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Effect of Hydrocortisone on Mortality and Organ Support in Patients With Severe COVID-19: The REMAP-CAP COVID-19 Corticosteroid Domain Randomized Clinical Trial.

Authors :
Angus DC
Derde L
Al-Beidh F
Annane D
Arabi Y
Beane A
van Bentum-Puijk W
Berry L
Bhimani Z
Bonten M
Bradbury C
Brunkhorst F
Buxton M
Buzgau A
Cheng AC
de Jong M
Detry M
Estcourt L
Fitzgerald M
Goossens H
Green C
Haniffa R
Higgins AM
Horvat C
Hullegie SJ
Kruger P
Lamontagne F
Lawler PR
Linstrum K
Litton E
Lorenzi E
Marshall J
McAuley D
McGlothin A
McGuinness S
McVerry B
Montgomery S
Mouncey P
Murthy S
Nichol A
Parke R
Parker J
Rowan K
Sanil A
Santos M
Saunders C
Seymour C
Turner A
van de Veerdonk F
Venkatesh B
Zarychanski R
Berry S
Lewis RJ
McArthur C
Webb SA
Gordon AC
Al-Beidh F
Angus D
Annane D
Arabi Y
van Bentum-Puijk W
Berry S
Beane A
Bhimani Z
Bonten M
Bradbury C
Brunkhorst F
Buxton M
Cheng A
De Jong M
Derde L
Estcourt L
Goossens H
Gordon A
Green C
Haniffa R
Lamontagne F
Lawler P
Litton E
Marshall J
McArthur
McAuley D
McGuinness S
McVerry B
Montgomery S
Mouncey P
Murthy S
Nichol A
Parke R
Rowan K
Seymour C
Turner A
van de Veerdonk F
Webb S
Zarychanski R
Campbell L
Forbes A
Gattas D
Heritier S
Higgins L
Kruger P
Peake S
Presneill J
Seppelt I
Trapani T
Young P
Bagshaw S
Daneman N
Ferguson N
Misak C
Santos M
Hullegie S
Pletz M
Rohde G
Rowan K
Alexander B
Basile K
Girard T
Horvat C
Huang D
Linstrum K
Vates J
Beasley R
Fowler R
McGloughlin S
Morpeth S
Paterson D
Venkatesh B
Uyeki T
Baillie K
Duffy E
Fowler R
Hills T
Orr K
Patanwala A
Tong S
Netea M
Bihari S
Carrier M
Fergusson D
Goligher E
Haidar G
Hunt B
Kumar A
Laffan M
Lawless P
Lother S
McCallum P
Middeldopr S
McQuilten Z
Neal M
Pasi J
Schutgens R
Stanworth S
Turgeon A
Weissman A
Adhikari N
Anstey M
Brant E
de Man A
Lamonagne F
Masse MH
Udy A
Arnold D
Begin P
Charlewood R
Chasse M
Coyne M
Cooper J
Daly J
Gosbell I
Harvala-Simmonds H
Hills T
MacLennan S
Menon D
McDyer J
Pridee N
Roberts D
Shankar-Hari M
Thomas H
Tinmouth A
Triulzi D
Walsh T
Wood E
Calfee C
O’Kane C
Shyamsundar M
Sinha P
Thompson T
Young I
Bihari S
Hodgson C
Laffey J
McAuley D
Orford N
Neto A
Detry M
Fitzgerald M
Lewis R
McGlothlin A
Sanil A
Saunders C
Berry L
Lorenzi E
Miller E
Singh V
Zammit C
van Bentum Puijk W
Bouwman W
Mangindaan Y
Parker L
Peters S
Rietveld I
Raymakers K
Ganpat R
Brillinger N
Markgraf R
Ainscough K
Brickell K
Anjum A
Lane JB
Richards-Belle A
Saull M
Wiley D
Bion J
Connor J
Gates S
Manax V
van der Poll T
Reynolds J
van Beurden M
Effelaar E
Schotsman J
Boyd C
Harland C
Shearer A
Wren J
Clermont G
Garrard W
Kalchthaler K
King A
Ricketts D
Malakoutis S
Marroquin O
Music E
Quinn K
Cate H
Pearson K
Collins J
Hanson J
Williams P
