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Thromb Haemost 2023; 123(07): 723-733
DOI: 10.1055/a-2059-4844
Stroke, Systemic or Venous Thromboembolism

Atorvastatin versus Placebo in ICU Patients with COVID-19: Ninety-day Results of the INSPIRATION-S Trial

Azita H. Talasaz 
1   Tehran Heart Center, Tehran University of Medical Sciences, Tehran, Iran
2   Department of Pharmacotherapy and Outcome Sciences, Virginia Commonwealth University, Richmond, Virginia, United States
,
Parham Sadeghipour 
3   Rajaie Cardiovascular Medical and Research Center, Iran University of Medical Sciences, Tehran, Iran
4   Clinical Trial Center, Rajaie Cardiovascular, Medical, and Research Center, Iran University of Medical Sciences, Tehran, Iran
5   Cardiovascular Intervention Research Center, Rajaie Cardiovascular, Medical, and Research Center, Iran University of Medical Sciences, Tehran, Iran
,
Hooman Bakhshandeh
3   Rajaie Cardiovascular Medical and Research Center, Iran University of Medical Sciences, Tehran, Iran
4   Clinical Trial Center, Rajaie Cardiovascular, Medical, and Research Center, Iran University of Medical Sciences, Tehran, Iran
,
Babak Sharif-Kashani
6   Tobacoo Prevention and Control Research Center, National Research Institute of Tuberculosis and Lung Diseases (NRITLD), Shahid Beheshti University of Medical Sciences, Tehran, Iran
7   Department of Cardiology, Lung Transplantation Research Center, National Research Institute of Tuberculosis and Lung Diseases (NRITLD), Shahid Beheshti University of Medical Sciences, Tehran, Iran
,
Farid Rashidi
8   Tuberclosis and Lung Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
,
Mohammad Taghi Beigmohammadi
9   Department of Intensive Care, Tehran University of Medical Sciences, Imam Khomeini Hospital Complex, Tehran, Iran
,
Keivan Gohari Moghadam
10   Department of Internal Medicine, School of Medicine, Shariati Hospital, Tehran, Iran
,
Somaye Rezaian
11   Department of Internal Medicine, Alborz University of Medicine Science, Karaj, Iran
,
Ali Dabbagh 
12   Department of Anesthesiology, School of Medicine Anesthesiology Research Center Shahid Modarres Hospital, Shahid Beheshti 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
,
Mohsen Farrokhpour
14   Department of Internal Medicine, Iran University of Medical Sciences, Firouzgar Hospital, Tehran, Iran
,
Atefeh Abedini
15   Chronic Respiratory Disease Research Center, Shahid Beheshti University of Medical Sciences, Masih Daneshvari Hospital, Tehran, Iran
,
Rasoul Aliannejad
16   Department of Pulmonary and Critical Care, School of Medicine, Shariati Hospital, Tehran, Iran
17   Advanced Thoracic Research Center, Tehran University of Medical Sciences, Tehran, Iran
,
Taghi Riahi
18   Department of Internal Medicine, Rasoul-e-Akram Hospital, Iran University of Medical Sciences, Tehran, Iran
,
Mahdi Yadollahzadeh
14   Department of Internal Medicine, Iran University of Medical Sciences, Firouzgar Hospital, Tehran, Iran
,
Somayeh Lookzadeh
15   Chronic Respiratory Disease Research Center, Shahid Beheshti University of Medical Sciences, Masih Daneshvari Hospital, Tehran, Iran
,
Parisa Rezaeifar
8   Tuberclosis and Lung Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
,
Samira Matin
8   Tuberclosis and Lung Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
,
Ouria Tahamtan
8   Tuberclosis and Lung Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
,
Keyhan Mohammadi
19   Department of Clinical Pharmacy, School of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
,
Elnaz Zoghi
19   Department of Clinical Pharmacy, School of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
,
Hamid Rahmani
19   Department of Clinical Pharmacy, School of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
,
Seyed Hossein Hosseini
19   Department of Clinical Pharmacy, School of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
,
Seyed Masoud Mousavian
18   Department of Internal Medicine, Rasoul-e-Akram Hospital, Iran University of Medical Sciences, Tehran, Iran
,
Homa Abri
14   Department of Internal Medicine, Iran University of Medical Sciences, Firouzgar Hospital, Tehran, Iran
,
Pardis Sadeghipour
14   Department of Internal Medicine, Iran University of Medical Sciences, Firouzgar Hospital, Tehran, Iran
,
Elahe Baghizadeh
3   Rajaie Cardiovascular Medical and Research Center, Iran University of Medical Sciences, Tehran, Iran
,
Farnaz Rafiee
3   Rajaie Cardiovascular Medical and Research Center, Iran University of Medical Sciences, Tehran, Iran
,
Sepehr Jamalkhani
20   Student Research Committee, Iran University of Medical Sciences, Tehran, Iran
21   Department of Pharmacotherapy, Tehran University of Medical Sciences, Imam Khomeini Hospital Complex, Tehran, Iran
,
Ahmad Amin
3   Rajaie Cardiovascular Medical and Research Center, Iran University of Medical Sciences, Tehran, Iran
,
Bahram Mohebbi
5   Cardiovascular Intervention Research Center, Rajaie Cardiovascular, Medical, and Research Center, Iran University of Medical Sciences, Tehran, Iran
,
Seyed Ehsan Parhizgar
3   Rajaie Cardiovascular Medical and Research Center, Iran University of Medical Sciences, Tehran, Iran
,
Mahshid Soleimanzadeh
12   Department of Anesthesiology, School of Medicine Anesthesiology Research Center Shahid Modarres Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran
,
Maryam Aghakouchakzadeh
19   Department of Clinical Pharmacy, School of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
,
Vahid Eslami
22   Department of Emergency Medicine, Cardiovascular Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
,
Pooya Payandemehr
23   Department of Emergency Medicine, Sina Hospital, Tehran University of Medical Sciences, Tehran, Iran
,
Hossein Khalili
21   Department of Pharmacotherapy, Tehran University of Medical Sciences, Imam Khomeini Hospital Complex, Tehran, Iran
,
Hamed Talakoob
