Article ; Online: 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.
2021 Volume 325, Issue 16, Page(s) 1620–1630
Abstract: ... the effects of intermediate-dose vs standard-dose prophylactic anticoagulation among patients with COVID-19 ... of intermediate-dose prophylactic anticoagulation in unselected patients admitted to the ICU with COVID-19 ... and relevance: Among patients admitted to the ICU with COVID-19, intermediate-dose prophylactic ...
| 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. Trial registration: ClinicalTrials.gov Identifier: NCT04486508. |
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| MeSH term(s) | Aged ; Anticoagulants/administration & dosage ; Anticoagulants/adverse effects ; COVID-19/complications ; COVID-19/mortality ; Drug Administration Schedule ; Enoxaparin/administration & dosage ; Enoxaparin/adverse effects ; Extracorporeal Membrane Oxygenation ; Female ; Hemorrhage/chemically induced ; Hospitalization ; Humans ; Intensive Care Units ; Iran ; Length of Stay/statistics & numerical data ; Male ; Middle Aged ; Odds Ratio ; Outcome Assessment, Health Care ; Oxygen Inhalation Therapy/methods ; Pulmonary Embolism/epidemiology ; Thrombocytopenia/chemically induced ; Thrombosis/etiology ; Thrombosis/mortality ; Thrombosis/prevention & control ; Treatment Outcome ; Venous Thrombosis/epidemiology ; Venous Thrombosis/mortality | |||||
| Chemical Substances | Anticoagulants ; Enoxaparin | |||||
| Language | English | |||||
| Publishing date | 2021-03-18 | |||||
| Publishing country | United States | |||||
| Document type | Journal Article ; Multicenter Study ; Randomized Controlled Trial ; Research Support, Non-U.S. Gov't | |||||
| ZDB-ID | 2958-0 | |||||
| ISSN | 1538-3598 ; 0254-9077 ; 0002-9955 ; 0098-7484 | |||||
| ISSN (online) | 1538-3598 | |||||
| ISSN | 0254-9077 ; 0002-9955 ; 0098-7484 | |||||
| DOI | 10.1001/jama.2021.4152 | |||||
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| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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