Lopinavir-ritonavir and hydroxychloroquine for critically ill patients with COVID-19: REMAP-CAP randomized controlled trial.
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., 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., REMAP-CAP Investigators None.
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.