Lopinavir-ritonavir and hydroxychloroquine for critically ill patients with COVID-19: REMAP-CAP randomized controlled trial

Yaseen M. Arabi; Anthony C. Gordon; Lennie P. G. Derde; Alistair D. Nichol; Srinivas Murthy; Farah Al-Beidh; Djillali Annane; Lolowa Al Swaidan; Abi Beane; Richard Beasley; Lindsay R. Berry; Zahra Bhimani; Marc J.M. Bonten; Charlotte A. Bradbury; Frank M. Brunkhorst; Meredith Buxton; Adrian Buzgau; Allen Cheng; Menno De Jong; Michelle A. Detry; Eamon Duffy; Lise J. Estcourt; Mark Fitzgerald; Rob Fowler; Timothy D. Girard; Ewan C. Goligher; Herman Goossens; Rashan Haniffa; Alisa M. Higgins; Thomas E. Hills; Christopher M. Horvat; David T. Huang; Andrew J. King; Francois Lamontagne; Patrick Lawler; Roger Lewis; Kelsey Linstrum; Edward Litton; Elizabeth Lorenzi; Salim Malakouti; Daniel F. McAuley; Anna McGlothlin; Shay McGuinness; Bryan J. McVerry; Stephanie K. Montgomery; Susan C. Morpeth; Paul R. Mouncey; Katrina Orr; Rachael Parke; Jane C. Parker; Asad E. Patanwala; Kathryn M. Rowan; Marlene S. Santos; Christina T. Saunders; Christopher W. Seymour; Manu Shankar-Hari; Steven Y.C. Tong; Alexis F. Turgeon; Anne M. Turner; Frank Leo van de Veerdonk; Ryan Zarychanski; Cameron Green; Scott Berry; John C. Marshall; Colin McArthur; Derek C. Angus; Steven A. Webb; the REMAP-CAP Investigators; Shailesh Bihari; Russell D. Laver; Tapaswi Shrestha

doi:10.1007/s00134-021-06448-5

Lopinavir-ritonavir and hydroxychloroquine for critically ill patients with COVID-19: REMAP-CAP randomized controlled trial

Yaseen M. Arabi, Anthony C. Gordon, Lennie P. G. Derde, Alistair D. Nichol, Srinivas Murthy, Farah Al-Beidh, Djillali Annane, Lolowa Al Swaidan, Abi Beane, Richard Beasley, Lindsay R. Berry, Zahra Bhimani, Marc J.M. Bonten, Charlotte A. Bradbury, Frank M. Brunkhorst, Meredith Buxton, Adrian Buzgau, Allen Cheng, Menno De Jong, Michelle A. DetryEamon Duffy, Lise J. Estcourt, Mark Fitzgerald, Rob Fowler, Timothy D. Girard, Ewan C. Goligher, Herman Goossens, Rashan Haniffa, Alisa M. Higgins, Thomas E. Hills, Christopher M. Horvat, David T. Huang, Andrew J. King, Francois Lamontagne, Patrick Lawler, Roger Lewis, Kelsey Linstrum, Edward Litton, Elizabeth Lorenzi, Salim Malakouti, Daniel F. McAuley, Anna McGlothlin, Shay McGuinness, Bryan J. McVerry, Stephanie K. Montgomery, Susan C. Morpeth, Paul R. Mouncey, Katrina Orr, Rachael Parke, Jane C. Parker, Asad E. Patanwala, Kathryn M. Rowan, Marlene S. Santos, Christina T. Saunders, Christopher W. Seymour, Manu Shankar-Hari, Steven Y.C. Tong, Alexis F. Turgeon, Anne M. Turner, Frank Leo van de Veerdonk, Ryan Zarychanski, Cameron Green, Scott Berry, John C. Marshall, Colin McArthur, Derek C. Angus, Steven A. Webb, the REMAP-CAP Investigators, Shailesh Bihari, Russell D. Laver, Tapaswi Shrestha

College of Medicine and Public Health

Research output: Contribution to journal › Article › peer-review

73 Citations (Scopus)

Abstract

Purpose:

To study the efficacy of lopinavir-ritonavir and hydroxychloroquine in critically ill patients with coronavirus disease 2019 (COVID-19).

