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.

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.

• Authors: 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
• Journal: JAMA (JAMA) Vol. 325 Issue 16 Pg. 1620-1630 (04 27 2021) ISSN: 1538-3598 [Electronic] United States
• PMID: 33734299 (Publication Type: Journal Article, Multicenter Study, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)

Chemical References

• Anticoagulants
• Enoxaparin

Topics

• Aged
• Anticoagulants (administration & dosage, adverse effects)
• COVID-19 (complications, mortality)
• Drug Administration Schedule
• Enoxaparin (administration & dosage, 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, mortality, prevention & control)
• Treatment Outcome
• Venous Thrombosis (epidemiology, mortality)