Atorvastatin versus placebo in patients with covid-19 in intensive care: randomized controlled trial
BMJ 2022; 376 doi: https://doi.org/10.1136/bmj-2021-068407 (Published 07 January 2022) Cite this as: BMJ 2022;376:e068407
- INSPIRATION-S Investigators
- Correspondence to: P Sadeghipour(https://orcid.org/0000-0001-9602-0513), Rajaie Cardiovascular Medical and Research Centre, Tehran, Iran psadeghipour{at}hotmail.com
- Accepted 7 December 2021
Abstract
Objective To assess the effect of statin treatment versus placebo on clinical outcomes in patients with covid-19 admitted to the intensive care unit (ICU).
Design INSPIRATION/INSPIRATION-S was a multicenter, randomized controlled trial with a 2×2 factorial design. Results for the anticoagulation randomization have been reported previously. Results for the double blind randomization to atorvastatin versus placebo are reported here.
Setting 11 hospitals in Iran.
Participants Adults aged ≥18 years with covid-19 admitted to the ICU.
Intervention Atorvastatin 20 mg orally once daily versus placebo, to be continued for 30 days from randomization irrespective of hospital discharge status.
Main outcome measures The primary efficacy outcome was a composite of venous or arterial thrombosis, treatment with extracorporeal membrane oxygenation, or all cause mortality within 30 days from randomization. Prespecified safety outcomes included increase in liver enzyme levels more than three times the upper limit of normal and clinically diagnosed myopathy. A clinical events committee blinded to treatment assignment adjudicated the efficacy and safety outcomes.
Results Of 605 patients randomized between 29 July 2020 and 4 April 2021 for statin randomization in the INSPIRATION-S trial, 343 were co-randomized to intermediate dose versus standard dose prophylactic anticoagulation with heparin based regimens, whereas 262 were randomized after completion of the anticoagulation study. 587 of the 605 participants were included in the primary analysis of INSPIRATION-S, reported here: 290 were assigned to atorvastatin and 297 to placebo (median age 57 years (interquartile range 45-68 years); 256 (44%) women). The primary outcome occurred in 95 (33%) patients assigned to atorvastatin and 108 (36%) assigned to placebo (odds ratio 0.84, 95% confidence interval 0.58 to 1.21). Death occurred in 90 (31%) patients in the atorvastatin group and 103 (35%) in the placebo group (odds ratio 0.84, 95% confidence interval 0.58 to 1.22). Rates for venous thromboembolism were 2% (n=6) in the atorvastatin group and 3% (n=9) in the placebo group (odds ratio 0.71, 95% confidence interval 0.24 to 2.06). Myopathy was not clinically diagnosed in either group. Liver enzyme levels were increased in five (2%) patients assigned to atorvastatin and six (2%) assigned to placebo (odds ratio 0.85, 95% confidence interval 0.25 to 2.81).
Conclusions In adults with covid-19 admitted to the ICU, atorvastatin was not associated with a significant reduction in the composite of venous or arterial thrombosis, treatment with extracorporeal membrane oxygenation, or all cause mortality compared with placebo. Treatment was, however, found to be safe. As the overall event rates were lower than expected, a clinically important treatment effect cannot be excluded.
Trial registration ClinicalTrials.gov NCT04486508.
Footnotes
Authors of study (see supplementary file for full list of author affiliations)
Behnood Bikdeli, Azita H Talasaz, Babak Sharif-Kashani, Farid Rashidi, Mohammad Taghi Beigmohammadi, Keivan Gohari Moghadam, Somaye Rezaian, Ali Dabbagh, Seyed Hashem Sezavar, Mohsen Farrokhpour, Hooman Bakhshandeh, Atefeh Abedini, Rasoul Aliannejad, Taghi Riahi, Mahdi Yadollahzadeh, Somayeh Lookzadeh, Parisa Rezaeifar, Samira Matin, Ouria Tahamtan, Keyhan Mohammadi, Elnaz Zoghi, Hamid Rahmani, Seyed Hossein Hosseini, Seyed Masoud Mousavian, Homa Abri, Pardis Sadeghipour, Elahe Baghizadeh, Farnaz Rafiee, Sepehr Jamalkhani, Ahmad Amin, Bahram Mohebbi, Seyed Ehsan Parhizgar, Mahshid Soleimanzadeh, Maryam Aghakouchakzadeh, Vahid Eslami, Pooya Payandemehr, Hossein Khalili, Hamed Talakoob, Taranom Tojari, Shadi Shafaghi, Samrand Fattah Ghazi, Sanaz Tabrizi, Hessam Kakavand, Alireza Kashefizadeh, Shaghayegh Shahmirzaei, Atabak Najafi, Mohammad Fathi, David Jimenez, Aakriti Gupta, Mahesh V Madhavan, Sanjum S Sethi, Sahil A. Parikh, Manuel Monreal, Naser Hadavand, Alireza Hajighasemi, Khalil Ansarin, Majid Maleki, Saeed Sadeghian, Gregory Piazza, Ajay J Kirtane, Benjamin W Van Tassell, Gregg W Stone, Gregory Y H Lip, Harlan M Krumholz, Samuel Z Goldhaber, Parham Sadeghipour.
