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

Behnood Bikdeli, Azita H Talasaz, Farid Rashidi, Babak Sharif-Kashani, Mohsen Farrokhpour, Hooman Bakhshandeh, Hashem Sezavar, Ali Dabbagh, Mohammad Taghi Beigmohammadi, Pooya Payandemehr, Mahdi Yadollahzadeh, Taghi Riahi, Hossein Khalili, Sepehr Jamalkhani, Parisa Rezaeifar, Atefeh Abedini, Somayeh Lookzadeh, Shaghayegh Shahmirzaei, Ouria Tahamtan, Samira Matin, Ahmad Amin, Seyed Ehsan Parhizgar, David Jimenez, Aakriti Gupta, Mahesh V Madhavan, Sahil A Parikh, Manuel Monreal, Naser Hadavand, Alireza Hajighasemi, Majid Maleki, Saeed Sadeghian, Bahram Mohebbi, Gregory Piazza, Ajay J Kirtane, Gregory Y H Lip, Harlan M Krumholz, Samuel Z Goldhaber, Parham Sadeghipour, Behnood Bikdeli, Azita H Talasaz, Farid Rashidi, Babak Sharif-Kashani, Mohsen Farrokhpour, Hooman Bakhshandeh, Hashem Sezavar, Ali Dabbagh, Mohammad Taghi Beigmohammadi, Pooya Payandemehr, Mahdi Yadollahzadeh, Taghi Riahi, Hossein Khalili, Sepehr Jamalkhani, Parisa Rezaeifar, Atefeh Abedini, Somayeh Lookzadeh, Shaghayegh Shahmirzaei, Ouria Tahamtan, Samira Matin, Ahmad Amin, Seyed Ehsan Parhizgar, David Jimenez, Aakriti Gupta, Mahesh V Madhavan, Sahil A Parikh, Manuel Monreal, Naser Hadavand, Alireza Hajighasemi, Majid Maleki, Saeed Sadeghian, Bahram Mohebbi, Gregory Piazza, Ajay J Kirtane, Gregory Y H Lip, Harlan M Krumholz, Samuel Z Goldhaber, Parham Sadeghipour

Abstract

Background: Microvascular and macrovascular thrombotic events are among the hallmarks of coronavirus disease 2019 (COVID-19). Furthermore, the exuberant immune response is considered an important driver of pulmonary and extrapulmonary manifestations of COVID-19. The optimal management strategy to prevent thrombosis in critically-ill patients with COVID-19 remains unknown.

Methods: The Intermediate versus Standard-dose Prophylactic anticoagulation In cRitically-ill pATIents with COVID-19: An opeN label randomized controlled trial (INSPIRATION) and INSPIRATION-statin (INSPIRATION-S) studies test two independent hypotheses within a randomized controlled trial with 2 × 2 factorial design. Hospitalized critically-ill patients with reverse transcription polymerase chain reaction confirmed COVID-19 will be randomized to intermediate-dose versus standard dose prophylactic anticoagulation. The 600 patients undergoing this randomization will be screened and if meeting the eligibility criteria, will undergo an additional double-blind stratified randomization to atorvastatin 20 mg daily versus matching placebo. The primary endpoint, for both hypotheses will be tested for superiority and includes a composite of adjudicated acute arterial thrombosis, venous thromboembolism (VTE), use of extracorporeal membrane oxygenation, or all-cause death within 30 days from enrollment. Key secondary endpoints include all-cause mortality, adjudicated VTE, and ventilator-free days. Key safety endpoints include major bleeding according to the Bleeding Academic Research Consortium definition and severe thrombocytopenia (platelet count <20,000/fL) for the anticoagulation hypothesis. In a prespecified secondary analysis for non-inferiority, the study will test for the non-inferiority of intermediate intensity versus standard dose anticoagulation for major bleeding, considering a non-inferiority margin of 1.8 based on odds ratio. Key safety endpoints for the statin hypothesis include rise in liver enzymes >3 times upper normal limit and clinically-diagnosed myopathy. The primary analyses will be performed in the modified intention-to-treat population. Results will be tested in exploratory analyses across key subgroups and in the intention-to-treat and per-protocol cohorts.

Conclusions: INSPIRATION and INSPIRATON-S studies will help address clinically-relevant questions for antithrombotic therapy and thromboinflammatory therapy in critically-ill patients with COVID-19.