24   Cardiovascular Research Center, Alborz University of Medical Sciences, Karaj, Iran
,
Taranom Tojari
25   Department of Biotechnology, Faculty of Biological Sciences, Alzahra University, Tehran, Iran
,
Shadi Shafaghi
7   Department of Cardiology, Lung Transplantation Research Center, National Research Institute of Tuberculosis and Lung Diseases (NRITLD), Shahid Beheshti University of Medical Sciences, Tehran, Iran
,
Sanaz Tabrizi
18   Department of Internal Medicine, Rasoul-e-Akram Hospital, Iran University of Medical Sciences, Tehran, Iran
,
Hessam Kakavand
19   Department of Clinical Pharmacy, School of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
,
Alireza Kashefizadeh
26   Department of Internal Medicine, Shahid Dr. Labbafinejad Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran
,
Atabak Najafi
22   Department of Emergency Medicine, Cardiovascular Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
,
David Jimenez 
27   Respiratory Department, Hospital Ramón y Cajal (IRYCIS), Madrid, Spain
28   Medicine Department, Universidad de Alcalá (IRYCIS), Madrid, Spain
29   CIBER Enfermedades Respiratorias (CIBERES), Madrid, Spain
,
Aakriti Gupta
30   Yale/YNHH Center for Outcomes Research and Evaluation (CORE), New Haven, Connecticut, United States
31   Cedars-Sinai Medical Center, Smidt Heart Institute, Los Angeles, California, United States
,
Mahesh V. Madhavan
32   Cardiovascular Research Foundation (CRF), New York, New York, United States
33   Division of Cardiology, Columbia University Irving Medical Center/NewYork-Presbyterian Hospital, New York, New York, United States
,
Sanjum S. Sethi
32   Cardiovascular Research Foundation (CRF), New York, New York, United States
33   Division of Cardiology, Columbia University Irving Medical Center/NewYork-Presbyterian Hospital, New York, New York, United States
,
Sahil A. Parikh
32   Cardiovascular Research Foundation (CRF), New York, New York, United States
33   Division of Cardiology, Columbia University Irving Medical Center/NewYork-Presbyterian Hospital, New York, New York, United States
,
Manuel Monreal 
34   Cátedra de Enfermedad Tromboembólica, Universidad Católica de Murcia, Murcia, Spain
,
Naser Hadavand
3   Rajaie Cardiovascular Medical and Research Center, Iran University of Medical Sciences, Tehran, Iran
,
Alireza Hajighasemi
1   Tehran Heart Center, Tehran University of Medical Sciences, Tehran, Iran
,
Khalil Ansarin
8   Tuberclosis and Lung Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
,
Majid Maleki
3   Rajaie Cardiovascular Medical and Research Center, Iran University of Medical Sciences, Tehran, Iran
,
Saeed Sadeghian
1   Tehran Heart Center, Tehran University of Medical Sciences, Tehran, Iran
,
Stefano Barco 
35   Department of Angiology, University Hospital Zurich, Zurich, Switzerland
36   Center for Thrombosis and Hemostasis, Johannes Gutenberg University Mainz, Mainz, Germany
,
Bob Siegerink
37   Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, The Netherlands
,
Erica S. Spatz
38   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
,
Gregory Piazza 
40   Cardiovascular Medicine Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States
41   Thrombosis Research Group, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States
,
Ajay J. Kirtane
40   Cardiovascular Medicine Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States
41   Thrombosis Research Group, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States
,
Benjamin W. Van Tassell
2   Department of Pharmacotherapy and Outcome Sciences, Virginia Commonwealth University, Richmond, Virginia, United States
,
Gregory Y. H. Lip
42   Liverpool Centre for Cardiovascular Science, University of Liverpool and Liverpool Heart and Chest Hospital, Liverpool, United Kingdom
43   Department of Clinical Medicine, Aalborg University, Aalborg, Denmark
,
Frederikus A. Klok 
44   Department of Medicine - Thrombosis and Hemostasis, Leiden University Medical Centre, Leiden, The Netherlands
,
Samuel Z. Goldhaber
40   Cardiovascular Medicine Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States
41   Thrombosis Research Group, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States
,
Gregg W. Stone
32   Cardiovascular Research Foundation (CRF), New York, New York, United States
45   The Zena and Michael A. Wiener Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, New York, New York, United States
,
Harlan M. Krumholz
30   Yale/YNHH Center for Outcomes Research and Evaluation (CORE), New Haven, Connecticut, United States
39   Section of Cardiovascular Medicine, Department of Internal Medicine, Yale School of Medicine, New Haven, Connecticut, United States
46   Department of Health Policy and Management, Yale School of Public Health, New Haven, Connecticut, United States
,
Behnood Bikdeli
32   Cardiovascular Research Foundation (CRF), New York, New York, United States
38   Yale/YNHH Center for Outcomes Research and Evaluation, New Haven, Connecticut, United States
40   Cardiovascular Medicine Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States
41   Thrombosis Research Group, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States
› Author Affiliations Funding The study was funded by the Rajaie Cardiovascular Medical and Research Center. Atorvastatin and matching placebo were provided by Sobhan Darou, which is not among the study sponsors. Neither the funder nor the company who donated the study drugs 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; or the decision to submit the manuscript(s) for publication. Dr. Bikdeli is supported by the Scott Schoen and Nancy Adams IGNITE Award from the Mary Horrigan Connors Center for Women's Health and Gender Biology at Brigham and Women's Hospital and a Career Development Award from the American Heart Association and VIVA Physicians (#938814).
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Abstract