See Appendix for trial committees and subcommittees.
The study coordinating centres were the Rajaie Cardiovascular Medical and Research Center and the Tehran Heart Center. The trial protocol (see supplementary appendix 1) was approved by the Rajaie Cardiovascular Medical and Research Center ethics committee and accepted by all enrolling sites.
Contributors: PS and HB take responsibility for the integrity of the data and the accuracy of the analyses in this manuscript. They are the guarantors. BB, PS, and AHT designed the trial. FR, PPM, HB, DJ, AG, MVM, SAP, MM, GP, AJK, BVT, GWS, GYL, SZG, and HK contributed to the trial design. PS, AHT, BS, FR, MTB, KG, SR, AD, SHS, MF, AA, RA, TR, MY, SL, PR, SM, OT, KM, EZ, HR, SHS, SMS, HA, PS, MS, MA, VE, PP, HK, HT, TT, SS, SF, ST, HK, AK, and SS were responsible for collection and acquisition of the data. BB, PS, AHT, and HB drafted the manuscript, which was critically revised by all INSPIRATION-S investigators. BB and PS controlled the analysis plan and the decision to submit. HB conducted the analyses with help from PS and BB. PS an HB had full access to all the study data an vouch for the accuracy of the analyses. All authors take the responsibility for the decision to submit for publication. The corresponding author attests that all listed authors meet authorship criteria and that no others meeting the criteria have been omitted.
Funding: The study was funded by the Rajaie Cardiovascular Medical and Research Center. Some study authors, including the senior author, are affiliated with 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 for publication.
Competing interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/disclosure-of-interest/ and declare: BB reports that he is a consulting expert, on behalf of the plaintiff, for litigation related to two specific brand models of IVC filters. DJ has served as an advisor or consultant for Bayer HealthCare Pharmaceuticals, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, Leo Pharma, Pfizer, ROVI, and Sanofi; served as a speaker or a member of a speakers’ bureau for Bayer HealthCare Pharmaceuticals, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, Leo Pharma, ROVI, and Sanofi; and received grants for clinical research from Daiichi Sankyo, Sanofi, and ROVI. AG received payment from the Arnold & Porter Law Firm for work related to the Sanofi clopidogrel litigation and from the Ben C Martin Law Firm for work related to the Cook inferior vena cava filter litigation. AG holds equity in a healthcare telecardiology start-up, Heartbeat Health, and received consulting fees from Edwards LifeSciences. MVM was supported by a grant from the National Institutes of Health/National Heart, Lung, and Blood Institute to Columbia University Irving Medical Center (T32 HL007854). SSS reports receiving personal fees from Janssen and Chiesi and grants from the American Heart Association outside the submitted work. SAP reports receiving grants from Abbott Vascular, Boston Scientific, Surmodics, and TriReme Medical; non-financial support from Cordis, Medtronic, Philips, and Cardiovascular Systems; and personal fees from Terumo, Abiomed, Inari, and Penumbra outside the submitted work. GP has received research grant support to Brigham and Women’s Hospital from EKOS, a BTG International Group company, Bayer, the Bristol Myers Squibb/Pfizer Alliance, Portola, and Janssen. He has received consulting fees from Amgen, Pfizer, Boston Scientific, and Thrombolex. AJK reports receiving institutional funding to Columbia University and/or the Cardiovascular Research Foundation from Medtronic, Boston Scientific, Abbott Vascular, Abiomed, Cardiovascular Systems, 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, CathWorks, Siemens, Philips, ReCor Medical, Chiesi, OpSens, Zoll, and Regeneron. BWVT has received research support from Novartis, Swedish Orphan Biovitrum, Olatec Therapeutics, and Serpin Pharma and has been a consultant for R-Pharm and Serpin Pharma. GWS reports 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, and Cardiac Success; personal fees and equity/equity options from Spectrawave, Valfix, and Ancora; and personal fees, equity/equity options, and honorarium from Orchestra Biomed, and outside the submitted work. GYHL reports being a consultant and speaker for BMS/Pfizer, Boehringer Ingelheim and Daiichi-Sankyo. No fees are received personally. HMK reports 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. SZG has received research support from Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Boston Scientific, Daiichi-Sankyo, Janssen, the National Heart, Lung, and Blood Institute, and the Thrombosis Research Institute; and has received consulting fees from Bayer, Agile, Boston Scientific, and Boehringer Ingelheim.
BB and PS affirm that the manuscript is an honest, accurate, and transparent account of the study being reported; that no important aspects of the study have been omitted; and that any discrepancies from the study as originally planned (and, if relevant, registered) have been explained.
Dissemination to participants and related patient and public communities: The study was designed during the second wave of the covid-19 pandemic at a rapid pace, and consequently no specific plan was made for dissemination of the trial’s results to patients and public communities. Upon publication of the manuscript, appropriate communications will be made with the press, and an excerpt of the findings will be shared on social media, with appropriate citations to the work.
Provenance and peer review: Not commissioned; externally peer reviewed.
Data availability statement
Data will become available to interested investigators upon submitting a reasonable research request by email and approved by the steering committee of the trial to B Bikdeli (bbikdeli@bwh.harvard.edu) or P Sadeghipour (psadeghipour@hotmail.com).
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