Jackson S
Asghar A
Dyas S
Sutu M
Murphy S
Williamson D
Mguni N
Potter A
Porter D
Goodwin J
Rook C
Harrison S
Williams H
Campbell H
Lomme K
Williamson J
Sheffield J
van’t Hoff W
McCracken P
Young M
Board J
Mart E
Knott C
Smith J
Boschert C
Affleck J
Ramanan M
D’Souza R
Pateman K
Shakih A
Cheung W
Kol M
Wong H
Shah A
Wagh A
Simpson J
Duke G
Chan P
Cartner B
Hunter S
Laver R
Shrestha T
Regli A
Pellicano A
McCullough J
Tallott M
Kumar N
Panwar R
Brinkerhoff G
Koppen C
Cazzola F
Brain M
Mineall S
Fischer R
Biradar V
Soar N
White H
Estensen K
Morrison L
Smith J
Cooper M
Health M
Shehabi Y
Al-Bassam W
Hulley A
Whitehead C
Lowrey J
Gresha R
Walsham J
Meyer J
Harward M
Venz E
Williams P
Kurenda C
Smith K
Smith M
Garcia R
Barge D
Byrne D
Byrne K
Driscoll A
Fortune L
Janin P
Yarad E
Hammond N
Bass F
Ashelford A
Waterson S
Wedd S
McNamara R
Buhr H
Coles J
Schweikert S
Wibrow B
Rauniyar R
Myers E
Fysh E
Dawda A
Mevavala B
Litton E
Ferrier J
Nair P
Buscher H
Reynolds C
Santamaria J
Barbazza L
Homes J
Smith R
Murray L
Brailsford J
Forbes L
Maguire T
Mariappa V
Smith J
Simpson S
Maiden M
Bone A
Horton M
Salerno T
Sterba M
Geng W
Depuydt P
De Waele J
De Bus L
Fierens J
Bracke S
Reeve B
Dechert W
Chassé M
Carrier FM
Boumahni D
Benettaib F
Ghamraoui A
Bellemare D
Cloutier È
Francoeur C
Lamontagne F
D’Aragon F
Carbonneau E
Leblond J
Vazquez-Grande G
Marten N
Wilson
Albert M
Serri K
Cavayas A
Duplaix M
Williams V
Rochwerg B
Karachi T
Oczkowski S
Centofanti J
Millen T
Duan E
Tsang J
Patterson L
English S
Watpool I
Porteous R
Miezitis S
McIntyre L
Brochard L
Burns K
Sandhu G
Khalid I
Binnie A
Powell E
McMillan A
Luk T
Aref N
Andric Z
Cviljevic S
Đimoti R
Zapalac M
Mirković G
Baršić B
Kutleša M
Kotarski V
Vujaklija Brajković A
Babel J
Sever H
Dragija L
Kušan I
Vaara S
Pettilä L
Heinonen J
Kuitunen A
Karlsson S
Vahtera A
Kiiski H
Ristimäki S
Azaiz A
Charron C
Godement M
Geri G
Vieillard-Baron A
Pourcine F
Monchi M
Luis D
Mercier R
Sagnier A
Verrier N
Caplin C
Siami S
Aparicio C
Vautier S
Jeblaoui A
Fartoukh M
Courtin L
Labbe V
Leparco C
Muller G
Nay MA
Kamel T
Benzekri D
Jacquier S
Mercier E
Chartier D
Salmon C
Dequin P
Schneider F
Morel G
L’Hotellier S
Badie J
Berdaguer FD
Malfroy S
Mezher C
Bourgoin C
Megarbane B
Voicu
Deye N
Malissin I
Sutterlin L
Guitton C
Darreau C
Landais M
Chudeau N
Robert A
Moine P
Heming N
Maxime V
Bossard I
Nicholier TB
Colin G
Zinzoni V
Maquigneau N
Finn A
Kreß G
Hoff U
Friedrich Hinrichs C
Nee J
Pletz M
Hagel S
Ankert J
Kolanos S
Bloos F
Petros S
Pasieka B
Kunz K
Appelt P
Schütze B
Kluge S
Nierhaus A
Jarczak D
Roedl K
Weismann D
Frey A
Klinikum Neukölln V
Reill L
Distler M
Maselli A
Bélteczki J
Magyar I
Fazekas Á
Kovács S
Szőke V
Szigligeti G
Leszkoven J
Collins D
Breen P
