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

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

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. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s00134-021-06448-5.