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.

• Authors: 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, 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, REMAP-CAP Investigators
• Journal: Intensive care medicine (Intensive Care Med) Vol. 47 Issue 8 Pg. 867-886 (Aug 2021) ISSN: 1432-1238 [Electronic] United States
• PMID: 34251506 (Publication Type: Journal Article, Randomized Controlled Trial)
• Copyright: © 2021. Springer-Verlag GmbH Germany, part of Springer Nature.

Chemical References

• Antiviral Agents
• Drug Combinations
• Lopinavir
• Hydroxychloroquine
• Ritonavir

Topics

• Adult
• Antiviral Agents (therapeutic use)
• Bayes Theorem
• Critical Illness
• Drug Combinations
• Humans
• Hydroxychloroquine (therapeutic use)
• Lopinavir (therapeutic use)
• Ritonavir (therapeutic use)
• SARS-CoV-2
• COVID-19 Drug Treatment