Methods:

Critically ill adults with COVID-19 were randomized to receive lopinavir-ritonavir, hydroxychloroquine, combination therapy of lopinavir-ritonavir and hydroxychloroquine or no antiviral therapy (control). The primary endpoint was an ordinal scale of organ support-free days. Analyses used a Bayesian cumulative logistic model and expressed treatment effects as an adjusted odds ratio (OR) where an OR > 1 is favorable.

Results:

We randomized 694 patients to receive lopinavir-ritonavir (n = 255), hydroxychloroquine (n = 50), combination therapy (n = 27) or control (n = 362). The median organ support-free days among patients in lopinavir-ritonavir, hydroxychloroquine, and combination therapy groups was 4 (– 1 to 15), 0 (– 1 to 9) and—1 (– 1 to 7), respectively, compared to 6 (– 1 to 16) in the control group with in-hospital mortality of 88/249 (35%), 17/49 (35%), 13/26 (50%), respectively, compared to 106/353 (30%) in the control group. The three interventions decreased organ support-free days compared to control (OR [95% credible interval]: 0.73 [0.55, 0.99], 0.57 [0.35, 0.83] 0.41 [0.24, 0.72]), yielding posterior probabilities that reached the threshold futility (≥ 99.0%), and high probabilities of harm (98.0%, 99.9% and > 99.9%, respectively). The three interventions reduced hospital survival compared with control (OR [95% CrI]: 0.65 [0.45, 0.95], 0.56 [0.30, 0.89], and 0.36 [0.17, 0.73]), yielding high probabilities of harm (98.5% and 99.4% and 99.8%, respectively).

Conclusion:

Among critically ill patients with COVID-19, lopinavir-ritonavir, hydroxychloroquine, or combination therapy worsened outcomes compared to no antiviral therapy.

Original language	English
Pages (from-to)	867-886
Number of pages	20
Journal	Intensive Care Medicine
Volume	47
Issue number	8
DOIs	https://doi.org/10.1007/s00134-021-06448-5
Publication status	Published - Aug 2021

Keywords

Adaptive platform trial
COVID-19
Hydroxychloroquine
Intensive care
Lopinavir-ritonavir
Pandemic
Pneumonia

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1007/s00134-021-06448-5Licence: In Copyright

https://rdcu.be/dxmxtLicence: In Copyright

Cite this

Arabi, Y. M., Gordon, A. C., Derde, L. P. G., Nichol, A. D., Murthy, S., Al-Beidh, F., Annane, D., Swaidan, L. A., Beane, A., Beasley, R., Berry, L. R., Bhimani, Z., Bonten, M. J. M., Bradbury, C. A., Brunkhorst, F. M., Buxton, M., Buzgau, A., Cheng, A., De Jong, M., ... Shrestha, T. (2021). Lopinavir-ritonavir and hydroxychloroquine for critically ill patients with COVID-19: REMAP-CAP randomized controlled trial. Intensive Care Medicine, 47(8), 867-886. https://doi.org/10.1007/s00134-021-06448-5

