Lopinavir-ritonavir and hydroxychloroquine for critically ill patients with COVID-19: REMAP-CAP randomized controlled trial: 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 J. 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 R. 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; Olly Hamilton

doi:10.1007/s00134-021-06448-5

Lopinavir-ritonavir and hydroxychloroquine for critically ill patients with COVID-19: REMAP-CAP randomized controlled trial: 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 J. 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 R. 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, Olly Hamilton

Liverpool School of Tropical Medicine

King Saud bin Abdulaziz University for Health Sciences
Imperial College London
Imperial College Healthcare NHS Trust
Utrecht University
University College Dublin
Monash University
Alfred Health
University of British Columbia
Hôpital Raymond Poincaré
Université Paris-Saclay
ANR-18-RHUS60004
University of Oxford
Medical Research Institute of New Zealand
Berry Consultants
University of Toronto
University of Bristol
University Hospitals Bristol and Weston NHS Foundation Trust
Friedrich Schiller University Jena
Global Coalition for Adaptive Research
Academic Medical Center
Auckland District Health Board
NHS Blood and Transplant
Canadian Critical Care Trials Group
University of Pittsburgh
University of Antwerp
National Intensive Care Surveillance-Mahidol Oxford Research Unit
University College Hospital
Université de Sherbrooke
Centre Hospitalier Universitaire de Sherbrooke
Peter Munk Cardiac Centre
University of California at Los Angeles
Fiona Stanley Hospital
St John of God Health Care
University of Western Australia
Queen's University Belfast
Royal Victoria Hospital Belfast
Middlemore Hospital
Intensive Care National Audit and Research Centre
The University of Auckland

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

78 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 - 1 Aug 2021

Keywords

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

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10.1007/s00134-021-06448-5

Cite this

Arabi, Y. M., Gordon, A. C., Derde, L. P. G., Nichol, A. D., Murthy, S., Beidh, F. A., 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., ... Hamilton, O. (2021). Lopinavir-ritonavir and hydroxychloroquine for critically ill patients with COVID-19: REMAP-CAP randomized controlled trial: REMAP-CAP randomized controlled trial. Intensive Care Medicine, 47(8), 867-886. https://doi.org/10.1007/s00134-021-06448-5

@article{12080fcb3eb34f249305580ed7e68cc6,

title = "Lopinavir-ritonavir and hydroxychloroquine for critically ill patients with COVID-19: REMAP-CAP randomized controlled trial: 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 Beidh, \{Farah Al\} 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 Duffy, \{Eamon J.\} 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 Lawler, \{Patrick R.\} 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 Olly Hamilton",

year = "2021",

month = aug,

day = "1",

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

language = "English",

volume = "47",

pages = "867--886",

journal = "Intensive Care Medicine",

issn = "0342-4642",

publisher = "Springer Science and Business Media Deutschland GmbH",

number = "8",

}

Arabi, YM, Gordon, AC, Derde, LPG, Nichol, AD, Murthy, S, Beidh, FA, 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, EJ, 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, PR, 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 & Hamilton, O 2021, 'Lopinavir-ritonavir and hydroxychloroquine for critically ill patients with COVID-19: REMAP-CAP randomized controlled trial: 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: REMAP-CAP randomized controlled trial: 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 - Beidh, Farah Al

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 J.

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 R.

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 - Hamilton, Olly

PY - 2021/8/1

Y1 - 2021/8/1

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

U2 - 10.1007/s00134-021-06448-5

DO - 10.1007/s00134-021-06448-5

M3 - Article

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: REMAP-CAP randomized controlled trial

Abstract

Keywords

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