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Long-term (180-day) outcomes in critically ill patients with COVID-19 in the REMAP-CAP randomized clinical trial

Authors :
Florescu, S
Stanciu, D
Zaharia, M
Kosa, A
Codreanu, D
Kidwai, A
Masood, S
Kaye, C
Coutts, A
MacKay, L
Summers, C
Polgarova, P
Farahi, N
Fox, E
McWilliam, S
Hawcutt, D
Rad, L
O’Malley, L
Whitbread, J
Jones, D
Dore, R
Saunderson, P
Kelsall, O
Cowley, N
Wild, L
Thrush, J
Wood, H
Austin, K
Bélteczki, J
Magyar, I
Fazekas, Á
Kovács, S
Szőke, V
Donnelly, A
Kelly, M
Smyth, N
O’Kane, S
McClintock, D
Warnock, M
Campbell, R
McCallion, E
Azaiz, A
Charron, C
Godement, M
Geri, G
Vieillard-Baron, A
Johnson, P
McKenna, S
Hanley, J
Currie, A
Allen, B
McGoldrick, C
McMaster, M
Mani, A
Mathew, M
Kandeepan, R
Vignesh, C
TV, B
Ramakrishnan, N
James, A
Elvira, E
Jayakumar, D
Pratheema, R
Babu, S
Ebenezer, R
Krishnaoorthy, S
Ranganathan, L
Ganesan, M
Shree, M
Guilder, E
Butler, M
Cowdrey, K-A
Robertson, M
Ali, F
McMahon, E
Duffy, E
Chen, Y
Simmonds, C
McConnochie, R
O’Connor, C
El-Khawas, K
Richardson, A
Hill, D
Commons, R
Abdelkharim, H
Saxena, M
Muteithia, M
Dobell-Brown, K
Jha, R
Kalogirou, M
Ellis, C
Krishnamurthy, V
O’Connor, A
Thurairatnam, S
Mukherjee, D
Kaliappan, A
Vertue, M
Nicholson, A
Riches, J
Maloney, G
Kittridge, L
Solesbury, A
Ramos, A
Collins, D
Brickell, K
Reid, L
Smyth, M
Breen, P
Spain, S
Curley, G
McEvoy, N
Geoghegan, P
Clarke, J
Silversides, J
McGuigan, P
Ward, K
O’Neill, A
Finn, S
Wright, C
Green, J
Collins, É
Knott, C
Smith, J
Boschert, C
Slieker, K
Ewalds, E
Sanders, A
Wittenberg, W
Geurts, H
Poojara, L
Sara, T
Nand, K
Reeve, B
Dechert, W
Phillips, B
Oritz-Ruiz de Gordoa, L
Affleck, J
Shaikh, A
Murray, A
Ramanan, M
Frakking, T
Pinnell, J
Robinson, M
Gledhill, L
Wood, T
Sanghavi, R
Bhonagiri, D
Ford, M
Parikh, HG
Avard, B
Nourse, M
McDonald, B
Edmunds, N
Hoiting, O
Peters, M
Rengers, E
Evers, M
Prinssen, A
Morgan, M
Cole, J
Hill, H
Davies, M
Williams, A
Thomas, E
Davies, R
Wise, M
Grimm, P
Soukup, J
Wetzold, R
Löbel, M
Starke, L
Lellouche, F
Lizotte, P
Declerq, P
Antoine, M
Stephanie, G
Jean-Pierre, E
François, B
Marion, B
Philippe, R
Pourcine, F
Monchi, M
Luis, D
Mercier, R
Sagnier, A
Verrier, N
Caplin, C
Richecoeu, J
Combaux, D
Siami, S
Aparicio, C
Vautier, S
Jeblaoui, A
Lemaire-Brunel, D
D'Aragon, F
Carbonneau, E
Leblond, J
Plantefeve, G
Leparco, C
Contou, D
Fartoukh, M
Courtin, L
Labbe, V
Voiriot, G
Salhi, S
Chassé, M
Carrier, F
Boumahni, D
Benettaib, F
Ghamraoui, A
Sement, A
Gachet, A
Hanisch, A
Haffiane, A
Boivin, A-H
Barreau, A
Guerineau, E
Poupblanc, S
Egreteau, P
Lefevre, M
Bocher, S
Le Loup, G
Le Guen, L
Carn, V
Bertel, M
Antcliffe, D
Templeton, M
Rojo, R
Coghlan, P
Smee, J
Barker, G
Finn, A
Kreb, G
Hoff, U
Hinrichs, C
Nee, J
Mackay, E
Cort, J
Whileman, A
Spencer, T
Spittle, N
Beavis, S
Padmakumar, A
Dale, K
Hawes, J
Moakes, E
Gascoyne, R
Pritchard, K
Stevenson, L
Cooke, J
Nemeth-Roszpopa, K
Gauli, B
Bastola, S
Muller, G
Nay, M-A
Kamel, T
