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

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

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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 languageEnglish
Pages (from-to)867-886
Number of pages20
JournalIntensive Care Medicine
Issue number8
Publication statusPublished - Aug 2021


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

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