@article{3d35e3afdebc4f28ae1b9f3ef18914d2,

title = "Lopinavir-ritonavir and hydroxychloroquine for critically ill patients with COVID-19: REMAP-CAP randomized controlled trial",

abstract = "Purpose: To study the efficacy of lopinavir-ritonavir and hydroxychloroquine in critically ill patients with coronavirus disease 2019 (COVID-19). Methods: Critically ill adults with COVID-19 were randomized to receive lopinavir-ritonavir, hydroxychloroquine, combination therapy of lopinavir-ritonavir and hydroxychloroquine or no antiviral therapy (control). The primary endpoint was an ordinal scale of organ support-free days. Analyses used a Bayesian cumulative logistic model and expressed treatment effects as an adjusted odds ratio (OR) where an OR > 1 is favorable. Results: We randomized 694 patients to receive lopinavir-ritonavir (n = 255), hydroxychloroquine (n = 50), combination therapy (n = 27) or control (n = 362). The median organ support-free days among patients in lopinavir-ritonavir, hydroxychloroquine, and combination therapy groups was 4 (– 1 to 15), 0 (– 1 to 9) and—1 (– 1 to 7), respectively, compared to 6 (– 1 to 16) in the control group with in-hospital mortality of 88/249 (35%), 17/49 (35%), 13/26 (50%), respectively, compared to 106/353 (30%) in the control group. The three interventions decreased organ support-free days compared to control (OR [95% credible interval]: 0.73 [0.55, 0.99], 0.57 [0.35, 0.83] 0.41 [0.24, 0.72]), yielding posterior probabilities that reached the threshold futility (≥ 99.0%), and high probabilities of harm (98.0%, 99.9% and > 99.9%, respectively). The three interventions reduced hospital survival compared with control (OR [95% CrI]: 0.65 [0.45, 0.95], 0.56 [0.30, 0.89], and 0.36 [0.17, 0.73]), yielding high probabilities of harm (98.5% and 99.4% and 99.8%, respectively). Conclusion: Among critically ill patients with COVID-19, lopinavir-ritonavir, hydroxychloroquine, or combination therapy worsened outcomes compared to no antiviral therapy.",

keywords = "Adaptive platform trial, COVID-19, Hydroxychloroquine, Intensive care, Lopinavir-ritonavir, Pandemic, Pneumonia",

