗天数：18.5 与 18.2；差异，0.3 [95% CI，-2.1 至 2.6]；P=.85；无 ICU 天数：12.6 与 12.2；差异，0.5 [95% CI，-1.2 至 2.2]；不良事件发生率包括心律失常（27.9% vs 25.2%）、心肌缺血（6.6% vs 5.6%）、肠系膜缺血（3.2% vs 2.6%）和外周缺血（2.3% vs 2.3%）。结论和相关性 在接受去甲肾上腺素治疗的感染性休克患者中，与安慰剂相比，服用选择性加压素并没有改善 30 天内不使用血管加压药和呼吸机的天数。需要进一步的研究来评估选择性加压素对败血性休克中其他以患者为中心的结果的潜在作用。试验注册ClinicalTrials.gov 标识符：NCT02508649 这项 2b/3 期随机临床试验比较了接受去甲肾上腺素治疗的感染性休克成年患者中，选择性加压素 V1a 受体激动剂和非儿茶酚胺能血管加压药与安慰剂相比，在 30 天内不使用呼吸机和血管加压药的情况下，选择性加压素 V1a 受体激动剂和非儿茶酚胺能血管加压素的效果。
Key PointsQuestionFor adults with septic shock treated with norepinephrine, does use of selepressin, a selective vasopressin V1a receptor agonist, compared with placebo, improve patient outcome, defined as an increase in the number of days alive and free of both ventilation and vasopressor use? FindingsIn this randomized clinical trial that included 828 patients with septic shock requiring norepinephrine, treatment with selepressin compared with placebo resulted in 15.0 vs 14.4 ventilator- and vasopressor-free days within 30 days, a difference that was not statistically significant. MeaningTreatment with selepressin was not effective in improving ventilator- and vasopressor-free days.ImportanceNorepinephrine, the first-line vasopressor for septic shock, is not always effective and has important catecholaminergic adverse effects. Selepressin, a selective vasopressin V1a receptor agonist, is a noncatecholaminergic vasopressor that may mitigate sepsis-induced vasodilatation, vascular leakage, and edema, with fewer adverse effects. ObjectiveTo test whether selepressin improves outcome in septic shock. Design, Setting, and ParticipantsAn adaptive phase 2b/3 randomized clinical trial comprising 2 parts that included adult patients (n=868) with septic shock requiring more than 5 mu g/min of norepinephrine. Part 1 used a Bayesian algorithm to adjust randomization probabilities to alternative selepressin dosing regimens and to trigger transition to part 2, which would compare the best-performing regimen with placebo. The trial was conducted between July 2015 and August 2017 in 63 hospitals in Belgium, Denmark, France, the Netherlands, and the United States, and follow-up was completed by May 2018. InterventionsRandom assignment to 1 of 3 dosing regimens of selepressin (starting infusion rates of 1.7, 2.5, and 3.5 ng/kg/min; n=585) or to placebo (n=283), all administered as continuous infusions titrated according to hemodynamic parameters. Main Outcomes and MeasuresPrimary end point was ventilator- and vasopressor-free days within 30 days (deaths assigned zero days) of commencing study drug. Key secondary end points were 90-day mortality, kidney replacement therapy-free days, and ICU-free days. ResultsAmong 868 randomized patients, 828 received study drug (mean age, 66.3 years; 341 [41.2%] women) and comprised the primary analysis cohort, of whom 562 received 1 of 3 selepressin regimens, 266 received placebo, and 817 (98.7%) completed the trial. The trial was stopped for futility at the end of part 1. Median study drug duration was 37.8 hours (IQR, 17.8-72.4). There were no significant differences in the primary end point (ventilator- and vasopressor-free days: 15.0 vs 14.5 in the selepressin and placebo groups; difference, 0.6 [95% CI, -1.3 to 2.4]; P=.30) or key secondary end points (90-day mortality, 40.6% vs 39.4%; difference, 1.1% [95% CI, -6.5% to 8.8%]; P=.77; kidney replacement therapy-free days: 18.5 vs 18.2; difference, 0.3 [95% CI, -2.1 to 2.6]; P=.85; ICU-free days: 12.6 vs 12.2; difference, 0.5 [95% CI, -1.2 to 2.2]; P=.41). Adverse event rates included cardiac arrhythmias (27.9% vs 25.2% of patients), cardiac ischemia (6.6% vs 5.6%), mesenteric ischemia (3.2% vs 2.6%), and peripheral ischemia (2.3% vs 2.3%). Conclusions and RelevanceAmong patients with septic shock receiving norepinephrine, administration of selepressin, compared with placebo, did not result in improvement in vasopressor- and ventilator-free days within 30 days. Further research would be needed to evaluate the potential role of selepressin for other patient-centered outcomes in septic shock. Trial RegistrationClinicalTrials.gov Identifier: NCT02508649This phase 2b/3 randomized clinical trial compares the effects of selepressin, a selective vasopressin V1a receptor agonist and noncatecholaminergic vasopressor, vs placebo on ventilator- and vasopressor-free days within 30 days among adult patients with septic shock receiving norepinephrine.