Background In the INSPIRATION-S trial, atorvastatin versus placebo was associated with a nonsignificant 16% reduction in 30-day composite of venous/arterial thrombosis or death in intensive care unit (ICU) patients with COVID-19. Thrombo-inflammatory response in coronavirus disease 2019 (COVID-19) may last beyond the first 30 days.

Methods This article reports the effects of atorvastatin 20 mg daily versus placebo on 90-day clinical and functional outcomes from INSPIRATION-S, a double-blind multicenter randomized trial of adult ICU patients with COVID-19. The main outcome for this prespecified study was a composite of adjudicated venous/arterial thrombosis, treatment with extracorporeal membrane oxygenation (ECMO), or all-cause mortality. Functional status was assessed with the Post-COVID-19 Functional Scale.

Results In the primary analysis, 587 patients were included (age: 57 [Q1–Q3: 45–68] years; 44% women). By 90-day follow-up, the main outcome occurred in 96 (33.1%) patients assigned to atorvastatin and 113 (38.0%) assigned to placebo (hazard ratio [HR]: 0.80, 95% confidence interval [CI]: 0.60–1.05, p = 0.11). Atorvastatin in patients who presented within 7 days of symptom onset was associated with reduced 90-day hazard for the main outcome (HR: 0.60, 95% CI: 0.42–0.86, p interaction = 0.02). Atorvastatin use was associated with improved 90-day functional status, although the upper bound CI crossed 1.0 (ORordinal: 0.64, 95% CI: 0.41–1.01, p = 0.05).

Conclusion Atorvastatin 20 mg compared with placebo did not significantly reduce the 90-day composite of death, treatment with ECMO, or venous/arterial thrombosis. However, the point estimates do not exclude a potential clinically meaningful treatment effect, especially among patients who presented within 7 days of symptom onset (NCT04486508).

Keywords

statin - atorvastatin - lipid - COVID-19 - functional limitations

The review process for this paper was fully handled by Christian Weber, Editor in Chief.


Note

Tweet: #atorvastatin did NOT ↓composite of venous/arterial thrombosis/ECMO/mortality in 90-days F/U of #INSPIRATION-S in patients w #COVID19 admitted to ICU. Potential improvement in PCFS & hypothesis-generating improvement in pts presenting within 7 days need further validation.


Supplementary Material



Publication History

Received: 07 January 2023

Accepted: 19 March 2023

Accepted Manuscript online:
21 March 2023

Article published online:
12 May 2023

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