author = "Arabi, {Yaseen M.} and Gordon, {Anthony C.} and Derde, {Lennie P. G.} and Nichol, {Alistair D.} and Srinivas Murthy and Farah Al-Beidh and Djillali Annane and Swaidan, {Lolowa Al} and Abi Beane and Richard Beasley and Berry, {Lindsay R.} and Zahra Bhimani and Bonten, {Marc J.M.} and Bradbury, {Charlotte A.} and Brunkhorst, {Frank M.} and Meredith Buxton and Adrian Buzgau and Allen Cheng and {De Jong}, Menno and Detry, {Michelle A.} and Eamon Duffy and Estcourt, {Lise J.} and Mark Fitzgerald and Rob Fowler and Girard, {Timothy D.} and Goligher, {Ewan C.} and Herman Goossens and Rashan Haniffa and Higgins, {Alisa M.} and Hills, {Thomas E.} and Horvat, {Christopher M.} and Huang, {David T.} and King, {Andrew J.} and Francois Lamontagne and Patrick Lawler and Roger Lewis and Kelsey Linstrum and Edward Litton and Elizabeth Lorenzi and Salim Malakouti and McAuley, {Daniel F.} and Anna McGlothlin and Shay McGuinness and McVerry, {Bryan J.} and Montgomery, {Stephanie K.} and Morpeth, {Susan C.} and Mouncey, {Paul R.} and Katrina Orr and Rachael Parke and Parker, {Jane C.} and Patanwala, {Asad E.} and Rowan, {Kathryn M.} and Santos, {Marlene S.} and Saunders, {Christina T.} and Seymour, {Christopher W.} and Manu Shankar-Hari and Tong, {Steven Y.C.} and Turgeon, {Alexis F.} and Turner, {Anne M.} and {van de Veerdonk}, {Frank Leo} and Ryan Zarychanski and Cameron Green and Scott Berry and Marshall, {John C.} and Colin McArthur and Angus, {Derek C.} and Webb, {Steven A.} and {the REMAP-CAP Investigators} and {van Bentum-Puijk}, Wilma and Lewis Campbell and Andrew Forbes and David Gattas and Stephane Heritier and Peter Kruger and Sandra Peake and Jeffrey Presneill and Ian Seppelt and Tony Trapani and Paul Young and Brian Cuthbertson and Venika Manoharan and Diptesh Aryal and Dondrop, {Arjen M.} and Madiha Hashmi and Issrah Jawad and Devachandran Jayakumar and Timo Tolppa and Vanessa Singh and Maurizio Cecconi and Stephan Ehrmann and Lorraine Parker and Mathias Pletz and Pedro P{\'o}voa and Gernot Rohde and Brian Alexander and Kim Basile and Florian Mayr and Nick Daneman and Steve McGloughlin and David Paterson and Bala Venkatesh and Tim Uyeki and Kenneth Baillie and Nichola Cooper and Olaf Cremer and James Galea and Helen Leavis and Mihai Netea and Kayode Ogungbenro and Asad Patawala and Ville Pettil{\"a} and Emma Rademaker and Manoj Saxena and Wendy Sligl and Taryn Youngstein and Shailesh Bihari and Marc Carrier and Dean Fergusson and Beverley Hunt and Mike Laffan and Lother, {Sylvain A.} and Saskia Middeldorp and Zoe McQuilten and Anand Kumar and Matthew Neal and Roger Schutgens and Simon Stanworth and Alexandra Weissman and Niall Ferguson and Carol Hodgson and John Laffey and Ary Neto and Rebecca Baron and Slava Epelman and Claudia Frankfurter and Frank Gommans and Andrew Udy and Phoebe McCracken and Meredith Young and Jasmin Board and Emma Martin and Khaled El-Khawas and Angus Richardson and Dianne Hill and Robert Commons and Hussam Abdelkharim and Cameron Knott and Julie Smith and Catherine Boschert and Julia Affleck and Yogesh Apte and Umesh Subbanna and Roland Bartholdy and Thuy Frakking and Karuna Keat and Deepak Bhonagiri and Ritesh Sanghavi and Jodie Nema and Megan Ford and Parikh, {Harshel G.} and Bronwyn Avard and Mary Nourse and Winston Cheung and Helen Wong and Asim Shah and Atul Wagh and Joanna Simpson and Graeme Duke and Peter Chan and Brittney Carter and Stephanie Hunter and Laver, {Russell D.} and Tapaswi Shrestha and Xia Jin and Adrian Regli and Susan Pellicano and Annamaria Palermo and Ege Eroglu and Craig French and Samantha Bates and Miriam Towns and Yang Yang and Forbes McGain and James McCullough and Mandy Tallott and Nikhil Kumar and Rakshit Panwar and Gail Brinkerhoff and Cassandra Koppen and Federica Cazzola and Matthew Brain and Sarah Mineall and Roy Fischer and Vishwanath Biradar and Natalie Soar and Hayden White and Kristine Estensen and Lynette Morrison and Joanne Sutton and Melanie Cooper and Yahya Shehabi and Wisam Al-Bassam and Amanda Hulley and Umesh Kadam and Kushaharan Sathianathan and Christina Whitehead and Julie Lowrey and Rebecca Gresham and Kristy Masters and James Walsham and Jason Meyer and Meg Harward and Ellen Venz and Kara Brady and Cassandra Vale and Kiran Shekar and Jayshree Lavana and Dinesh Parmar and Patricia Williams and Catherine Kurenda and Helen Miles and Antony Attokaran and Samuel Gluck and Stephanie O{\textquoteright}Connor and Marianne Chapman and Kathleen Glasby and Kirsty Smyth and Margaret Phillips and Deborah Barge and Kathleen Byrne and Alana Driscoll and Louise Fortune and Pierre Janin and Elizabeth Yarad and Frances Bass and Matthew Anstey and David Roberts and Judith Smith and Paul Johnson and Kathryn Ward and Emma Thomas and Richard Clark and Richard Stewart and Neil Davidson and David Hope and Hamilton, {David Oliver} and Ian White and David Johnson and Simon Smith and Thomas Anderson and Amy Thomas",

