Thromb Haemost 2022; 122(01): 131-141
DOI: 10.1055/a-1485-2372
Stroke, Systemic or Venous Thromboembolism

Intermediate-Dose versus Standard-Dose Prophylactic Anticoagulation in Patients with COVID-19 Admitted to the Intensive Care Unit: 90-Day Results from the INSPIRATION Randomized Trial

Behnood Bikdeli*
1   Division of Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States
2   Yale/YNHH Center for Outcomes Research and Evaluation, New Haven, Connecticut, United States
3   Cardiovascular Research Foundation, New York, New York, United States
,
Azita H. Talasaz*
4   Tehran Heart Center, Tehran University of Medical Sciences, Tehran, Iran
,
Farid Rashidi
5   Tuberculosis and Lung Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
,
Hooman Bakhshandeh
6   Clinical Trial Center, Rajaie Cardiovascular, Medical, and Research Center, Iran University of Medical Sciences, Tehran, Iran
7   Rajaie Cardiovascular Medical and Research Center, Iran university of Medical Sciences, Tehran, Iran
,
Farnaz Rafiee
7   Rajaie Cardiovascular Medical and Research Center, Iran university of Medical Sciences, Tehran, Iran
,
Parisa Rezaeifar
5   Tuberculosis and Lung Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
,
Elahe Baghizadeh
7   Rajaie Cardiovascular Medical and Research Center, Iran university of Medical Sciences, Tehran, Iran
,
Samira Matin
5   Tuberculosis and Lung Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
,
Sepehr Jamalkhani
8   Student Research Committee, Iran University of Medical Sciences, Tehran, Iran
,
Ouria Tahamtan
5   Tuberculosis and Lung Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
,
Babak Sharif-Kashani
9   Tobacoo Prevention and Control Research Center, National Research Institute of Tuberculosis and Lung Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
10   Department of Cardiology, Lung Transplantation Research Center, National Research Institute of Tuberculosis and Lung Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
,
Mohammad Taghi Beigmohammadi
11   Anesthesiology and Intensive Care, Imam Khomeini Hospital Complex, Tehran University of Medical Sciences, Tehran, Iran
,
Mohsen Farrokhpour
12   Department of Internal Medicine, Firouzgar Hospital, Iran University of Medical Sciences, Tehran, Iran
,
Seyed Hashem Sezavar
13   Research Center for Prevention of Cardiovascular Disease, Institute of Endocrinology and Metabolism, Iran University of Medical Sciences, Tehran, Iran
,
Pooya Payandemehr
14   Sina Hospital, Tehran University of Medical Sciences, Tehran, Iran
,
15   Department of Anesthesiology, School of Medicine Anesthesiology Research Center, Shahid Modarres Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran
,
Keivan Gohari Moghadam
16   Department of Internal Medicine, School of Medicine, Shariati Hospital, Tehran, Iran
,
Hossein Khalili
17   Department of Pharmacotherapy, Imam Khomeini Hospital Complex, Tehran University of Medical Sciences, Tehran, Iran
,
Mahdi Yadollahzadeh
12   Department of Internal Medicine, Firouzgar Hospital, Iran University of Medical Sciences, Tehran, Iran
,
Taghi Riahi
18   Rasoul-e-Akram Hospital, Iran University of Medical Sciences, Tehran, Iran
,
Atefeh Abedini
19   Chronic Respiratory Disease Research Center, Masih Daneshvari Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran
,
Somayeh Lookzadeh
19   Chronic Respiratory Disease Research Center, Masih Daneshvari Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran
,
Hamid Rahmani
20   Department of Pharmacotherapy, Faculty of Pharmacy, Kermanshah University of Medical Sciences, Kermanshah, Iran
,
Elnaz Zoghi
21   School of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
,
Keyhan Mohammadi
21   School of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
,
Pardis Sadeghipour
12   Department of Internal Medicine, Firouzgar Hospital, Iran University of Medical Sciences, Tehran, Iran
,
Homa Abri
12   Department of Internal Medicine, Firouzgar Hospital, Iran University of Medical Sciences, Tehran, Iran
,
Sanaz Tabrizi
18   Rasoul-e-Akram Hospital, Iran University of Medical Sciences, Tehran, Iran
,
Seyed Masoud Mousavian
18   Rasoul-e-Akram Hospital, Iran University of Medical Sciences, Tehran, Iran
,
Shaghayegh Shahmirzaei
14   Sina Hospital, Tehran University of Medical Sciences, Tehran, Iran
,
Ahmad Amin
7   Rajaie Cardiovascular Medical and Research Center, Iran university of Medical Sciences, Tehran, Iran
,
Bahram Mohebbi
22   Cardiovascular Intervention Research Center, Rajaie Cardiovascular, Medical, and Research Center, Iran University of Medical Sciences, Tehran, Iran
,
Seyed Ehsan Parhizgar
7   Rajaie Cardiovascular Medical and Research Center, Iran university of Medical Sciences, Tehran, Iran
,
Rasoul Aliannejad