Conflict of interest statement

Dr. Bikdeli reports that he is a consulting expert, on behalf of the plaintiff, for litigation related to two specific brand models of IVC filters. Dr. Parikh reports being on the Advisory Board for Abbott, Boston Scientific, Medtronic, CSI, Philips, Janssen; Research Grants: Abbott, Boston Scientific, Surmodics, TriReme Medical, Shockwave Medical; and receiving Consulting fees from Terumo and Abiomed. Dr. Gupta 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. Dr. Gupta holds equity in a healthcare telecardiology startup, Heartbeat Health, Inc. and received consulting fees from Edwards LifeSciences. Dr. Madhavan has received support from an institutional grant by the National Institutes of Health/National Heart, Lung, and Blood Institute to Columbia University Irving Medical Center (T32 HL007854). Dr. Piazza 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 Corporation and Thrombolex. Dr. Kirtane reports Institutional funding to Columbia University and/or Cardiovascular Research Foundation from Medtronic, Boston Scientific, Abbott Vascular, Abiomed, CSI, CathWorks, Siemens, Philips, ReCor Medical. In addition to research grants, institutional funding includes fees paid to Columbia University and/or Cardiovascular Research Foundation for speaking engagements and/or consulting. Personal: Travel Expenses/Meals from Medtronic, Boston Scientific, Abbott Vascular, Abiomed, CSI, CathWorks, Siemens, Philips, ReCor Medical, Chiesi, OpSens, Zoll, and Regeneron. Dr. Lip reports consultant fees from Bayer/Janssen, BMS/Pfizer, Boehringer Ingelheim, Verseon and Daiichi-Sankyo and being a speaker for BMS/Pfizer, Boehringer Ingelheim, and Daiichi-Sankyo. No fees are directly received personally. Dr. Krumholz reports personal fees from UnitedHealth, personal fees from IBM Watson Health, personal fees from Element Science, personal fees from Aetna, personal fees from Facebook, personal fees from Siegfried & Jensen Law Firm, personal fees from Arnold & Porter Law Firm, personal fees from Ben C. Martin Law Firm, personal fees from National Center for Cardiovascular Diseases, Beijing, ownership of HugoHealth, ownership of Refactor Health, contracts from the Centers for Medicare & Medicaid Services, grants from Medtronic and the Food and Drug Administration, grants from Medtronic and Johnson and Johnson, grants from Shenzhen Center for Health Information, and is a Venture Partner at FPrime. outside the submitted work. All other authors report no relevant Disclosures. 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 and they had no other role and will not have a role in the design, conduct, analysis, or interpretation of the ongoing results or the decision to submit the resultant manuscript(s).

Copyright © 2020 Elsevier Ltd. All rights reserved.

Figures

Fig. 1
Fig. 1
Study flow diagram.
Fig. 2
Fig. 2
Ongoing randomized trials on anticoagulant therapy in COVID-19.
Fig. 2
Fig. 2
Ongoing randomized trials on anticoagulant therapy in COVID-19.
Fig. 2
Fig. 2
Ongoing randomized trials on anticoagulant therapy in COVID-19.
Fig. 2
Fig. 2
Ongoing randomized trials on anticoagulant therapy in COVID-19.
Fig. 3
Fig. 3
Ongoing randomized trials at statin therapy in COVID-19.

