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 - Funding Information:
Funding/Support: The study was funded by the Rajaie Cardiovascular Medical and Research Center. Some study authors, including the lead author, are affiliated with the Rajaie Cardiovascular Medical and Research Center. Enoxaparin was provided through Alborz Darou, Pooyesh Darou, and Caspian Pharmaceuticals companies, and atorvastatin and matching placebo was provided by Sobhan Darou. None of these companies were study sponsors.
Funding Information:
reported receiving personal fees from Bristol Myers Squibb, Daiichi-Sankyo, Bayer, Pfizer, Rovi, and Leo-Pharma and grants from Sanofi outside the submitted work. Dr Gupta reported receiving consulting fees from Edwards Lifesciences, Arnold
Funding Information:
Porter Law Firm, and Ben C. Martin Law Firm and equity from Heartbeat Health Inc outside the submitted work. Dr Madhavan reported receiving an institutional research grant to Columbia University Irving Medical Center (T32 HL007854) from the National Institutes of Health/National Heart, Lung, and Blood Institute during the conduct of the study. Dr Sethi reported receiving personal fees from Janssen and Chiesi and grants from the American Heart Association outside the submitted work. Dr Parikh reported receiving grants from Abbott Vascular, Boston Scientific, Surmodics, and TriReme Medical; nonfinancial support from Cordis, Medtronic, Philips, and Cardiovascular Systems Inc; and personal fees from Terumo, Abiomed, Inari, and Penumbra outside the submitted work. Dr Monreal reported receiving grants from Sanofi outside the submitted work. Dr Piazza reported receiving grants from Bristol Myers Squibb/Pfizer, Janssen, Portola, Boston Scientific, and Bayer and serving on a data and safety monitoring board for Prairie Education and Research Cooperative outside the submitted work. Dr Kirtane reported receiving institutional funding to Columbia University and/or the Cardiovascular Research Foundation from Medtronic, Boston Scientific, Abbott Vascular, Abiomed, Cardiovascular Systems Inc, CathWorks, Siemens, Philips, and ReCor Medical, including fees paid to Columbia University and/or the Cardiovascular Research Foundation for speaking engagements and/or consulting; consulting fees from Neurotronic; and travel expenses/meals from Medtronic, Boston Scientific, Abbott Vascular, Abiomed, Cardiovascular Systems Inc, CathWorks, Siemens, Philips, ReCor Medical, Chiesi, OpSens, Zoll, and Regeneron. Dr Dobesh reported receiving personal fees from the Pfizer/Bristol Myers Squibb Alliance and Janssen Pharmaceuticals outside the submitted work. Dr Stone reported receiving personal fees from Terumo, Cook, TherOx, Reva, Vascular Dynamics, Robocath, HeartFlow, Gore, Ablative Solutions, Matrizyme, Miracor Neovasc, V-wave, Abiomed, MAIA Pharmaceuticals, Shockwave, Vectorious, Cardiomech , and Elucid Bio; equity/equity options from Applied Therapeutics, MedFocus, Biostar, Aria, Cagent, Cardiac Success; personal fees and equity/equity options from Spectrawave, Valfix, Ancora; and personal fees, equity/equity options, and honorarium from Orchestra Biomed, and outside the submitted work. Dr Lip reported being a consultant and speaker for Bristol Myers Squibb/ Pfizer, Boehringer Ingelheim, and Daiichi-Sankyo outside the submitted work. Dr Krumholz reported receiving personal fees from UnitedHealth, IBM Watson Health, Element Science, Aetna, Facebook, Siegfried & Jensen Law Firm, Arnold & Porter Law Firm, Martin/Baughman Law Firm, F-Prime, and the National Center for Cardiovascular Diseases, Beijing; being the cofounder of HugoHealth, a personal health information platform, and Refactor Health, an enterprise health care artificial intelligence–augmented data management company; receiving contracts from the Centers for Medicare & Medicaid Services, through Yale New Haven Hospital, to develop and maintain measures of hospital performance; and receiving grants from Medtronic, the US Food and Drug Administration, Johnson & Johnson, and the Shenzhen Center for Health Information outside the submitted work. Dr Goldhaber reported receiving grants from Bayer, Boehringer-Ingelheim, Bristol Myers Squibb, Boston Scientific, Janssen, the National Heart, Lung, and Blood Institute, and Pfizer and personal fees from Agile, Bayer, Boehringer-Ingelheim, and Pfizer outside the submitted work. Dr Bikdeli reported being a consulting expert, on behalf of the plaintiff, for litigation related to 2 specific brand models of inferior vena cava filters. No other disclosures were reported.
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
VL - 325
SP - 1620
EP - 1630
JO - JAMA - Journal of the American Medical Association
JF - JAMA - Journal of the American Medical Association
SN - 0002-9955
IS - 16
ER -