Atorvastatin versus placebo in patients with covid-19 in intensive care: randomized controlled trial

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.

Conflict of interest statement

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.

© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.