Corresponding Authors: Parham Sadeghipour, MD, Cardiovascular Intervention Research Center, Rajaie Cardiovascular Medical and Research Center, Iran University of Medical Sciences, Vali-Asr Ave, Niyayesh Blvd, Tehran 1996911101, Iran (psadeghipour@hotmail.com); Behnood Bikdeli, MD, MS, Cardiovascular Medicine Division, Brigham and Women’s Hospital, 75 Francis St, Shapiro 5, Ste 5156, Boston, MA 02115 (bbikdeli@bwh.harvard.edu; behnood.bikdeli@yale.edu).
Accepted for Publication: March 4, 2021.
Published Online: March 18, 2021. doi:10.1001/jama.2021.4152
Authors/INSPIRATION Investigators: Parham Sadeghipour, MD; Azita H. Talasaz, PharmD; Farid Rashidi, MD; Babak Sharif-Kashani, MD; Mohammad Taghi Beigmohammadi, MD; Mohsen Farrokhpour, MD; Seyed Hashem Sezavar, MD; Pooya Payandemehr, MD; Ali Dabbagh, MD; Keivan Gohari Moghadam, MD; Sepehr Jamalkhani, MD (’23); Hossein Khalili, PharmD; Mahdi Yadollahzadeh, MD; Taghi Riahi, MD; Parisa Rezaeifar, MD; Ouria Tahamtan, MD; Samira Matin, MD; Atefeh Abedini, MD; Somayeh Lookzadeh, MD; Hamid Rahmani, PharmD; Elnaz Zoghi, PharmD; Keyhan Mohammadi, PharmD; Pardis Sadeghipour, MD; Homa Abri, MD; Sanaz Tabrizi, MD; Seyed Masoud Mousavian, MD; Shaghayegh Shahmirzaei, MD; Hooman Bakhshandeh, MD, PhD; Ahmad Amin, MD; Farnaz Rafiee, MD; Elahe Baghizadeh, MD; Bahram Mohebbi, MD; Seyed Ehsan Parhizgar, MD; Rasoul Aliannejad, MD; Vahid Eslami, MD; Alireza Kashefizadeh, MD; Hessam Kakavand, PharmD; Seyed Hossein Hosseini, PharmD; Shadi Shafaghi, MD; Samrand Fattah Ghazi, MD; Atabak Najafi, MD; David Jimenez, MD, PhD; Aakriti Gupta, MD, MS; Mahesh V. Madhavan, MD; Sanjum S. Sethi, MD, MPH; Sahil A. Parikh, MD; Manuel Monreal, MD; Naser Hadavand, PharmD; Alireza Hajighasemi, PharmD; Majid Maleki, MD; Saeed Sadeghian, MD; Gregory Piazza, MD, MS; Ajay J. Kirtane, MD, SM; Benjamin W. Van Tassell, PharmD; Paul P. Dobesh, PharmD; Gregg W. Stone, MD; Gregory Y. H. Lip, MD; Harlan M. Krumholz, MD, SM; Samuel Z. Goldhaber, MD; Behnood Bikdeli, MD, MS.