Frohlich S
Whelan R
McNicholas B
Scully M
Casey S
Kernan M
Doran P
O’Dywer M
Smyth M
Hayes L
Hoiting O
Peters M
Rengers E
Evers M
Prinssen A
Bosch Ziekenhuis J
Simons K
Rozendaal W
Polderman F
de Jager P
Moviat M
Paling A
Salet A
Rademaker E
Peters AL
de Jonge E
Wigbers J
Guilder E
Butler M
Cowdrey KA
Newby L
Chen Y
Simmonds C
McConnochie R
Ritzema Carter J
Henderson S
Van Der Heyden K
Mehrtens J
Williams T
Kazemi A
Song R
Lai V
Girijadevi D
Everitt R
Russell R
Hacking D
Buehner U
Williams E
Browne T
Grimwade K
Goodson J
Keet O
Callender O
Martynoga R
Trask K
Butler A
Schischka L
Young C
Lesona E
Olatunji S
Robertson Y
José N
Amaro dos Santos Catorze T
de Lima Pereira TNA
Neves Pessoa LM
Castro Ferreira RM
Pereira Sousa Bastos JM
Aysel Florescu S
Stanciu D
Zaharia MF
Kosa AG
Codreanu D
Marabi Y
Al Qasim E
Moneer Hagazy M
Al Swaidan L
Arishi H
Muñoz-Bermúdez R
Marin-Corral J
Salazar Degracia A
Parrilla Gómez F
Mateo López MI
Rodriguez Fernandez J
Cárcel Fernández S
Carmona Flores R
León López R
de la Fuente Martos C
Allan A
Polgarova P
Farahi N
McWilliam S
Hawcutt D
Rad L
O’Malley L
Whitbread J
Kelsall O
Wild L
Thrush J
Wood H
Austin K
Donnelly A
Kelly M
O’Kane S
McClintock D
Warnock M
Johnston P
Gallagher LJ
Mc Goldrick C
Mc Master M
Strzelecka A
Jha R
Kalogirou M
Ellis C
Krishnamurthy V
Deelchand V
Silversides J
McGuigan P
Ward K
O’Neill A
Finn S
Phillips B
Mullan D
Oritz-Ruiz de Gordoa L
Thomas M
Sweet K
Grimmer L
Johnson R
Pinnell J
Robinson M
Gledhill L
Wood T
Morgan M
Cole J
Hill H
Davies M
Antcliffe D
Templeton M
Rojo R
Coghlan P
Smee J
Mackay E
Cort J
Whileman A
Spencer T
Spittle N
Kasipandian V
Patel A
Allibone S
Genetu RM
Ramali M
Ghosh A
Bamford P
London E
Cawley K
Faulkner M
Jeffrey H
Smith T
Brewer C
Gregory J
Limb J
Cowton A
O’Brien J
Nikitas N
Wells C
Lankester L
Pulletz M
Williams P
Birch J
Wiseman S
Horton S
Alegria A
Turki S
Elsefi T
Crisp N
Allen L
McCullagh I
Robinson P
Hays C
Babio-Galan M
Stevenson H
Khare D
Pinder M
Selvamoni S
Gopinath A
Pugh R
Menzies D
Mackay C
Allan E
Davies G
Puxty K
McCue C
Cathcart S
Hickey N
Ireland J
Yusuff H
Isgro G
Brightling C
Bourne M
Craner M
Watters M
Prout R
Davies L
Pegler S
Kyeremeh L
Arbane G
Wilson K
Gomm L
Francia F
Brett S
Sousa Arias S
Elin Hall R
Budd J
Small C
Birch J
Collins E
Henning J
Bonner S
Hugill K
Cirstea E
Wilkinson D
Karlikowski M
Sutherland H
Wilhelmsen E
Woods J
North J
Sundaran D
Hollos L
Coburn S
Walsh J
Turns M
Hopkins P
Smith J
Noble H
Depante MT
Clarey E
Laha S
Verlander M
Williams A
Huckle A
Hall A
Cooke J
Gardiner-Hill C
Maloney C
Qureshi H
Flint N
Nicholson S
Southin S
Nicholson A
Borgatta B
Turner-Bone I
Reddy A
Wilding L
Chamara Warnapura L
Agno Sathianathan R
Golden D
Hart C
Jones J
Bannard-Smith J