References

    1. Zheng Y.-Y., Ma Y.-T., Zhang J.-Y., Xie X. COVID-19 and the cardiovascular system. Nat. Rev. Cardiol. 2020;17:259–260.
    1. Clerkin K.J., Fried J.A., Raikhelkar J., Sayer G., Griffin J.M., Masoumi A., Jain S.S., Burkhoff D., Kumaraiah D., Rabbani L. COVID-19 and cardiovascular disease. Circulation. 2020;141:1648–1655.
    1. Coronavirus Disease 2019 (COVID-19). Situation Report - 150. World Health Organization; 18 June 2020.
    1. Johns Hopkins COVID-19 dashboard. Accessible at: , Date last accessed: August 16, 2020.
    1. Böhm M., Frey N., Giannitsis E., Sliwa K., Zeiher A.M. Coronavirus disease 2019 (COVID-19) and its implications for cardiovascular care: expert document from the German Cardiac Society and the World Heart Federation. Clin. Res. Cardiol. 2020:1–14.
    1. Gupta A., Madhavan M.V., Sehgal K., Nair N., Mahajan S., Sehrawat T.S., Bikdeli B., Ahluwalia N., Ausiello J.C., Wan E.Y., Freedberg D.E., Kirtane A.J., Parikh S.A., Maurer M.S., Nordvig A.S., Accili D., Bathon J.M., Mohan S., Bauer K.A., Leon M.B., Krumholz H.M., Uriel N., Mehra M.R., Elkind M.S.V., Stone G.W., Schwartz A., Ho D.D., Bilezikian J.P., Landry D.W. Extrapulmonary manifestations of COVID-19. Nat. Med. 2020;26(7):1017–1032.
    1. Bikdeli B., Madhavan M.V., Jimenez D., Chuich T., Dreyfus I., Driggin E., Nigoghossian C., Ageno W., Madjid M., Guo Y., Tang L.V., Hu Y., Giri J., Cushman M., Quéré I., Dimakakos E.P., Gibson C.M., Lippi G., Favaloro E.J., Fareed J., Caprini J.A., Tafur A.J., Burton J.R., Francese D.P., Wang E.Y., Falanga A., McLintock C., Hunt B.J., Spyropoulos A.C., Barnes G.D., Eikelboom J.W., Weinberg I., Schulman S., Carrier M., Piazza G., Beckman J.A., Steg P.G., Stone G.W., Rosenkranz S., Goldhaber S.Z., Parikh S.A., Monreal M., Krumholz H.M., Konstantinides S.V., Weitz J.I., Lip G.Y.H. 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;75:2950–2973.
    1. Bikdeli B., Madhavan M.V., Gupta A., Jimenez D., Burton J.R., Der Nigoghossian C., Chuich T., Nouri S.N., Dreyfus I., Driggin E., Sethi S., Sehgal K., Chatterjee S., Ageno W., Madjid M., Guo Y., Tang L.V., Hu Y., Bertoletti L., Giri J., Cushman M., Quéré I., Dimakakos E.P., Gibson C.M., Lippi G., Favaloro E.J., Fareed J., Tafur A.J., Francese D.P., Batra J., Falanga A., Clerkin K.J., Uriel N., Kirtane A., McLintock C., Hunt B.J., Spyropoulos A.C., Barnes G.D., Eikelboom J.W., Weinberg I., Schulman S., Carrier M., Piazza G., Beckman J.A., Leon M.B., Stone G.W., Rosenkranz S., Goldhaber S.Z., Parikh S.A., Monreal M., Krumholz H.M., Konstantinides S.V., Weitz J.I., Lip G.Y.H. Pharmacological agents targeting thromboinflammation in COVID-19: review and implications for future research. Thromb. Haemost. 2020;120:1004–1024.
    1. Manne B.K., Denorme F., Middleton E.A., Portier I., Rowley J.W., Stubben C.J., Petrey A.C., Tolley N.D., Guo L., Cody M.J., Weyrich A.S., Yost C.C., Rondina M.T., Campbell R.A. Platelet gene expression and function in COVID-19 patients. Blood. 2020;136(11):1317–1329. doi: 10.1182/blood.2020007214.
    1. Goyal P., Choi J.J., Pinheiro L.C., Schenck E.J., Chen R., Jabri A., Satlin M.J., Campion T.R., Jr., Nahid M., Ringel J.B., Hoffman K.L., Alshak M.N., Li H.A., Wehmeyer G.T., Rajan M., Reshetnyak E., Hupert N., Horn E.M., Martinez F.J., Gulick R.M., Safford M.M. Clinical characteristics of Covid-19 in New York City. N. Engl. J. Med. 2020;382:2372–2374.
    1. Poissy J., Goutay J., Caplan M., Parmentier E., Duburcq T., Lassalle F., Jeanpierre E., Rauch A., Labreuche J., Susen S. Pulmonary embolism in COVID-19 patients: awareness of an increased prevalence. Circulation. 2020;142(2):184–186. doi: 10.1161/CIRCULATIONAHA.120.047430.