Affiliations of Authors/INSPIRATION Investigators: Cardiovascular Intervention Research Center, Rajaie Cardiovascular, Medical, and Research Center, Iran University of Medical Sciences, Tehran, Iran (Parham Sadeghipour, Mohebbi); Clinical Trial Center, Rajaie Cardiovascular, Medical, and Research Center, Iran University of Medical Sciences, Tehran, Iran (Parham Sadeghipour, Bakhshandeh); Tehran Heart Center, Tehran University of Medical Sciences, Tehran, Iran (Talasaz, Hajighasemi, Sadeghian); Tuberculosis and Lung Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, Iran (Rashidi, Rezaeifar, Tahamtan, Matin); Tobacoo Prevention and control Research center, National Research institute of Tuberculosis and Lung Diseases (NRITLD), Shahid Beheshti University of Medical Sciences, Tehran, Iran (Sharif-Kashani); Lung Transplantation Research Center, Department of Cardiology, National Research Institute of Tuberculosis and Lung Diseases (NRITLD), Shahid Beheshti University of Medical Sciences, Tehran, Iran (Sharif-Kashani, Shafaghi); Anesthesiology and Intensive Care, Imam Khomeini Hospital Complex, Tehran University of Medical Sciences, Tehran, Iran (Beigmohammadi, Ghazi); Firouzgar hospital, Department of internal medicine, Iran University of Medical Sciences, Tehran, Iran (Farrokhpour, Yadollahzadeh, Pardis Sadeghipour, Abri); Research Center for Prevention of Cardiovascular Disease, Institute of Endocrinology & Metabolism, Iran University of Medical Sciences, Tehran, Iran (Sezavar); Sina Hospital, Tehran University of Medical Sciences, Tehran, Iran (Payandemehr, Shahmirzaei, Najafi); Department of Anesthesiology, School of Medicine Anesthesiology Research Center Shahid Modarres Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran (Dabbagh); School of Medicine, Department of Internal Medicine, Shariati Hospital, Tehran, Iran (Moghadam); Student Research Committee, Iran University of Medical Sciences, Tehran, Iran (Jamalkhani); Department of Pharmacotherapy, Imam Khomeini Hospital Complex, Tehran University of Medical Sciences, Tehran, Iran (Khalili); Rasoul-e-Akram Hospital, Iran University of Medical Sciences, Tehran, Iran (Riahi, Tabrizi, Mousavian); Chronic Respiratory Disease Research Center, Masih Daneshvari Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran (Abedini, Lookzadeh); Department of Pharmacotherapy, Faculty of Pharmacy, Kermanshah University of Medical Sciences, Kermanshah, Iran (Rahmani); School of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran (Zoghi, Mohammadi, Kakavand, Hosseini); Rajaie Cardiovascular Medical and Research Center, Iran university of Medical sciences, Tehran, Iran (Bakhshandeh, Amin, Rafiee, Baghizadeh, Parhizgar, Hadavand, Maleki); School of Medicine, Department of Pulmonary and Critical Care, Shariati Hospital, Tehran, Iran (Aliannejad); Advanced Thoracic Research Center, Tehran University of Medical Sciences, Tehran, Iran (Aliannejad); Cardiovascular Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran (Eslami); Shahid Dr Labbafinejad Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran (Kashefizadeh); Respiratory Department, Hospital Ramón y Cajal (IRYCIS), Madrid, Spain (Jimenez); Medicine Department, Universidad de Alcalá (IRYCIS), Madrid, Spain (Jimenez); CIBER Enfermedades Respiratorias (CIBERES), Madrid, Spain (Jimenez); Cardiovascular Research Foundation (CRF), New York, New York (Gupta, Madhavan, Sethi, Parikh, Kirtane, Stone, Bikdeli); Division of Cardiology, Columbia University Irving Medical Center/NewYork-Presbyterian Hospital, New York, New York (Gupta, Madhavan, Sethi, Parikh, Kirtane); Yale/YNHH Center for Outcomes Research & Evaluation, New Haven, Connecticut (Gupta, Krumholz, Bikdeli); Department of Internal Medicine, Hospital Germans Trias i Pujol, Badalona, Barcelona, Universidad Católica de Murcia, Murcia, Spain (Monreal); Cardiovascular Medicine Division, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts (Piazza, Goldhaber, Bikdeli); School of Pharmacy, Department of Pharmacotherapy and Outcome Science, Virginia Commonwealth University, Richmond, Virginia (Van Tassell); School of Pharmacy, Pauley Heart Center, Division of Cardiology, Department of Internal Medicine, Virginia Commonwealth University, Richmond, Virginia (Van Tassell); College of Pharmacy, University of Nebraska Medical Center, Omaha (Dobesh); The Zena and Michael A. Wiener Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, New York, New York (Stone); Liverpool Centre for Cardiovascular Science, University of Liverpool and Liverpool Heart & Chest Hospital, Liverpool, United Kingdom (Lip); Aalborg University, Aalborg, Denmark (Lip); Section of Cardiovascular Medicine, Department of Internal Medicine, Yale School of Medicine, New Haven, Connecticut (Krumholz); Department of Health Policy and Administration, Yale School of Public Health, New Haven, Connecticut (Krumholz).