Henry J
Birchall K
Pomeroy F
Quayle R
Makowski A
Misztal B
Ahmed I
KyereDiabour T
Naiker K
Stewart R
Mwaura E
Mew L
Wren L
Willams F
Innes R
Doble P
Hutter J
Shovelton C
Plumb B
Szakmany T
Hamlyn V
Hawkins N
Lewis S
Dell A
Gopal S
Ganguly S
Smallwood A
Harris N
Metherell S
Lazaro JM
Newman T
Fletcher S
Nortje J
Fottrell-Gould D
Randell G
Zaman M
Elmahi E
Jones A
Hall K
Mills G
Ryalls K
Bowler H
Sall J
Bourne R
Borrill Z
Duncan T
Lamb T
Shaw J
Fox C
Moreno Cuesta J
Xavier K
Purohit D
Elhassan M
Bakthavatsalam D
Rowland M
Hutton P
Bashyal A
Davidson N
Hird C
Chhablani M
Phalod G
Kirkby A
Archer S
Netherton K
Reschreiter H
Camsooksai J
Patch S
Jenkins S
Pogson D
Rose S
Daly Z
Brimfield L
Claridge H
Parekh D
Bergin C
Bates M
Dasgin J
McGhee C
Sim M
Hay SK
Henderson S
Phull MK
Zaidi A
Pogreban T
Rosaroso LP
Harvey D
Lowe B
Meredith M
Ryan L
Hormis A
Walker R
Collier D
Kimpton S
Oakley S
Rooney K
Rodden N
Hughes E
Thomson N
McGlynn D
Walden A
Jacques N
Coles H
Tilney E
Vowell E
Schuster-Bruce M
Pitts S
Miln R
Purandare L
Vamplew L
Spivey M
Bean S
Burt K
Moore L
Day C
Gibson C
Gordon E
Zitter L
Keenan S
Baker E
Cherian S
Cutler S
Roynon-Reed A
Harrington K
Raithatha A
Bauchmuller K
Ahmad N
Grecu I
Trodd D
Martin J
Wrey Brown C
Arias AM
Craven T
Hope D
Singleton J
Clark S
Rae N
Welters I
Hamilton DO
Williams K
Waugh V
Shaw D
Puthucheary Z
Martin T
Santos F
Uddin R
Somerville A
Tatham KC
Jhanji S
Black E
Dela Rosa A
Howle R
Tully R
Drummond A
Dearden J
Philbin J
Munt S
Vuylsteke A
Chan C
Victor S
Matsa R
Gellamucho M
Creagh-Brown B
Tooley J
Montague L
De Beaux F
Bullman L
Kersiake I
Demetriou C
Mitchard S
Ramos L
White K
Donnison P
Johns M
Casey R
Mattocks L
Salisbury S
Dark P
Claxton A
McLachlan D
Slevin K
Lee S
Hulme J
Joseph S
Kinney F
Senya HJ
Oborska A
Kayani A
Hadebe B
Orath Prabakaran R
Nichols L
Thomas M
Worner R
Faulkner B
Gendall E
Hayes K
Hamilton-Davies C
Chan C
Mfuko C
Abbass H
Mandadapu V
Leaver S
Forton D
Patel K
Paramasivam E
Powell M
Gould R
Wilby E
Howcroft C
Banach D
Fernández de Pinedo Artaraz Z
Cabreros L
White I
Croft M
Holland N
Pereira R
Zaki A
Johnson D
Jackson M
Garrard H
Juhaz V
Roy A
Rostron A
Woods L
Cornell S
Pillai S
Harford R
Rees T
Ivatt H
Sundara Raman A
Davey M
Lee K
Barber R
Chablani M
Brohi F
Jagannathan V
Clark M
Purvis S
Wetherill B
Dushianthan A
Cusack R
de Courcy-Golder K
Smith S
Jackson S
Attwood B
Parsons P
Page V
Zhao XB
Oza D
Rhodes J
Anderson T
Morris S
Xia Le Tai C
Thomas A
Keen A
Digby S
Cowley N
Wild L
Southern D
Reddy H
Campbell A
Watkins C
Smuts S
Touma O
Barnes N
Alexander P
Felton T
Ferguson S
Sellers K
Bradley-Potts J
Yates D
Birkinshaw I
Kell K
Marshall N
Carr-Knott L
Summers C
Source :
JAMA [JAMA] 2020 Oct 06; Vol. 324 (13), pp. 1317-1329.
