TY - JOUR
T1 - 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
T2 - The INSPIRATION Randomized Clinical Trial
AU - Sadeghipour, Parham
AU - Talasaz, Azita H.
AU - Rashidi, Farid
AU - Sharif-Kashani, Babak
AU - Beigmohammadi, Mohammad Taghi
AU - Farrokhpour, Mohsen
AU - Sezavar, Seyed Hashem
AU - Payandemehr, Pooya
AU - Dabbagh, Ali
AU - Moghadam, Keivan Gohari
AU - Jamalkhani, Sepehr
AU - Khalili, Hossein
AU - Yadollahzadeh, Mahdi
AU - Riahi, Taghi
AU - Rezaeifar, Parisa
AU - Tahamtan, Ouria
AU - Matin, Samira
AU - Abedini, Atefeh
AU - Lookzadeh, Somayeh
AU - Rahmani, Hamid
AU - Zoghi, Elnaz
AU - Mohammadi, Keyhan
AU - Sadeghipour, Pardis
AU - Abri, Homa
AU - Tabrizi, Sanaz
AU - Mousavian, Seyed Masoud
AU - Shahmirzaei, Shaghayegh
AU - Bakhshandeh, Hooman
AU - Amin, Ahmad
AU - Rafiee, Farnaz
AU - Baghizadeh, Elahe
AU - Mohebbi, Bahram
AU - Parhizgar, Seyed Ehsan
AU - Aliannejad, Rasoul
AU - Eslami, Vahid
AU - Kashefizadeh, Alireza
AU - Kakavand, Hessam
AU - Hosseini, Seyed Hossein
AU - Shafaghi, Shadi
AU - Ghazi, Samrand Fattah
AU - Najafi, Atabak
AU - Jimenez, David
AU - Gupta, Aakriti
AU - Madhavan, Mahesh V.
AU - Sethi, Sanjum S.
AU - Parikh, Sahil A.
AU - Monreal, Manuel
AU - Hadavand, Naser
AU - Hajighasemi, Alireza
AU - Maleki, Majid
AU - Sadeghian, Saeed
AU - Piazza, Gregory
AU - Kirtane, Ajay J.
AU - Van Tassell, Benjamin W.
AU - Dobesh, Paul P.
AU - Stone, Gregg W.
AU - Lip, Gregory Y.H.
AU - Krumholz, Harlan M.
AU - Goldhaber, Samuel Z.
AU - Bikdeli, Behnood
N1 - Publisher Copyright:
© 2021 American Medical Association. All rights reserved.
PY - 2021/4/27
Y1 - 2021/4/27
N2 - 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.
AB - 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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U2 - 10.1001/jama.2021.4152
DO - 10.1001/jama.2021.4152
M3 - Article
C2 - 33734299
AN - SCOPUS:85102861485
SN - 0098-7484
VL - 325
SP - 1620
EP - 1630
JO - JAMA - Journal of the American Medical Association
JF - JAMA - Journal of the American Medical Association
IS - 16
ER -