Original Investigation March 18, 2021
Effect of Intermediate-Dose vs Standard-Dose Prophylactic Anticoagulation on Thrombotic Events, Extracorporeal Membrane Oxygenation Treatment, or Mortality Among Patients With COVID-19 Admitted to the Intensive Care Unit: The INSPIRATION Randomized Clinical Trial
INSPIRATION Investigators
JAMA. Published online March 18, 2021. doi:10.1001/jama.2021.4152
Abstract
Importance 背景
Thrombotic events are commonly reported in critically ill patients with COVID-19. Limited data exist to guide the intensity of antithrombotic prophylaxis.
新冠肺炎危重患者常常发生血栓事件。有关指导抗栓预防强度方面仅有有限的资料。
Objective 目的
To evaluate the effects of intermediate-dose vs standard-dose prophylactic anticoagulation among patients with COVID-19 admitted to the intensive care unit (ICU).
评估收入ICU的新冠肺炎患者接受中等剂量与标准剂量预防性抗凝的效果。
Design, Setting, and Participants 设计，场景及研究对象
Multicenter randomized trial with a 2 × 2 factorial design performed in 10 academic centers in Iran comparing intermediate-dose vs standard-dose prophylactic anticoagulation (first hypothesis) and statin therapy vs matching placebo (second hypothesis; not reported in this article) among adult patients admitted to the ICU with COVID-19. Patients were recruited between July 29, 2020, and November 19, 2020. The final follow-up date for the 30-day primary outcome was December 19, 2020.
在伊朗10个医学中心进行的多中心2x2析因设计、随机临床试验，在收入ICU的新冠肺炎患者比较中等剂量与标准剂量预防性抗凝（第一假设）以及他汀治疗与安慰剂（第二假设，本文未予报告）。2020年7月29日至11月19日间入选患者。30天主要结局指标的最后随访日期为2020年12月19日。
Interventions 干预措施
Intermediate-dose (enoxaparin, 1 mg/kg daily) (n = 276) vs standard prophylactic anticoagulation (enoxaparin, 40 mg daily) (n = 286), with modification according to body weight and creatinine clearance. The assigned treatments were planned to be continued until completion of 30-day follow-up.
中等剂量（依诺肝素enoxaparin, 1 mg/kg/日) (n = 276) 与标准预防抗凝 (依诺肝素enoxaparin, 40 mg/日) (n = 286)，药物剂量根据体重及肌酐清除率进行调整。分配的治疗计划持续到完成30天随访。
Main Outcomes and Measures 主要预后指标
The primary efficacy outcome was a composite of venous or arterial thrombosis, treatment with extracorporeal membrane oxygenation, or mortality within 30 days, assessed in randomized patients who met the eligibility criteria and received at least 1 dose of the assigned treatment. Prespecified safety outcomes included major bleeding according to the Bleeding Academic Research Consortium (type 3 or 5 definition), powered for noninferiority (a noninferiority margin of 1.8 based on odds ratio), and severe thrombocytopenia (platelet count <20 ×103/µL). All outcomes were blindly adjudicated.
主要预后指标为复合指标，对于满足入选标准且接受至少一剂治疗的患者进行评估，包括30天内静脉或动脉血栓形成，接受ECMO治疗或死亡。预先确定的安全指标包括根据出血学术研究会定义的大出血（3型或5型定义）（非劣效边界比数比1.8），重度血小板缺乏（血小板计数<20 ×103/µL）。所有结局指标的评估均设盲。
Results 结果
Among 600 randomized patients, 562 (93.7%) were included in the primary analysis (median [interquartile range] age, 62 [50-71] years; 237 [42.2%] women). The primary efficacy outcome occurred in 126 patients (45.7%) in the intermediate-dose group and 126 patients (44.1%) in the standard-dose prophylaxis group (absolute risk difference, 1.5% [95% CI, −6.6% to 9.8%]; odds ratio, 1.06 [95% CI, 0.76-1.48]; P = .70). Major bleeding occurred in 7 patients (2.5%) in the intermediate-dose group and 4 patients (1.4%) in the standard-dose prophylaxis group (risk difference, 1.1% [1-sided 97.5% CI, −∞ to 3.4%]; odds ratio, 1.83 [1-sided 97.5% CI, 0.00-5.93]), not meeting the noninferiority criteria (P for noninferiority >.99). Severe thrombocytopenia occurred only in patients assigned to the intermediate-dose group (6 vs 0 patients; risk difference, 2.2% [95% CI, 0.4%-3.8%]; P = .01).
共600名患者接受随机分组，562名 (93.7%) 纳入主要分析（中位 [四分位区间] 年龄, 62 [50-71] 岁; 237名 [42.2%] 女性)。中等剂量组126名 (45.7%) 患者与标准剂量组126 名 (44.1%) 患者发生主要疗效结局事件（绝对风险差异, 1.5% [95% CI, −6.6% to 9.8%]; 比数比, 1.06 [95% CI, 0.76-1.48]; P = .70）。中等剂量组7名 (2.5%) 患者及标准剂量组4名 (1.4%) 患者发生大出血（风险差异, 1.1% [1-sided 97.5% CI, −∞ to 3.4%]; 比数比, 1.83 [1-sided 97.5% CI, 0.00-5.93]），未达到非劣效标准（非劣效P值 >.99)。仅中等剂量组患者发生重度血小板缺乏（6 vs 0 名患者; 风险差异, 2.2% [95% CI, 0.4%-3.8%]; P = .01）。
Conclusions and Relevance 结论与意义
Among patients admitted to the ICU with COVID-19, intermediate-dose prophylactic anticoagulation, compared with standard-dose prophylactic anticoagulation, did not result in a significant difference in the primary outcome of a composite of adjudicated venous or arterial thrombosis, treatment with extracorporeal membrane oxygenation, or mortality within 30 days. These results do not support the routine empirical use of intermediate-dose prophylactic anticoagulation in unselected patients admitted to the ICU with COVID-19.
对于收入ICU的新冠肺炎患者，与标准剂量预防性抗凝相比，中等剂量预防性抗凝对包括30天内静脉或动脉血栓形成、ECMO治疗或死亡在内的复合预后指标没有显著影响。这些结果不支持对于收入ICU的新冠肺炎患者不加选择地常规经验性采用中等剂量预防性抗凝。
Trial Registration
ClinicalTrials.gov Identifier: NCT04486508