year = "2021",

month = aug,

doi = "10.1007/s00134-021-06448-5",

language = "English",

volume = "47",

pages = "867--886",

journal = "Intensive Care Medicine",

issn = "0342-4642",

publisher = "Springer Verlag",

number = "8",

}

Arabi, YM, Gordon, AC, Derde, LPG, Nichol, AD, Murthy, S, Al-Beidh, F, Annane, D, Swaidan, LA, Beane, A, Beasley, R, Berry, LR, Bhimani, Z, Bonten, MJM, Bradbury, CA, Brunkhorst, FM, Buxton, M, Buzgau, A, Cheng, A, De Jong, M, Detry, MA, Duffy, E, Estcourt, LJ, Fitzgerald, M, Fowler, R, Girard, TD, Goligher, EC, Goossens, H, Haniffa, R, Higgins, AM, Hills, TE, Horvat, CM, Huang, DT, King, AJ, Lamontagne, F, Lawler, P, Lewis, R, Linstrum, K, Litton, E, Lorenzi, E, Malakouti, S, McAuley, DF, McGlothlin, A, McGuinness, S, McVerry, BJ, Montgomery, SK, Morpeth, SC, Mouncey, PR, Orr, K, Parke, R, Parker, JC, Patanwala, AE, Rowan, KM, Santos, MS, Saunders, CT, Seymour, CW, Shankar-Hari, M, Tong, SYC, Turgeon, AF, Turner, AM, van de Veerdonk, FL, Zarychanski, R, Green, C, Berry, S, Marshall, JC, McArthur, C, Angus, DC, Webb, SA, the REMAP-CAP Investigators, Bihari, S, Laver, RD & Shrestha, T 2021, 'Lopinavir-ritonavir and hydroxychloroquine for critically ill patients with COVID-19: REMAP-CAP randomized controlled trial', Intensive Care Medicine, vol. 47, no. 8, pp. 867-886. https://doi.org/10.1007/s00134-021-06448-5

TY - JOUR

T1 - Lopinavir-ritonavir and hydroxychloroquine for critically ill patients with COVID-19

T2 - REMAP-CAP randomized controlled trial

AU - Arabi, Yaseen M.

AU - Gordon, Anthony C.

AU - Derde, Lennie P. G.

AU - Nichol, Alistair D.

AU - Murthy, Srinivas

AU - Al-Beidh, Farah

AU - Annane, Djillali

AU - Swaidan, Lolowa Al

AU - Beane, Abi

AU - Beasley, Richard

AU - Berry, Lindsay R.

AU - Bhimani, Zahra

AU - Bonten, Marc J.M.

AU - Bradbury, Charlotte A.

AU - Brunkhorst, Frank M.

AU - Buxton, Meredith

AU - Buzgau, Adrian

AU - Cheng, Allen

AU - De Jong, Menno

AU - Detry, Michelle A.

AU - Duffy, Eamon

AU - Estcourt, Lise J.

AU - Fitzgerald, Mark

AU - Fowler, Rob

AU - Girard, Timothy D.

AU - Goligher, Ewan C.

AU - Goossens, Herman

AU - Haniffa, Rashan

AU - Higgins, Alisa M.

AU - Hills, Thomas E.

AU - Horvat, Christopher M.

AU - Huang, David T.

AU - King, Andrew J.

AU - Lamontagne, Francois

AU - Lawler, Patrick

AU - Lewis, Roger

AU - Linstrum, Kelsey

AU - Litton, Edward

AU - Lorenzi, Elizabeth

AU - Malakouti, Salim

AU - McAuley, Daniel F.

AU - McGlothlin, Anna

AU - McGuinness, Shay

AU - McVerry, Bryan J.

AU - Montgomery, Stephanie K.