Author Contributions: Dr Sadeghipour had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Concept and design: Parham Sadeghipour, Talasaz, Rashidi, Sharif-Kashani, Beigmohammadi, Sezavar, Payandemehr, Dabbagh, Gohari Moghadam, Riahi, Abedini, Mohebbi, Kakavand, Fattah Ghazi, Najafi, Jimenez, Sethi, Monreal, Hajighasemi, Sadeghian, Piazza, Kirtane, Dobesh, Bikdeli.
Acquisition, analysis, or interpretation of data: Parham Sadeghipour, Talasaz, Sharif-Kashani, Beigmohammadi, Farrokhpour, Payandemehr, Dabbagh, Jamalkhani, Khalili, Yadollahzadeh, Rezaeifar, Tahamtan, Matin, Lookzadeh, Rahmani, Zoghi, Mohammadi, Pardis Sadeghipour, Abri, Tabrizi, Mousavian, Shahmirzaei, Bakhshandeh, Amin, Rafiee, Baghizadeh, Mohebbi, Parhizgar, Aliannejad, Eslami, Kashefizadeh, Hosseini, Shafaghi, Jimenez, Gupta, Madhavan, Sethi, Parikh, Hadavand, Maleki, Piazza, Van Tassell, Stone, Lip, Krumholz, Goldhaber, Bikdeli.
Drafting of the manuscript: Parham Sadeghipour, Talasaz, Sharif-Kashani, Farrokhpour, Payandemehr, Jamalkhani, Khalili, Yadollahzadeh, Riahi, Rezaeifar, Tahamtan, Matin, Lookzadeh, Pardis Sadeghipour, Abri, Tabrizi, Mousavian, Shahmirzaei, Rafiee, Baghizadeh, Mohebbi, Parhizgar, Eslami, Kashefizadeh, Hosseini, Shafaghi, Fattah Ghazi, Najafi, Bikdeli.
Critical revision of the manuscript for important intellectual content: Parham Sadeghipour, Talasaz, Rashidi, Beigmohammadi, Sezavar, Payandemehr, Dabbagh, Gohari Moghadam, Abedini, Rahmani, Zoghi, Mohammadi, Bakhshandeh, Amin, Mohebbi, Aliannejad, Kakavand, Najafi, Jimenez, Gupta, Madhavan, Sethi, Parikh, Monreal, Hadavand, Hajighasemi, Maleki, Sadeghian, Piazza, Kirtane, Van Tassell, Dobesh, Stone, Lip, Krumholz, Goldhaber, Bikdeli.
Statistical analysis: Parham Sadeghipour, Bakhshandeh, Mohebbi, Jimenez.
Obtained funding: Parham Sadeghipour, Abedini, Najafi.
Administrative, technical, or material support: Parham Sadeghipour, Talasaz, Beigmohammadi, Payandemehr, Gohari Moghadam, Khalili, Abedini, Rahmani, Zoghi, Mohammadi, Amin, Mohebbi, Parhizgar, Aliannejad, Kakavand, Fattah Ghazi, Najafi, Sethi, Hadavand, Hajighasemi, Maleki, Sadeghian, Piazza, Bikdeli.
Supervision: Parham Sadeghipour, Talasaz, Rashidi, Sharif-Kashani, Beigmohammadi, Payandemehr, Gohari Moghadam, Riahi, Mohebbi, Gupta, Monreal, Piazza, Van Tassell, Dobesh, Goldhaber, Bikdeli.