Benzekri, D
Jacquier, S
Runge, I
Mathonnet, A
Barbier, F
Bretagnol, A
Carter, J
Van Der Heyden, K
Mehrtens, J
Morris, A
Morgan, S
Burke, T
Mercier, E
Chartier, D
Salmon, C
Dequin, P-F
Garot, D
Bellemare, D
Cloutier, È
Daher, R
Costerousse, O
Boulanger, M-C
Couillard-Chénard, É
Lauzier, F
Francoeur, C
Francois, B
Gay, A
Anne-Laure, F
Ramali, M
HC, O
Ghosh, A
Osagie, R
Arachchige, M
Hartley, M
Cheung, W
Wong, H
Seigne, P
Eustace, J
O'Callaghan, A-M
O'Brien, F
Bamford, P
Reid, A
Cawley, K
Faulkner, M
Pickering, C
Raj, A
Tsinaslanidis, G
Khade, R
Agha, G
Sekiwala, R
Smith, T
Brewer, C
Gregory, J
Limb, J
Cowton, A
O’Brien, J
Postlethwaite, K
Malakouti, S
Music, E
Ricketts, D
King, A
Clermont, G
Bart, R
Mayr, F
Schoenling, A
Andreae, M
Shetty, V
Brant, E
Malley, B
Donadee, C
Sackrowitz, R
Weissman, A
Yealy, D
Barton, D
Talia, N
Nikitas, N
Wells, C
Lankester, L
McMillan, H
Van den Oever, H
Kruisdijk-Gerritsen, A
Haidar, G
Bain, W
Barbash, I
Fitzpatrick, M
Franz, C
Kitsios, G
Moghbeli, K
Rosborough, B
Shah, F
Suber, T
Pulletz, M
Williams, P
Birch, J
Wiseman, S
Horton, S
Alegria, A
Turki, S
Elsefi, T
Crisp, N
Allen, L
Truman, N
Smith, M
Chukkambotla, S
Goddard, W
Duberley, S
Khan, M
Kazi, A
Simpson, J
Duke, G
Chan, P
Carter, B
Hunter, S
Voigt, I
Schueler, R
Blank, E
Hüning, V
Steffen, M
Goralski, P
Litton, E
Regli, A
Pellicano, S
Palermo, A
Eroglu, E
Bihari, S
Laver, RD
Jin, X
Brown, J
McIntyre, J
French, C
Bates, S
Towns, M
Yang, Y
McGain, F
McCullagh, I
Cairns, T
Hanson, H
Patel, B
Clement, I
Evetts, G
Touma, O
Holland, S
Hodge, C
Taylor, H
Alderman, M
Barnes, N
Da Rocha, J
Smith, C
Brooks, N
Weerasinghe, T
Sinclair, J-A
Abusamra, Y
Doherty, R
Cudlipp, J
Singh, R
Yu, H
Daebis, A
Ng, C
Kendrick, S
Saran, A
Makky, A
Greener, D
Rowe-Leete, L
Edwards, A
Bland, Y
Dolman, R
Foster, T
Laffey, J
McNicholas, B
Scully, M
Casey, S
Kernan, M
Brennan, A
Rangan, R
Tully, R
Corbett, S
McCarthy, A
Duffy, O
Burke, D
Linnett, V
Sanderson, A
Ritzema, J
Wild, H
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McCullough, J
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Brett, S
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Boyd, C
Harland, C
Shearer, A
Wren, J
Attanayaka, U
Darshana, S
Ishani, P
Udayanga, I
Higgins, AM
Berry, LR
Lorenzi, E
Murthy, S
McQuilten, Z
Mouncey, PR
Al-Beidh, F
Annane, D
Arabi, YM
Beane, A
Van Bentum-Puijk, W
Bhimani, Z
Bonten, MJM
Bradbury, CA
Brunkhorst, FM
Buzgau, A
Buxton, M
Charles, WN
Cove, M
Detry, MA
Estcourt, LJ
Fagbodun, EO
Fitzgerald, M
Girard, TD
Goligher, EC
Goossens, H
Haniffa, R
Hills, T
Horvat, CM
Huang, DT
Ichihara, N
Lamontagne, F
Marshall, JC
McAuley, DF
McGlothlin, A
McGuinness, SP
McVerry, BJ
Neal, MD
Nichol, AD
Parke, RL
Parker, JC
Parry-Billings, K
Peters, SEC
Reyes, LF
Rowan, KM
Saito, H
Santos, MS
Saunders, CT
Serpa-Neto, A
Seymour, CW
Shankar-Hari, M
Stronach, LM
Turgeon, AF
Turner, AM
Van de Veerdonk, FL
Zarychanski, R
Green, C
Lewis, RJ
Angus, DC
McArthur, CJ
Berry, S
Derde, LPG