Publication Year :
2020

Abstract

Importance: Evidence regarding corticosteroid use for severe coronavirus disease 2019 (COVID-19) is limited.<br />Objective: To determine whether hydrocortisone improves outcome for patients with severe COVID-19.<br />Design, Setting, and Participants: An ongoing adaptive platform trial testing multiple interventions within multiple therapeutic domains, for example, antiviral agents, corticosteroids, or immunoglobulin. Between March 9 and June 17, 2020, 614 adult patients with suspected or confirmed COVID-19 were enrolled and randomized within at least 1 domain following admission to an intensive care unit (ICU) for respiratory or cardiovascular organ support at 121 sites in 8 countries. Of these, 403 were randomized to open-label interventions within the corticosteroid domain. The domain was halted after results from another trial were released. Follow-up ended August 12, 2020.<br />Interventions: The corticosteroid domain randomized participants to a fixed 7-day course of intravenous hydrocortisone (50 mg or 100 mg every 6 hours) (n = 143), a shock-dependent course (50 mg every 6 hours when shock was clinically evident) (n = 152), or no hydrocortisone (n = 108).<br />Main Outcomes and Measures: The primary end point was organ support-free days (days alive and free of ICU-based respiratory or cardiovascular support) within 21 days, where patients who died were assigned -1 day. The primary analysis was a bayesian cumulative logistic model that included all patients enrolled with severe COVID-19, adjusting for age, sex, site, region, time, assignment to interventions within other domains, and domain and intervention eligibility. Superiority was defined as the posterior probability of an odds ratio greater than 1 (threshold for trial conclusion of superiority >99%).<br />Results: After excluding 19 participants who withdrew consent, there were 384 patients (mean age, 60 years; 29% female) randomized to the fixed-dose (n = 137), shock-dependent (n = 146), and no (n = 101) hydrocortisone groups; 379 (99%) completed the study and were included in the analysis. The mean age for the 3 groups ranged between 59.5 and 60.4 years; most patients were male (range, 70.6%-71.5%); mean body mass index ranged between 29.7 and 30.9; and patients receiving mechanical ventilation ranged between 50.0% and 63.5%. For the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively, the median organ support-free days were 0 (IQR, -1 to 15), 0 (IQR, -1 to 13), and 0 (-1 to 11) days (composed of 30%, 26%, and 33% mortality rates and 11.5, 9.5, and 6 median organ support-free days among survivors). The median adjusted odds ratio and bayesian probability of superiority were 1.43 (95% credible interval, 0.91-2.27) and 93% for fixed-dose hydrocortisone, respectively, and were 1.22 (95% credible interval, 0.76-1.94) and 80% for shock-dependent hydrocortisone compared with no hydrocortisone. Serious adverse events were reported in 4 (3%), 5 (3%), and 1 (1%) patients in the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively.<br />Conclusions and Relevance: Among patients with severe COVID-19, treatment with a 7-day fixed-dose course of hydrocortisone or shock-dependent dosing of hydrocortisone, compared with no hydrocortisone, resulted in 93% and 80% probabilities of superiority with regard to the odds of improvement in organ support-free days within 21 days. However, the trial was stopped early and no treatment strategy met prespecified criteria for statistical superiority, precluding definitive conclusions.<br />Trial Registration: ClinicalTrials.gov Identifier: NCT02735707.

Details

Language :
English
ISSN :
1538-3598
Volume :
324
Issue :
13
Database :
MEDLINE
Journal :
JAMA
Publication Type :
Academic Journal
Accession number :
32876697
Full Text :
https://doi.org/10.1001/jama.2020.17022