Other - monitoring of the study progress, supporting patient recruitment, data clarifications, and data entry: Sharif-Kashani, Farrokhpour, Sezavar, Jamalkhani, Yadollahzadeh, Rezaeifar, Tahamtan, Matin, Lookzadeh, Pardis Sadeghipour, Abri, Tabrizi, Mousavian, Shahmirzaei, Eslami, Kashefizadeh, Hosseini, Shafaghi.
Conflict of Interest Disclosures: Dr Jimenez 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 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.
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.
Role of the Funder/Sponsor: Some study authors are affiliated with the study funder (Rajaie Cardiovascular and Medical Research Center). Neither the funder, nor the companies who donated the study drugs (Alborz Darou, Pooyesh Darou and Caspian Pharmaceuticals) had any role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.
Group Information: A list of the INSPIRATION collaborators appears in Supplement 4.
Data Sharing Statement: See Supplement 5.
Additional Contributions: The authors would like to thank the members of the data and safety monitoring board, Saeideh Mazloomzadeh, MD, PhD; Shiva Khaleghparast, PhD; Behshid Ghadrdoost, PhD; Mostafa Mousavizadeh, MD; and Mohammad Reza Baay, MD (Rajaie Cardiovascular, Medical and Research Center). The authors would also like to thank Feridoun Noohi, MD (Rajaie Cardiovascular, Medical and Research Center), for his support for performing this study, Hamidreza Sharifnia, MD; Arezoo Ahmadi, MD (Sina Hospital, Tehran University of Medical Sciences, Tehran, Iran); Sasan Tavana, MD; Nasser Malekpour Alamdari, MD; Mohammad Fathi, MD; Mahshid Soleimanzadeh, MD (Shahid Modarres Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran); Mostafa Mohammadi, MD (Imam Khomeini Hospital Complex, Tehran University of Medical Sciences, Tehran, Iran); and Navid Davoody, MD (Rasoul-e-Akram Hospital, Iran University of Medical Sciences, Tehran, Iran), for their kind support for patient recruitment and Maryam Zarinsadaf, Sara Tayyebi, MS; Fahimeh Farrokhzadeh, MS; Faeze Nezamabadi, MS; and Esmaeil Soomari, MS (Rajaie Cardiovascular, Medical and Research Center), for their support and contribution to the INSPIRATION study.
2.Wichmann
D , Sperhake
JP , Lütgehetmann
M ,
et al. Autopsy findings and venous thromboembolism in patients with COVID-19: a prospective cohort study.
Ann Intern Med. 2020;173(4):268-277. doi:
10.7326/M20-2003PubMedGoogle ScholarCrossref 4.Bikdeli
B , Madhavan
MV , Jimenez
D ,
et al; Global COVID-19 Thrombosis Collaborative Group, Endorsed by the ISTH, NATF, ESVM, and the IUA, Supported by the ESC Working Group on Pulmonary Circulation and Right Ventricular Function. COVID-19 and thrombotic or thromboembolic disease: implications for prevention, antithrombotic therapy, and follow-up: jacc state-of-the-art review.
J Am Coll Cardiol. 2020;75(23):2950-2973. doi:
10.1016/j.jacc.2020.04.031PubMedGoogle ScholarCrossref 7.Bikdeli
B , Madhavan
MV , Gupta
A ,
et al; Global COVID-19 Thrombosis Collaborative Group. Pharmacological agents targeting thromboinflammation in COVID-19: review and implications for future research.
Thromb Haemost. 2020;120(7):1004-1024. doi:
10.1055/s-0040-1713152PubMedGoogle ScholarCrossref 9.Al-Samkari
H , Gupta
S , Karp Leaf
R ,
et al Thrombosis, bleeding, and the effect of anticoagulation on survival in critically ill patients with COVID-19 in the United States.
Res Pract Thromb Haemost. 2020;4.
Google Scholar 14.Ramacciotti
E , Macedo
AS , Biagioni
RB ,
et al. Evidence-based practical guidance for the antithrombotic management in patients with coronavirus disease (COVID-19) in 2020.