Gordon, AC
Webb, SA
Lawler, PR
Comm REMAP-CAP Investigators
Apollo - University of Cambridge Repository
Intensive Care Medicine
Université de Versailles Saint-Quentin-en-Yvelines - UFR Sciences de la santé Simone Veil (UVSQ Santé)
Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)
Hôpital Raymond Poincaré [Garches]
Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)
Pittsburgh Foundation, PF
Amgen
Health Research Board, HRB: CTN 2014-012
Horizon 2020 Framework Programme, H2020: 101003589
Translational Breast Cancer Research Consortium, TBCRC
Canadian Institutes of Health Research, IRSC: 158584
Heart and Stroke Foundation of Canada, HSF
National Institute for Health and Care Research, NIHR
European Commission, EC
National Health and Medical Research Council, NHMRC: 1101719, APP194811, CS-2016-16-011, GNT2008447, RP-2015-06-18
Office of Health and Medical Research, OHMR
Health Research Council of New Zealand, HRC: 16/631
Eisai
Ministère des Affaires Sociales et de la Santé: PHRC-20-0147
Université Pierre et Marie Curie, UPMC
NIHR Imperial Biomedical Research Centre, BRC
Minderoo Foundation
Funding/Support : The Platform for European Preparedness Against (Re-) emerging Epidemics (PREPARE) consortium by the European Union, FP7-HEALTH-2013-INNOVATION-1 (#602525), the Rapid European COVID-19 Emergency Research response (RECOVER) consortium by the European Union’s Horizon 2020 research and innovation programme (#101003589), the Australian National Health and Medical Research Council (#APP1101719), the Australian Medical Research Future Fund (#APP2002132), the Health Research Council of New Zealand (#16/631), the Canadian Institutes of Health Research Strategy for Patient-Oriented Research Innovative Clinical Trials Program Grant (#158584) and the Canadian Institute of Health Research COVID-19 Rapid Research Funding (#447335), the UK National Institute for Health Research (NIHR) and the NIHR Imperial Biomedical Research Centre, the Health Research Board of Ireland (CTN 2014-012), the UPMC Learning While Doing Program, the Translational Breast Cancer Research Consortium, the French Ministry of Health (PHRC-20-0147), the Wellcome Trust Innovations Project (215522), the Minderoo Foundation, the EU Programme Emergency Support Instrument, the NHS Blood and Transplant Research and Development Programme, the Translational Breast Cancer Research Consortium, the NSW Office of Health and Medical Research, Amgen, Eisai, and the Pittsburgh Foundation. Dr Higgins is funded by an NHMRC Emerging Leadership Fellowship (GNT2008447). Dr McQuilten is funded by an NHMRC Emerging Leadership Fellowship (APP194811). Dr Gordon is funded by an NIHR Research Professorship (RP-2015-06-18) and Dr Shankar-Hari by an NIHR Clinician Scientist Fellowship (CS-2016-16-011). Dr Turgeon is the Chairholder of the Canada Research Chair in Critical Care Neurology and Trauma. Dr Lawler is supported by a career award from the Heart and Stroke Foundation of Canada.