    1. Moores L.K., Tritschler T., Brosnahan S., Carrier M., Collen J.F., Doerschug K., Holley A.B., Jimenez D., LeGal G., Rali P., Wells P. Prevention, diagnosis, and treatment of VTE in patients with COVID-19: CHEST guideline and expert panel report. Chest. 2020;158(3):1143–1163. doi: 10.1016/j.chest.2020.05.559.
    1. Middeldorp S., Coppens M., van Haaps T.F., Foppen M., Vlaar A.P., Müller M.C.A., Bouman C.C.S., Beenen L.F.M., Kootte R.S., Heijmans J., Smits L.P., Bonta P.I., van Es N. Incidence of venous thromboembolism in hospitalized patients with COVID-19. J. Thromb. Haemost. 2020;18(8):1995–2002. doi: 10.1111/jth.14888.
    1. Klok F.A., Kruip M., van der Meer N.J.M., Arbous M.S., Gommers D., Kant K.M., Kaptein F.H.J., van Paassen J., Stals M.A.M., Huisman M.V., Endeman H. Incidence of thrombotic complications in critically ill ICU patients with COVID-19. Thromb. Res. 2020;191:145–147.
    1. Cui S., Chen S., Li X., Liu S., Wang F. Prevalence of venous thromboembolism in patients with severe novel coronavirus pneumonia. J. Thromb. Haemost. 2020;18:1421–1424.
    1. Helms J., Tacquard C., Severac F., Leonard-Lorant I., Ohana M., Delabranche X., Merdji H., Clere-Jehl R., Schenck M., Fagot Gandet F., Fafi-Kremer S., Castelain V., Schneider F., Grunebaum L., Anglés-Cano E., Sattler L., Mertes P.M., Meziani F. High risk of thrombosis in patients with severe SARS-CoV-2 infection: a multicenter prospective cohort study. Intensive Care Med. 2020;46:1089–1098.
    1. Lodigiani C., Iapichino G., Carenzo L., Cecconi M., Ferrazzi P., Sebastian T., Kucher N., Studt J.D., Sacco C., Alexia B., Sandri M.T., Barco S. Venous and arterial thromboembolic complications in COVID-19 patients admitted to an academic hospital in Milan, Italy. Thromb Res. 2020;191:9–14.
    1. Kunutsor S.K., Laukkanen J.A. Incidence of venous and arterial thromboembolic complications in COVID-19: a systematic review and meta-analysis. Thromb. Res. 2020;196:27–30.
    1. Wichmann D., Sperhake J.P., Lütgehetmann M., Steurer S., Edler C., Heinemann A., Heinrich F., Mushumba H., Kniep I., Schröder A.S., Burdelski C., de Heer G., Nierhaus A., Frings D., Pfefferle S., Becker H., Bredereke-Wiedling H., de Weerth A., Paschen H.R., Sheikhzadeh-Eggers S., Stang A., Schmiedel S., Bokemeyer C., Addo M.M., Aepfelbacher M., Püschel K., Kluge S. Autopsy findings and venous thromboembolism in patients with COVID-19. Ann. Intern. Med. 2020;173(4):268–277. doi: 10.7326/M20-2003.
    1. Ackermann M., Verleden S.E., Kuehnel M., Haverich A., Welte T., Laenger F., Vanstapel A., Werlein C., Stark H., Tzankov A., Li W.W., Li V.W., Mentzer S.J., Jonigk D. Pulmonary vascular endothelialitis, thrombosis, and angiogenesis in Covid-19. N. Engl. J. Med. 2020;383:120–128.
    1. Hanley B, Naresh KN, Roufosse C, Nicholson AG, Weir J, Cooke GS, Thursz M, Manousou P, Corbett R, Goldin R, Al-Sarraj S, Abdolrasouli A, Swann OC, Baillon L, Penn R, Barclay WS, Viola P, Osborn M.
    1. National Institutes of Health . June 25, 2020. COVID-19 Treatment Guidelines.
    1. World Health Organization . January 28, 2020. Clinical Management of Severe Acute Respiratory Infection when Novel Coronavirus (2019-nCoV) Infection Is Suspected.
    1. Fernandez-Capitan C.B.R., Diaz-Pedroche M., Siguenza P., Demelo-Rodriguez P., Siniscalchi C., Pedrajas J.M., Farfan-Sedano A.I., Olivera P.E., Gomez-Cuervo C., Llamas P., Villares P., Sanchez O., Lopez-Reyes R., Catella J., Bikdeli B., Weinberg I., Tafur A.J., Jimenez D., Monreal M., RIETE Investigators Presenting characteristics, treatment patterns and outcomes among patients with venous thromboembolism during hospitalization for COVID-19. Semin. Thromb. Hemost. 2020 (In-Press)