AU - Morpeth, Susan C.

AU - Mouncey, Paul R.

AU - Orr, Katrina

AU - Parke, Rachael

AU - Parker, Jane C.

AU - Patanwala, Asad E.

AU - Rowan, Kathryn M.

AU - Santos, Marlene S.

AU - Saunders, Christina T.

AU - Seymour, Christopher W.

AU - Shankar-Hari, Manu

AU - Tong, Steven Y.C.

AU - Turgeon, Alexis F.

AU - Turner, Anne M.

AU - van de Veerdonk, Frank Leo

AU - Zarychanski, Ryan

AU - Green, Cameron

AU - Berry, Scott

AU - Marshall, John C.

AU - McArthur, Colin

AU - Angus, Derek C.

AU - Webb, Steven A.

AU - the REMAP-CAP Investigators

AU - van Bentum-Puijk, Wilma

AU - Campbell, Lewis

AU - Forbes, Andrew

AU - Gattas, David

AU - Heritier, Stephane

AU - Kruger, Peter

AU - Peake, Sandra

AU - Presneill, Jeffrey

AU - Seppelt, Ian

AU - Trapani, Tony

AU - Young, Paul

AU - Cuthbertson, Brian

AU - Manoharan, Venika

AU - Aryal, Diptesh

AU - Dondrop, Arjen M.

AU - Hashmi, Madiha

AU - Jawad, Issrah

AU - Jayakumar, Devachandran

AU - Tolppa, Timo

AU - Singh, Vanessa

AU - Cecconi, Maurizio

AU - Ehrmann, Stephan

AU - Parker, Lorraine

AU - Pletz, Mathias

AU - Póvoa, Pedro

AU - Rohde, Gernot

AU - Alexander, Brian

AU - Basile, Kim

AU - Mayr, Florian

AU - Daneman, Nick

AU - McGloughlin, Steve

AU - Paterson, David

AU - Venkatesh, Bala

AU - Uyeki, Tim

AU - Baillie, Kenneth

AU - Cooper, Nichola

AU - Cremer, Olaf

AU - Galea, James

AU - Leavis, Helen

AU - Netea, Mihai

AU - Ogungbenro, Kayode

AU - Patawala, Asad

AU - Pettilä, Ville

AU - Rademaker, Emma

AU - Saxena, Manoj

AU - Sligl, Wendy

AU - Youngstein, Taryn

AU - Bihari, Shailesh

AU - Carrier, Marc

AU - Fergusson, Dean

AU - Hunt, Beverley

AU - Laffan, Mike

AU - Lother, Sylvain A.

AU - Middeldorp, Saskia

AU - McQuilten, Zoe

AU - Kumar, Anand

AU - Neal, Matthew

AU - Schutgens, Roger

AU - Stanworth, Simon

AU - Weissman, Alexandra

AU - Ferguson, Niall

AU - Hodgson, Carol

AU - Laffey, John

AU - Neto, Ary

AU - Baron, Rebecca

AU - Epelman, Slava

AU - Frankfurter, Claudia

AU - Gommans, Frank

AU - Udy, Andrew

AU - McCracken, Phoebe

AU - Young, Meredith

AU - Board, Jasmin

AU - Martin, Emma

AU - El-Khawas, Khaled

AU - Richardson, Angus

AU - Hill, Dianne

AU - Commons, Robert

AU - Abdelkharim, Hussam

AU - Knott, Cameron

AU - Smith, Julie

AU - Boschert, Catherine

AU - Affleck, Julia

AU - Apte, Yogesh

AU - Subbanna, Umesh

AU - Bartholdy, Roland

AU - Frakking, Thuy

AU - Keat, Karuna

AU - Bhonagiri, Deepak

AU - Sanghavi, Ritesh

AU - Nema, Jodie

AU - Ford, Megan

AU - Parikh, Harshel G.

