背景:糖皮质激素可能改善社区获得性肺炎(CAP)住院患者的预后。在这项针对人类败血症性休克(APROCCHSS)试验的3期随机对照活化蛋白C和皮质类固醇的先验计划的探索性亚组分析中,我们旨在调查CAP和非CAP相关性感染性休克对氢化可的松+氟氢可的松的反应.
方法:APROCCHSS是一项随机对照试验,研究氢化可的松加氟氢可的松的效果,drotrecogin-alfa(激活),或者在二乘二析因设计中对感染性休克的死亡率都有影响;在drotrecogin-alfa于2011年10月从市场撤出后,试验在两个平行组继续进行.它在法国的34个中心进行。在这个亚组研究中,CAP患者是针对APROCCHSS试验中氢化可的松联合氟氢可的松治疗感染性休克的探索性二次分析的预选亚组.感染性休克的成年人被随机分为1:1,以双盲的方式,7天的治疗,每天给药静脉内氢化可的松50毫克推注,每6小时和50μg的氟氢可的松片剂通过鼻胃管,或者他们的安慰剂。主要结果是90天全因死亡率。次要结局包括重症监护病房(ICU)的全因死亡率和出院,28天和180天死亡率,存活和没有血管加压药的天数,机械通气,或者器官衰竭,ICU和医院免费天数到90天。在意向治疗人群中进行分析。该试验在ClinicalTrials.gov(NCT00625209)注册。
结果:在纳入APROCCHSS试验的1241例患者中,不能排除31名患者的CAP,562诊断为CAP(安慰剂组279例,皮质类固醇组283例),648例患者无CAP(安慰剂组329例,皮质类固醇组319例).在CAP患者中,在第90天接受氢化可的松联合氟氢可的松治疗的283例患者中有109例(39%)死亡,在接受安慰剂治疗的279例患者中有143例(51%)死亡(比值比[OR]0·60,95%CI0·43-0·83).在没有CAP的患者中,在第90天,氢化可的松和氟氢可的松组的319例患者中有148例(46%)死亡,安慰剂组的329例患者中有157例(48%)死亡(OR0·95,95%CI0·70~1·29).在有CAP和无CAP的亚组中,皮质类固醇对90天死亡率的影响存在显着异质性(对于乘法和加性相互作用测试,p=0·046;中等可信度)。在纳入APROCCHSS试验的1241名患者中,648(52%)患有ARDS(安慰剂组328和皮质类固醇组320)。在90天时,皮质类固醇组320例患者中有155例(48%)死亡,安慰剂组328例患者中有186例(57%)死亡。ARDS患者第90天死亡的OR为0·72(95%CI0·53-0·98),无ARDS患者的OR为0·85(0·61-1·20)(p=0·45乘法相互作用,p=0·42加性相互作用)。在随机分组后180天内观察到至少一个严重不良事件(皮质类固醇组与安慰剂组)的OR在CAP亚组中为0·64(95%CI0·46-0·89),在非CAP亚组中为1·02(0·75-1·39)(对于乘法相互作用,p=0·044,对于累加相互作用,p=0·042)。
结论:在针对CAP和感染性休克患者的APROCCHSS试验的预先指定的亚组分析中,与安慰剂相比,氢化可的松加氟氢可的松降低了死亡率。尽管大部分CAP患者也符合ARDS标准,亚组分析在完全区分ARDS和CAP对皮质类固醇降低死亡率的影响方面的作用不足.在非CAP亚组中没有明显的糖皮质激素治疗效果的证据。
背景:法国卫生部医院医疗计划,由节目d\'调查d\'Avenir,法国2030年和IAHU-ANR-0004。
BACKGROUND: Glucocorticoids probably improve outcomes in patients hospitalised for community acquired pneumonia (CAP). In this a priori planned exploratory subgroup analysis of the phase 3 randomised controlled Activated Protein C and Corticosteroids for Human Septic Shock (APROCCHSS)
trial, we aimed to investigate responses to hydrocortisone plus fludrocortisone between CAP and non-CAP related septic shock.
METHODS: APROCCHSS was a randomised controlled trial that investigated the effects of hydrocortisone plus fludrocortisone, drotrecogin-alfa (activated), or both on mortality in septic shock in a two-by-two factorial design; after drotrecogin-alfa was withdrawn on October 2011, from the market, the trial continued on two parallel groups. It was conducted in 34 centres in France. In this subgroup
study, patients with CAP were a preselected subgroup for an exploratory secondary analysis of the APROCCHSS
trial of hydrocortisone plus fludrocortisone in septic shock. Adults with septic shock were randomised 1:1 to receive, in a double-blind manner, a 7-day treatment with daily administration of intravenous hydrocortisone 50 mg bolus every 6h and a tablet of 50 μg of fludrocortisone via the nasogastric tube, or their placebos. The primary outcome was 90-day all-cause mortality. Secondary outcomes included all-cause mortality at intensive care unit (ICU) and hospital discharge, 28-day and 180-day mortality, the number of days alive and free of vasopressors, mechanical ventilation, or organ failure, and ICU and hospital free-days to 90-days. Analysis was done in the intention-to-treat population. The
trial was registered at ClinicalTrials.gov (NCT00625209).
RESULTS: Of 1241 patients included in the APROCCHSS
trial, CAP could not be ruled in or out in 31 patients, 562 had a diagnosis of CAP (279 in the placebo group and 283 in the corticosteroid group), and 648 patients did not have CAP (329 in the placebo group and 319 in the corticosteroid group). In patients with CAP, there were 109 (39%) deaths of 283 patients at day 90 with hydrocortisone plus fludrocortisone and 143 (51%) of 279 patients receiving placebo (odds ratio [OR] 0·60, 95% CI 0·43-0·83). In patients without CAP, there were 148 (46%) deaths of 319 patients at day 90 in the hydrocortisone and fludrocortisone group and 157 (48%) of 329 patients in the placebo group (OR 0·95, 95% CI 0·70-1·29). There was significant heterogeneity in corticosteroid effects on 90-day mortality across subgroups with CAP and without CAP (p=0·046 for both multiplicative and additive interaction tests; moderate credibility). Of 1241 patients included in the APROCCHSS trial, 648 (52%) had ARDS (328 in the placebo group and 320 in the corticosteroid group). There were 155 (48%) deaths of 320 patients at day 90 in the corticosteroid group and 186 (57%) of 328 patients in the placebo group. The OR for death at day 90 was 0·72 (95% CI 0·53-0·98) in patients with ARDS and 0·85 (0·61-1·20) in patients without ARDS (p=0·45 for multiplicative interaction and p=0·42 for additive interaction). The OR for observing at least one serious adverse event (corticosteroid group vs placebo) within 180 days post randomisation was 0·64 (95% CI 0·46-0·89) in the CAP subgroup and 1·02 (0·75-1·39) in the non-CAP subgroup (p=0·044 for multiplicative interaction and p=0·042 for additive interaction).
CONCLUSIONS: In a pre-specified subgroup analysis of the APROCCHSS trial of patients with CAP and septic shock, hydrocortisone plus fludrocortisone reduced mortality as compared with placebo. Although a large proportion of patients with CAP also met criteria for ARDS, the subgroup analysis was underpowered to fully discriminate between ARDS and CAP modifying effects on mortality reduction with corticosteroids. There was no evidence of a significant treatment effect of corticosteroids in the non-CAP subgroup.
BACKGROUND: Programme Hospitalier de Recherche Clinique of the French Ministry of Health, by Programme d\'Investissements d\'Avenir, France 2030, and IAHU-ANR-0004.