    1. Cattaneo M., Bertinato E.M., Birocchi S., Brizio C., Malavolta D., Manzoni M., Muscarella G., Orlandi M. Pulmonary embolism or pulmonary thrombosis in COVID-19? Is the recommendation to use high-dose heparin for thromboprophylaxis justified? Thromb. Haemost. 2020;120:1230–1232.
    1. Spyropoulos A.C., Levy J.H., Ageno W., Connors J.M., Hunt B.J., Iba T., Levi M., Samama C.M., Thachil J., Giannis D., Douketis J.D. Scientific and standardization committee communication: clinical guidance on the diagnosis, prevention, and treatment of venous thromboembolism in hospitalized patients with COVID-19. J. Thromb. Haemost. 2020;18:1859–1865.
    1. Paranjpe I., Fuster V., Lala A., Russak A.J., Glicksberg B.S., Levin M.A., Charney A.W., Narula J., Fayad Z.A., Bagiella E., Zhao S., Nadkarni G.N. Association of treatment dose anticoagulation with in-hospital survival among hospitalized patients with COVID-19. J. Am. Coll. Cardiol. 2020;76:122–124.
    1. Stessel B., Vanvuchelen C., Bruckers L., Geebelen L., Callebaut I., Vandenbrande J., Pellens B., Van Tornout M., Ory J.P., van Halem K., Messiaen P., Herbots L., Ramaekers D., Dubois J. Impact of implementation of an individualised thromboprophylaxis protocol in critically ill ICU patients with COVID-19: a longitudinal controlled before-after study. Thromb. Res. 2020;194:209–215.
    1. Ware L.B., Matthay M.A. The acute respiratory distress syndrome. N. Engl. J. Med. 2000;342:1334–1349.
    1. Mitchell W.B. Thromboinflammation in COVID-19 acute lung injury. Paediatr. Respir. Rev. 2020;35:20–24. doi: 10.1016/j.prrv.2020.06.004.
    1. Tay M.Z., Poh C.M., Rénia L., MacAry P.A., Ng L.F.P. The trinity of COVID-19: immunity, inflammation and intervention. Nat Rev Immunol. 2020;20:363–374.
    1. Jacobson J.R., Barnard J.W., Grigoryev D.N., Ma S.F., Tuder R.M., Garcia J.G. Simvastatin attenuates vascular leak and inflammation in murine inflammatory lung injury. Am J Physiol Lung Cell Mol Physiol. 2005;288:L1026–L1032.
    1. McAuley D.F., Laffey J.G., O’Kane C.M., Perkins G.D., Mullan B., Trinder T.J., Johnston P., Hopkins P.A., Johnston A.J., McDowell C., McNally C. Simvastatin in the acute respiratory distress syndrome. N. Engl. J. Med. 2014;371:1695–1703.
    1. Calfee C.S., Delucchi K.L., Sinha P., Matthay M.A., Hackett J., Shankar-Hari M., McDowell C., Laffey J.G., O’Kane C.M., McAuley D.F. Acute respiratory distress syndrome subphenotypes and differential response to simvastatin: secondary analysis of a randomised controlled trial. Lancet Respir. Med. 2018;6:691–698.
    1. Eck R.J., Bult W., Wetterslev J., Gans R.O.B., Meijer K., Keus F., van der Horst I.C.C. Intermediate dose low-molecular-weight heparin for thrombosis prophylaxis: systematic review with meta-analysis and trial sequential analysis. Semin. Thromb. Hemost. 2019;45:810–824.
    1. Bikdeli B., Madhavan M.V., Gupta A., Jimenez D., Burton J.R., Der Nigoghossian C., Chuich T., Nouri S.N., Dreyfus I., Driggin E., Sethi S., Sehgal K., Chatterjee S., Ageno W., Madjid M., Guo Y., Tang L.V., Hu Y., Bertoletti L., Giri J., Cushman M., Quéré I., Dimakakos E.P., Gibson C.M., Lippi G., Favaloro E.J., Fareed J., Tafur A.J., Francese D.P., Batra J., Falanga A., Clerkin K.J., Uriel N., Kirtane A., McLintock C., Hunt B.J., Spyropoulos A.C., Barnes G.D., Eikelboom J.W., Weinberg I., Schulman S., Carrier M., Piazza G., Beckman J.A., Leon M.B., Stone G.W., Rosenkranz S., Goldhaber S.Z., Parikh S.A., Monreal M., Krumholz H.M., Konstantinides S.V., Weitz J.I., Lip G.Y.H. Pharmacological agents targeting thromboinflammation in COVID-19: review and implications for future research. Thromb. Haemost. 2020;120(7):1004–1024. doi: 10.1055/s-0040-1713152.
