伊朗医科大学Parham Sadeghipour团队联合美国布列根和妇女医院Behnood Bikdeli团队比较了中等剂量与标准剂量预防性抗凝对重症监护病房COVID-19患者血栓事件、体外膜肺氧合治疗或死亡率的影响。2021年3月18日，该研究发表在《美国医学会杂志》上。

COVID-19危重患者通常会发生血栓性事件。目前用于指导抗血栓预防强度的资料很有限。

为了评价中等剂量与标准剂量预防性抗凝治疗对重症监护病房（ICU）COVID-19患者的影响，研究组在伊朗的10个学术中心进行了一项多中心随机试验，采用2×2析因设计，比较了COVID-19患者入住ICU后中等剂量与标准剂量预防性抗凝（第一个假设）和他汀类药物与匹配安慰剂治疗（第二个假设）之间的差异。

2020年7月29日至11月19日，研究组共招募了562例COVID-19重症患者，将其随机分组，其中276例接受中等剂量依诺肝素预防性抗凝，286例接受标准剂量依诺肝素预防性抗凝，并根据体重和肌酐清除率进行调整。持续进行指定治疗，直到完成30天随访。主要疗效结局是静脉或动脉血栓形成、体外膜肺氧合治疗、或30天内死亡的综合结果。预先指定的安全性结局包括根据出血学术研究联合会定义的严重出血、非劣效性和严重血小板减少。

562例患者的中位年龄为62岁，其中42.2%为女性。中等剂量组中有126例（45.7%）患者发生主要疗效结局，标准剂量组中有126例（44.1%），差异不显著。中等剂量组中有7例（2.5%）患者发生大出血，标准剂量组中有4例（1.4%），比值比为1.83，不符合非劣效性标准。中等剂量组还发生6例严重血小板减少（2.2%），而标准剂量组则没有。

研究结果表明，对于COVID-19 ICU患者，与标准剂量预防性抗凝相比，采用中等剂量预防性抗凝治疗，并不能改善静脉或动脉血栓形成、体外膜肺氧合治疗、或30天内死亡的综合结局。

附：英文原文

Title: 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

Author: INSPIRATION Investigators, Parham Sadeghipour, Azita H. Talasaz, Farid Rashidi, Babak Sharif-Kashani, Mohammad Taghi Beigmohammadi, Mohsen Farrokhpour, Seyed Hashem Sezavar, Pooya Payandemehr, Ali Dabbagh, Keivan Gohari Moghadam, Sepehr Jamalkhani, Hossein Khalili, Mahdi Yadollahzadeh, Taghi Riahi, Parisa Rezaeifar, Ouria Tahamtan, Samira Matin, Atefeh Abedini, Somayeh Lookzadeh, Hamid Rahmani, Elnaz Zoghi, Keyhan Mohammadi, Pardis Sadeghipour, Homa Abri, Sanaz Tabrizi, Seyed Masoud Mousavian, Shaghayegh Shahmirzaei, Hooman Bakhshandeh, Ahmad Amin, Farnaz Rafiee, Elahe Baghizadeh, Bahram Mohebbi, Seyed Ehsan Parhizgar, Rasoul Aliannejad, Vahid Eslami, Alireza Kashefizadeh, Hessam Kakavand, Seyed Hossein Hosseini, Shadi Shafaghi, Samrand Fattah Ghazi, Atabak Najafi, David Jimenez, Aakriti Gupta, Mahesh V. Madhavan, Sanjum S. Sethi, Sahil A. Parikh, Manuel Monreal, Naser Hadavand, Alireza Hajighasemi, Majid Maleki, Saeed Sadeghian, Gregory Piazza, Ajay J. Kirtane, Benjamin W. Van Tassell, Paul P. Dobesh, Gregg W. Stone, Gregory Y. H. Lip, Harlan M. Krumholz, Samuel Z. Goldhaber, Behnood Bikdeli

Issue&Volume: 2021-03-18

Abstract:

Importance  Thrombotic events are commonly reported in critically ill patients with COVID-19. Limited data exist to guide the intensity of antithrombotic prophylaxis.

Objective  To evaluate the effects of intermediate-dose vs standard-dose prophylactic anticoagulation among patients with COVID-19 admitted to the intensive care unit (ICU).

Design, Setting, and Participants  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.

Interventions  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.

Main Outcomes and Measures  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.

Results  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).

Conclusions and Relevance  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.

DOI: 10.1001/jama.2021.4152

Source: https://jamanetwork.com/journals/jama/fullarticle/2777829