23   Department of Pulmonary and Critical Care, School of Medicine, Shariati Hospital, Tehran, Iran
24   Advanced Thoracic Research Center, Tehran University of Medical Sciences, Tehran, Iran
,
Vahid Eslami
25   Cardiovascular Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
,
Alireza Kashefizadeh
26   Shahid Dr. Labbafinejad Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran
,
Paul P. Dobesh
27   College of Pharmacy, University of Nebraska Medical Center, Omaha, Nebraska, United States
,
Hessam Kakavand
21   School of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
,
Seyed Hossein Hosseini
21   School of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
,
Shadi Shafaghi
10   Department of Cardiology, Lung Transplantation Research Center, National Research Institute of Tuberculosis and Lung Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
,
Samrand Fattah Ghazi
11   Anesthesiology and Intensive Care, Imam Khomeini Hospital Complex, Tehran University of Medical Sciences, Tehran, Iran
,
Atabak Najafi
14   Sina Hospital, Tehran University of Medical Sciences, Tehran, Iran
,
David Jimenez
28   Respiratory Department, Hospital Ramón y Cajal, Madrid, Spain
29   Medicine Department, Universidad de Alcalá, Madrid, Spain
30   CIBER Enfermedades Respiratorias, Madrid, Spain
,
Aakriti Gupta
2   Yale/YNHH Center for Outcomes Research and Evaluation, New Haven, Connecticut, United States
3   Cardiovascular Research Foundation, New York, New York, United States
31   Division of Cardiology, Columbia University Irving Medical Center/NewYork-Presbyterian Hospital, New York, New York, United States
,
Mahesh V. Madhavan
3   Cardiovascular Research Foundation, New York, New York, United States
31   Division of Cardiology, Columbia University Irving Medical Center/NewYork-Presbyterian Hospital, New York, New York, United States
,
Sanjum S. Sethi
3   Cardiovascular Research Foundation, New York, New York, United States
31   Division of Cardiology, Columbia University Irving Medical Center/NewYork-Presbyterian Hospital, New York, New York, United States
,
Sahil A. Parikh
3   Cardiovascular Research Foundation, New York, New York, United States
31   Division of Cardiology, Columbia University Irving Medical Center/NewYork-Presbyterian Hospital, New York, New York, United States
,
Manuel Monreal
32   Department of Internal Medicine, Hospital Germans Trias i Pujol, Badalona, Barcelona, Spain
33   Universidad Católica de Murcia, Murcia, Spain
,
Naser Hadavand
7   Rajaie Cardiovascular Medical and Research Center, Iran university of Medical Sciences, Tehran, Iran
,
Alireza Hajighasemi
4   Tehran Heart Center, Tehran University of Medical Sciences, Tehran, Iran
,
Majid Maleki
7   Rajaie Cardiovascular Medical and Research Center, Iran university of Medical Sciences, Tehran, Iran
,
Saeed Sadeghian
4   Tehran Heart Center, Tehran University of Medical Sciences, Tehran, Iran
,
Gregory Piazza
1   Division of Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States
,
Ajay J. Kirtane
3   Cardiovascular Research Foundation, New York, New York, United States
31   Division of Cardiology, Columbia University Irving Medical Center/NewYork-Presbyterian Hospital, New York, New York, United States
,
Benjamin W. Van Tassell
34   Department of Pharmacotherapy and Outcome Science, School of Pharmacy, Virginia Commonwealth University, Richmond, Virginia, United States
35   Division of Cardiology, Department of Internal Medicine, Pauley Heart Center, School of Pharmacy, Virginia Commonwealth University, Richmond, Virginia, United States
,
Gregg W. Stone
3   Cardiovascular Research Foundation, New York, New York, United States
36   The Zena and Michael A. Wiener Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, New York, New York, United States
,
37   Liverpool Centre for Cardiovascular Science, University of Liverpool and Liverpool Heart and Chest Hospital, Liverpool, United Kingdom
38   Aalborg University, Aalborg, Denmark
,
Harlan M. Krumholz
2   Yale/YNHH Center for Outcomes Research and Evaluation, New Haven, Connecticut, United States
39   Section of Cardiovascular Medicine, Department of Internal Medicine, Yale School of Medicine, New Haven, Connecticut, United States
40   Department of Health Policy and Administration, Yale School of Public Health, New Haven, Connecticut, United States
,
Samuel Z. Goldhaber
1   Division of Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States
,
6   Clinical Trial Center, Rajaie Cardiovascular, Medical, and Research Center, Iran University of Medical Sciences, Tehran, Iran
7   Rajaie Cardiovascular Medical and Research Center, Iran university of Medical Sciences, Tehran, Iran
21   School of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
› Author Affiliations
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Abstract