AU - Avard, Bronwyn

AU - Nourse, Mary

AU - Cheung, Winston

AU - Wong, Helen

AU - Shah, Asim

AU - Wagh, Atul

AU - Simpson, Joanna

AU - Duke, Graeme

AU - Chan, Peter

AU - Carter, Brittney

AU - Hunter, Stephanie

AU - Laver, Russell D.

AU - Shrestha, Tapaswi

AU - Jin, Xia

AU - Regli, Adrian

AU - Pellicano, Susan

AU - Palermo, Annamaria

AU - Eroglu, Ege

AU - French, Craig

AU - Bates, Samantha

AU - Towns, Miriam

AU - Yang, Yang

AU - McGain, Forbes

AU - McCullough, James

AU - Tallott, Mandy

AU - Kumar, Nikhil

AU - Panwar, Rakshit

AU - Brinkerhoff, Gail

AU - Koppen, Cassandra

AU - Cazzola, Federica

AU - Brain, Matthew

AU - Mineall, Sarah

AU - Fischer, Roy

AU - Biradar, Vishwanath

AU - Soar, Natalie

AU - White, Hayden

AU - Estensen, Kristine

AU - Morrison, Lynette

AU - Sutton, Joanne

AU - Cooper, Melanie

AU - Shehabi, Yahya

AU - Al-Bassam, Wisam

AU - Hulley, Amanda

AU - Kadam, Umesh

AU - Sathianathan, Kushaharan

AU - Whitehead, Christina

AU - Lowrey, Julie

AU - Gresham, Rebecca

AU - Masters, Kristy

AU - Walsham, James

AU - Meyer, Jason

AU - Harward, Meg

AU - Venz, Ellen

AU - Brady, Kara

AU - Vale, Cassandra

AU - Shekar, Kiran

AU - Lavana, Jayshree

AU - Parmar, Dinesh

AU - Williams, Patricia

AU - Kurenda, Catherine

AU - Miles, Helen

AU - Attokaran, Antony

AU - Gluck, Samuel

AU - O’Connor, Stephanie

AU - Chapman, Marianne

AU - Glasby, Kathleen

AU - Smyth, Kirsty

AU - Phillips, Margaret

AU - Barge, Deborah

AU - Byrne, Kathleen

AU - Driscoll, Alana

AU - Fortune, Louise

AU - Janin, Pierre

AU - Yarad, Elizabeth

AU - Bass, Frances

AU - Anstey, Matthew

AU - Roberts, David

AU - Smith, Judith

AU - Johnson, Paul

AU - Ward, Kathryn

AU - Thomas, Emma

AU - Clark, Richard

AU - Stewart, Richard

AU - Davidson, Neil

AU - Hope, David

AU - Hamilton, David Oliver

AU - White, Ian

AU - Johnson, David

AU - Smith, Simon

AU - Anderson, Thomas

AU - Thomas, Amy

PY - 2021/8

Y1 - 2021/8

N2 - Purpose: To study the efficacy of lopinavir-ritonavir and hydroxychloroquine in critically ill patients with coronavirus disease 2019 (COVID-19). Methods: Critically ill adults with COVID-19 were randomized to receive lopinavir-ritonavir, hydroxychloroquine, combination therapy of lopinavir-ritonavir and hydroxychloroquine or no antiviral therapy (control). The primary endpoint was an ordinal scale of organ support-free days. Analyses used a Bayesian cumulative logistic model and expressed treatment effects as an adjusted odds ratio (OR) where an OR > 1 is favorable. Results: We randomized 694 patients to receive lopinavir-ritonavir (n = 255), hydroxychloroquine (n = 50), combination therapy (n = 27) or control (n = 362). The median organ support-free days among patients in lopinavir-ritonavir, hydroxychloroquine, and combination therapy groups was 4 (– 1 to 15), 0 (– 1 to 9) and—1 (– 1 to 7), respectively, compared to 6 (– 1 to 16) in the control group with in-hospital mortality of 88/249 (35%), 17/49 (35%), 13/26 (50%), respectively, compared to 106/353 (30%) in the control group. The three interventions decreased organ support-free days compared to control (OR [95% credible interval]: 0.73 [0.55, 0.99], 0.57 [0.35, 0.83] 0.41 [0.24, 0.72]), yielding posterior probabilities that reached the threshold futility (≥ 99.0%), and high probabilities of harm (98.0%, 99.9% and > 99.9%, respectively). The three interventions reduced hospital survival compared with control (OR [95% CrI]: 0.65 [0.45, 0.95], 0.56 [0.30, 0.89], and 0.36 [0.17, 0.73]), yielding high probabilities of harm (98.5% and 99.4% and 99.8%, respectively). Conclusion: Among critically ill patients with COVID-19, lopinavir-ritonavir, hydroxychloroquine, or combination therapy worsened outcomes compared to no antiviral therapy.