European Project: 602525,EC:FP7:HEALTH,FP7-HEALTH-2013-INNOVATION-1,PREPARE(2014)
Source :
JAMA : the journal of the American Medical Association, JAMA, 329(1), 39-51. American Medical Association, Journal of the American Medical Association, Journal of the American Medical Association, 2023, 329 (1), pp.39-51. ⟨10.1001/jama.2022.23257⟩, Jama : Journal of the American Medical Association, 329, 1, pp. 39-51, Higgins, A M, Berry, L R, Lorenzi, E, Murthy, S, McQuilten, Z, Mouncey, P R, Al-Beidh, F, Annane, D, Arabi, Y M, Beane, A, Van Bentum-Puijk, W, Bhimani, Z, Bonten, M J M, Bradbury, C A, Brunkhorst, F M, Burrell, A, Buzgau, A, Buxton, M, Charles, W N, Cove, M, Detry, M A, Estcourt, L J, Fagbodun, E O, Fitzgerald, M, Girard, T D, Goligher, E C, Goossens, H, Haniffa, R, Hills, T, Horvat, C M, Huang, D T, Ichihara, N, Lamontagne, F, Marshall, J C, McAuley, D F, McGlothlin, A, McGuinness, S P, McVerry, B J, Neal, M D, Nichol, A D, Parke, R L, Parker, J C, Parry-Billings, K, Peters, S E C, Reyes, L F, Rowan, K M, Saito, H, Santos, M S, Saunders, C T & Serpa-Neto, A 2023, ' Long-term (180-day) outcomes in critically ill patients with COVID-19 in the REMAP-CAP randomized clinical trial ', JAMA, vol. 329, no. 1, pp. 39-51 . https://doi.org/10.1001/jama.2022.23257, Bradbury, C A & Higgins, A M 2023, ' Long-term (180-Day) Outcomes in Critically Ill Patients With COVID-19 in the REMAP-CAP Randomized Clinical Trial ', JAMA-Journal of the American Medical Association, vol. 329, no. 1, pp. 39-51 . https://doi.org/10.1001/jama.2022.23257, Jama : Journal of the American Medical Association, 329, 39-51, JAMA
Publication Year :
2023

Abstract

ImportanceThe longer-term effects of therapies for the treatment of critically ill patients with COVID-19 are unknown.ObjectiveTo determine the effect of multiple interventions for critically ill adults with COVID-19 on longer-term outcomes.Design, Setting, and ParticipantsPrespecified secondary analysis of an ongoing adaptive platform trial (REMAP-CAP) testing interventions within multiple therapeutic domains in which 4869 critically ill adult patients with COVID-19 were enrolled between March 9, 2020, and June 22, 2021, from 197 sites in 14 countries. The final 180-day follow-up was completed on March 2, 2022.InterventionsPatients were randomized to receive 1 or more interventions within 6 treatment domains: immune modulators (n = 2274), convalescent plasma (n = 2011), antiplatelet therapy (n = 1557), anticoagulation (n = 1033), antivirals (n = 726), and corticosteroids (n = 401).Main Outcomes and MeasuresThe main outcome was survival through day 180, analyzed using a bayesian piecewise exponential model. A hazard ratio (HR) less than 1 represented improved survival (superiority), while an HR greater than 1 represented worsened survival (harm); futility was represented by a relative improvement less than 20% in outcome, shown by an HR greater than 0.83.ResultsAmong 4869 randomized patients (mean age, 59.3 years; 1537 [32.1%] women), 4107 (84.3%) had known vital status and 2590 (63.1%) were alive at day 180. IL-6 receptor antagonists had a greater than 99.9% probability of improving 6-month survival (adjusted HR, 0.74 [95% credible interval {CrI}, 0.61-0.90]) and antiplatelet agents had a 95% probability of improving 6-month survival (adjusted HR, 0.85 [95% CrI, 0.71-1.03]) compared with the control, while the probability of trial-defined statistical futility (HR >0.83) was high for therapeutic anticoagulation (99.9%; HR, 1.13 [95% CrI, 0.93-1.42]), convalescent plasma (99.2%; HR, 0.99 [95% CrI, 0.86-1.14]), and lopinavir-ritonavir (96.6%; HR, 1.06 [95% CrI, 0.82-1.38]) and the probabilities of harm from hydroxychloroquine (96.9%; HR, 1.51 [95% CrI, 0.98-2.29]) and the combination of lopinavir-ritonavir and hydroxychloroquine (96.8%; HR, 1.61 [95% CrI, 0.97-2.67]) were high. The corticosteroid domain was stopped early prior to reaching a predefined statistical trigger; there was a 57.1% to 61.6% probability of improving 6-month survival across varying hydrocortisone dosing strategies.Conclusions and RelevanceAmong critically ill patients with COVID-19 randomized to receive 1 or more therapeutic interventions, treatment with an IL-6 receptor antagonist had a greater than 99.9% probability of improved 180-day mortality compared with patients randomized to the control, and treatment with an antiplatelet had a 95.0% probability of improved 180-day mortality compared with patients randomized to the control. Overall, when considered with previously reported short-term results, the findings indicate that initial in-hospital treatment effects were consistent for most therapies through 6 months.

Details

Language :
English
ISSN :
00987484 and 15383598
Database :
OpenAIRE
Journal :
JAMA : the journal of the American Medical Association
Accession number :
edsair.doi.dedup.....95f91977e02cef294ec43548f54d8c74