Background Thrombotic complications are considered among the main extrapulmonary manifestations of coronavirus disease 2019 (COVID-19). The optimal type and duration of prophylactic antithrombotic therapy in these patients remain unknown.

Methods This article reports the final (90-day) results of the Intermediate versus Standard-dose Prophylactic anticoagulation In cRitically-ill pATIents with COVID-19: An opeN label randomized controlled trial (INSPIRATION) study. Patients with COVID-19 admitted to intensive care were randomized to intermediate-dose versus standard-dose prophylactic anticoagulation for 30 days, irrespective of hospital discharge status. The primary efficacy outcome was a composite of adjudicated venous or arterial thrombosis, treatment with extracorporeal membrane oxygenation (ECMO), or all-cause death. The main safety outcome was major bleeding.

Results Of 600 randomized patients, 562 entered the modified intention-to-treat analysis (median age [Q1, Q3]: 62 [50, 71] years; 237 [42.2%] women), of whom 336 (59.8%) survived to hospital discharge. The primary outcome occurred in 132 (47.8%) of patients assigned to intermediate dose and 130 (45.4%) patients assigned to standard-dose prophylactic anticoagulation (hazard ratio [HR]: 1.21, 95% confidence interval [CI]: 0.95–1.55, p = 0.11). Findings were similar for other efficacy outcomes, and in the landmark analysis from days 31 to 90 (HR: 1.59, 95% CI: 0.45–5.06). There were 7 (2.5%) major bleeding events in the intermediate-dose group (including 3 fatal events) and 4 (1.4%) major bleeding events in the standard-dose group (none fatal) (HR: 1.82, 95% CI: 0.53–6.24).

Conclusion Intermediate-dose compared with standard-dose prophylactic anticoagulation did not reduce a composite of death, treatment with ECMO, or venous or arterial thrombosis at 90-day follow-up.

* Drs. Bikdeli and Talasaz contributed equally to this manuscript.


Supplementary Material



Publication History

Received: 07 April 2021

Accepted: 15 April 2021

Accepted Manuscript online:
17 April 2021

Article published online:
06 June 2021

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