Clin Appl Thromb Hemost. 2020;26:1076029620936350. doi:
10.1177/1076029620936350PubMedGoogle Scholar 16.Bikdeli
B , Talasaz
AH , Rashidi
F ,
et al. Intermediate versus standard-dose prophylactic anticoagulation and statin therapy versus placebo in critically-ill patients with COVID-19: rationale and design of the INSPIRATION/INSPIRATION-S studies.
Thromb Res. 2020;196:382-394. doi:
10.1016/j.thromres.2020.09.027PubMedGoogle ScholarCrossref 18.Cook
D , Meade
M , Guyatt
G ,
et al; PROTECT Investigators for the Canadian Critical Care Trials Group and the Australian and New Zealand Intensive Care Society Clinical Trials Group. Dalteparin versus unfractionated heparin in critically ill patients.
N Engl J Med. 2011;364(14):1305-1314. doi:
10.1056/NEJMoa1014475PubMedGoogle ScholarCrossref 19.Eck
RJ , Bult
W , Wetterslev
J ,
et al. Intermediate dose low-molecular-weight heparin for thrombosis prophylaxis: systematic review with meta-analysis and trial sequential analysis.
Semin Thromb Hemost. 2019;45(8):810-824. doi:
10.1055/s-0039-1696965PubMedGoogle ScholarCrossref 28.Pannucci
CJ , Fleming
KI , Agarwal
J , Rockwell
WB , Prazak
AM , Momeni
A . The impact of once- versus twice-daily enoxaparin prophylaxis on risk for venous thromboembolism and clinically relevant bleeding.
Plast Reconstr Surg. 2018;142(1):239-249. doi:
10.1097/PRS.0000000000004517PubMedGoogle ScholarCrossref 29.Yamakawa
K , Umemura
Y , Murao
S , Hayakawa
M , Fujimi
S . Optimal timing and early intervention with anticoagulant therapy for sepsis-induced disseminated intravascular coagulation.
Clin Appl Thromb Hemost. 2019;25:1076029619835055. doi:
10.1177/1076029619835055PubMedGoogle Scholar 31.Grasselli
G , Zangrillo
A , Zanella
A ,
et al; COVID-19 Lombardy ICU Network. Baseline characteristics and outcomes of 1591 patients infected with SARS-CoV-2 admitted to ICUs of the Lombardy Region, Italy.
JAMA. 2020;323(16):1574-1581. doi:
10.1001/jama.2020.5394PubMedGoogle ScholarCrossref 33.Talasaz AH, Sadeghipour P, Kakavand H, et al. Antithrombotic therapy in COVID-19: systematic summary of ongoing or completed randomized trials.
J Am Coll Cardiol. Published online March 16, 2021. doi:
10.1016/j.jacc.2021.02.035Google Scholar 35.Hendren
NS , de Lemos
JA , Ayers
C ,
et al. Association of body mass index and age with morbidity and mortality in patients hospitalized with COVID-19: results from the American Heart Association COVID-19 Cardiovascular Disease Registry.
Circulation. 2021;143(2):135-144. doi:
10.1161/CIRCULATIONAHA.120.051936PubMedGoogle ScholarCrossref 37.Tomazini
BM , Maia
IS , Cavalcanti
AB ,
et al; COALITION COVID-19 Brazil III Investigators. Effect of dexamethasone on days alive and ventilator-free in patients with moderate or severe acute respiratory distress syndrome and COVID-19: the CoDEX randomized clinical trial.
JAMA. 2020;324(13):1307-1316. doi:
10.1001/jama.2020.17021PubMedGoogle ScholarCrossref 38.Sterne
JAC , Murthy
S , Diaz
JV ,
et al; WHO Rapid Evidence Appraisal for COVID-19 Therapies (REACT) Working Group. Association between administration of systemic corticosteroids and mortality among critically ill patients with COVID-19: a meta-analysis.
JAMA. 2020;324(13):1330-1341. doi:
10.1001/jama.2020.17023PubMedGoogle ScholarCrossref