AB - Purpose: To study the efficacy of lopinavir-ritonavir and hydroxychloroquine in critically ill patients with coronavirus disease 2019 (COVID-19). Methods: Critically ill adults with COVID-19 were randomized to receive lopinavir-ritonavir, hydroxychloroquine, combination therapy of lopinavir-ritonavir and hydroxychloroquine or no antiviral therapy (control). The primary endpoint was an ordinal scale of organ support-free days. Analyses used a Bayesian cumulative logistic model and expressed treatment effects as an adjusted odds ratio (OR) where an OR > 1 is favorable. Results: We randomized 694 patients to receive lopinavir-ritonavir (n = 255), hydroxychloroquine (n = 50), combination therapy (n = 27) or control (n = 362). The median organ support-free days among patients in lopinavir-ritonavir, hydroxychloroquine, and combination therapy groups was 4 (– 1 to 15), 0 (– 1 to 9) and—1 (– 1 to 7), respectively, compared to 6 (– 1 to 16) in the control group with in-hospital mortality of 88/249 (35%), 17/49 (35%), 13/26 (50%), respectively, compared to 106/353 (30%) in the control group. The three interventions decreased organ support-free days compared to control (OR [95% credible interval]: 0.73 [0.55, 0.99], 0.57 [0.35, 0.83] 0.41 [0.24, 0.72]), yielding posterior probabilities that reached the threshold futility (≥ 99.0%), and high probabilities of harm (98.0%, 99.9% and > 99.9%, respectively). The three interventions reduced hospital survival compared with control (OR [95% CrI]: 0.65 [0.45, 0.95], 0.56 [0.30, 0.89], and 0.36 [0.17, 0.73]), yielding high probabilities of harm (98.5% and 99.4% and 99.8%, respectively). Conclusion: Among critically ill patients with COVID-19, lopinavir-ritonavir, hydroxychloroquine, or combination therapy worsened outcomes compared to no antiviral therapy.

KW - Adaptive platform trial

KW - COVID-19

KW - Hydroxychloroquine

KW - Intensive care

KW - Lopinavir-ritonavir

KW - Pandemic

KW - Pneumonia

UR - http://www.scopus.com/inward/record.url?scp=85112262081&partnerID=8YFLogxK

UR - http://purl.org/au-research/grants/NHMRC/1101719

UR - http://purl.org/au-research/grants/NHMRC/1116530

U2 - 10.1007/s00134-021-06448-5

DO - 10.1007/s00134-021-06448-5

M3 - Article

C2 - 34251506

AN - SCOPUS:85112262081

SN - 0342-4642

VL - 47

SP - 867

EP - 886

JO - Intensive Care Medicine

JF - Intensive Care Medicine

IS - 8

ER -

Lopinavir-ritonavir and hydroxychloroquine for critically ill patients with COVID-19: REMAP-CAP randomized controlled trial

Abstract

Keywords

UN SDGs

Access to Document

Other files and links

Fingerprint

Cite this