    1. Jalili M., Payandemehr P., Saghaei A., Sari H.N., Safikhani H., Kolivand P. Characteristics and mortality of hospitalized patients with COVID-19 in Iran: a National Retrospective Cohort Study. Ann. Intern. Med. 2020 doi: 10.7326/M20-2911.
    1. Mehran R., Rao S.V., Bhatt D.L., Gibson C.M., Caixeta A., Eikelboom J., Kaul S., Wiviott S.D., Menon V., Nikolsky E., Serebruany V., Valgimigli M., Vranckx P., Taggart D., Sabik J.F., Cutlip D.E., Krucoff M.W., Ohman E.M., Steg P.G., White H. Standardized bleeding definitions for cardiovascular clinical trials: a consensus report from the bleeding academic research consortium. Circulation. 2011;123:2736–2747.
    1. Klok F.A., Boon G., Barco S., Endres M., Geelhoed J.J.M., Knauss S., Rezek S.A., Spruit M.A., Vehreschild J., Siegerink B. The post-COVID-19 functional status scale: a tool to measure functional status over time after COVID-19. Eur. Respir. J. 2020;56
    1. Cook D., Meade M., Guyatt G., Walter S., Heels-Ansdell D., Warkentin T.E., Zytaruk N., Crowther M., Geerts W., Cooper D.J., Vallance S., Qushmaq I., Rocha M., Berwanger O., Vlahakis N.E. Dalteparin versus unfractionated heparin in critically ill patients. N. Engl. J. Med. 2011;364:1305–1314.
    1. Bassler D., Montori V.M., Briel M., Glasziou P., Guyatt G. Early stopping of randomized clinical trials for overt efficacy is problematic. J. Clin. Epidemiol. 2008;61:241–246.
    1. Horby P., Lim W.S., Emberson J.R., Mafham M., Bell J.L., Linsell L., Staplin N., Brightling C., Ustianowski A., Elmahi E., Prudon B., Green C., Felton T., Chadwick D., Rege K., Fegan C., Chappell L.C., Faust S.N., Jaki T., Jeffery K., Montgomery A., Rowan K., Juszczak E., Baillie J.K., Haynes R., Landray M.J. Dexamethasone in hospitalized patients with Covid-19 - preliminary report. N. Engl. J. Med. 2020 doi: 10.1056/NEJMoa2021436.
    1. Beigel J.H., Tomashek K.M., Dodd L.E., Mehta A.K., Zingman B.S., Kalil A.C., Hohmann E., Chu H.Y., Luetkemeyer A., Kline S., Lopez de Castilla D., Finberg R.W., Dierberg K., Tapson V., Hsieh L., Patterson T.F., Paredes R., Sweeney D.A., Short W.R., Touloumi G., Lye D.C., Ohmagari N., Oh M.D., Ruiz-Palacios G.M., Benfield T., Fätkenheuer G., Kortepeter M.G., Atmar R.L., Creech C.B., Lundgren J., Babiker A.G., Pett S., Neaton J.D., Burgess T.H., Bonnett T., Green M., Makowski M., Osinusi A., Nayak S., Lane H.C. Remdesivir for the treatment of Covid-19 - preliminary report. N. Engl. J. Med. 2020 doi: 10.1056/NEJMoa2007764.
    1. Gupta A., Madhavan M.V., Poterucha T.J., DeFilippis E.M., Hennessey J.A., Redfors B., Eckhardt C., Bikdeli B., Platt J., Nalbandian A., Elias P., Cummings M.J., Nouri S.N., Lawlor M., Ranard L.S., Li J., Boyle C., Givens R., Brodie D., Krumholz H.M., Stone G.W., Sethi S.S., Burkhoff D., Uriel N., Schwartz A., Leon M.B., Kirtane A.J., Wan E.Y., Parikh S.A. Association between antecedent statin use and decreased mortality in hospitalized patients with COVID-19. Res Sq. 2020 doi: 10.21203/-56210/v1.
    1. Chia Siang Kow S.S.H. Meta-analysis of effectiveness of statins in patients with severe COVID-19. Am. J. Cardiol. 2020 doi: 10.1016/j.amjcard.2020.08.004.

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