Division of Cardiovascular and Renal Products, Center for Drug Evaluation and Research, Food and Drug Administration, 10903 New Hampshire Ave, Bldg 22, Room #4128, Silver Spring, MD, USA.
Office of Clinical Pharmacology, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, MD, USA.
Am J Cardiovasc Drugs. 2019 Feb;19(1):11-20. doi: 10.1007/s40256-018-0297-9.
Distributive shock is a subset of shock marked by decreased systemic vascular resistance, organ hypoperfusion and altered oxygen extraction. Despite the use of intravenous fluids and either higher dose of catecholamines or other additional exogenous vasopressors to maintain blood pressure in the target range, the rate of mortality remains higher in patients with septic shock. Therefore, there is clearly an unmet need for additional safe and effective treatments. The use of angiotensin II to raise the mean arterial pressure (MAP) could provide additional therapy and the opportunity to evaluate a catecholamine-sparing effect by decreasing the dose of concomitant catecholamines while maintaining a target MAP. ATHOS-3 (Angiotensin II for the Treatment of High-Output Shock phase 3; ClinicalTrials.gov number, NCT02338843) was an adequate and well-controlled trial. The primary endpoint was the rate of MAP response at hour 3 of treatment with study drug, defined as either a 10-mmHg increase from baseline in MAP or a MAP of at least 75 mmHg. The secondary endpoints were changes from baseline in Sequential Organ Failure Assessment (SOFA) scores (total and cardiovascular). Mortality was an exploratory endpoint. The trial provided substantial evidence of the effectiveness of angiotensin II in raising blood pressure over placebo in patients with distributive shock, while keeping catecholamine levels constant. There was no change in the secondary endpoint of total SOFA scores relative to placebo when catecholamine use was reduced in lieu of angiotensin II treatment. There was a slight decrease in the secondary endpoint of cardiovascular SOFA score relative to placebo during the catecholamine-sparing phase, reflecting the catecholamine-sparing effect. There was a consistent trend in decreased mortality relative to placebo over the 28-day study period. Based on the agreements emanating from the special protocol assessment to assess blood pressure effects, the data from this single study supported approval of angiotensin II by the Food and Drug Administration for marketing in the USA.
分布性休克是休克的一个亚组，其特征为全身血管阻力降低、器官灌注不足和氧摄取改变。尽管使用静脉输液和更高剂量的儿茶酚胺或其他额外的外源性血管加压药来维持血压在目标范围内，但感染性休克患者的死亡率仍然较高。因此，显然需要额外的安全有效的治疗方法。使用血管紧张素 II 来提高平均动脉压（MAP）可能提供额外的治疗机会，并通过减少同时使用的儿茶酚胺剂量，同时保持目标 MAP，评估儿茶酚胺节省效应。ATHOS-3（血管紧张素 II 治疗高输出休克阶段 3；ClinicalTrials.gov 编号，NCT02338843）是一项充分和良好对照的试验。主要终点是研究药物治疗 3 小时时 MAP 反应率，定义为 MAP 从基线增加 10mmHg 或 MAP 至少为 75mmHg。次要终点是从基线开始的序贯器官衰竭评估（SOFA）评分（总分和心血管）的变化。死亡率是一个探索性终点。该试验提供了充分的证据表明，在分布性休克患者中，血管紧张素 II 升压作用优于安慰剂，同时保持儿茶酚胺水平不变。当用血管紧张素 II 治疗代替儿茶酚胺时，减少儿茶酚胺的使用并未改变次要终点总 SOFA 评分相对于安慰剂的变化。在儿茶酚胺节省阶段，相对于安慰剂，心血管 SOFA 评分的次要终点略有下降，反映了儿茶酚胺节省效应。与安慰剂相比，在 28 天的研究期间，死亡率呈持续下降趋势。基于评估血压效应的特殊方案评估的协议，来自该单一研究的数据支持食品和药物管理局批准血管紧张素 II 在美国上市。
