tetano
Editor, Senior Moderator
Intensive Care Med
. 2021 Jul 12.
doi: 10.1007/s00134-021-06448-5. Online ahead of print.
Lopinavir-ritonavir and hydroxychloroquine for critically ill patients with COVID-19: REMAP-CAP randomized controlled trial
Yaseen M Arabi[SUP] 1 2 3 [/SUP], Anthony C Gordon[SUP] 4 5 [/SUP], Lennie P G Derde[SUP] 6 7 [/SUP], Alistair D Nichol[SUP] 8 9 10 [/SUP], Srinivas Murthy[SUP] 11 [/SUP], Farah Al Beidh[SUP] 4 [/SUP], Djillali Annane[SUP] 12 13 14 [/SUP], Lolowa Al Swaidan[SUP] 15 16 17 [/SUP], Abi Beane[SUP] 18 [/SUP], Richard Beasley[SUP] 19 [/SUP], Lindsay R Berry[SUP] 20 [/SUP], Zahra Bhimani[SUP] 21 [/SUP], Marc J M Bonten[SUP] 7 22 [/SUP], Charlotte A Bradbury[SUP] 23 24 [/SUP], Frank M Brunkhorst[SUP] 25 [/SUP], Meredith Buxton[SUP] 26 [/SUP], Adrian Buzgau[SUP] 27 [/SUP], Allen Cheng[SUP] 27 28 [/SUP], Menno De Jong[SUP] 29 [/SUP], Michelle A Detry[SUP] 20 [/SUP], Eamon J Duffy[SUP] 30 [/SUP], Lise J Estcourt[SUP] 31 32 [/SUP], Mark Fitzgerald[SUP] 20 [/SUP], Rob Fowler[SUP] 33 34 35 [/SUP], Timothy D Girard[SUP] 36 37 [/SUP], Ewan C Goligher[SUP] 38 [/SUP], Herman Goossens[SUP] 39 [/SUP], Rashan Haniffa[SUP] 40 41 42 [/SUP], Alisa M Higgins[SUP] 9 [/SUP], Thomas E Hills[SUP] 19 43 [/SUP], Christopher M Horvat[SUP] 36 37 44 [/SUP], David T Huang[SUP] 36 37 [/SUP], Andrew J King[SUP] 37 [/SUP], Francois Lamontagne[SUP] 45 46 [/SUP], Patrick R Lawler[SUP] 33 38 47 [/SUP], Roger Lewis[SUP] 20 48 [/SUP], Kelsey Linstrum[SUP] 36 37 [/SUP], Edward Litton[SUP] 49 50 51 [/SUP], Elizabeth Lorenzi[SUP] 20 [/SUP], Salim Malakouti[SUP] 52 [/SUP], Daniel F McAuley[SUP] 53 54 [/SUP], Anna McGlothlin[SUP] 20 [/SUP], Shay Mcguinness[SUP] 19 27 55 [/SUP], Bryan J McVerry[SUP] 36 37 [/SUP], Stephanie K Montgomery[SUP] 36 37 [/SUP], Susan C Morpeth[SUP] 56 [/SUP], Paul R Mouncey[SUP] 57 [/SUP], Katrina Orr[SUP] 58 [/SUP], Rachael Parke[SUP] 19 55 59 [/SUP], Jane C Parker[SUP] 9 [/SUP], Asad E Patanwala[SUP] 60 61 [/SUP], Kathryn M Rowan[SUP] 62 [/SUP], Marlene S Santos[SUP] 21 [/SUP], Christina T Saunders[SUP] 20 [/SUP], Christopher W Seymour[SUP] 36 37 [/SUP], Manu Shankar-Hari[SUP] 63 64 [/SUP], Steven Y C Tong[SUP] 65 66 [/SUP], Alexis F Turgeon[SUP] 67 68 [/SUP], Anne M Turner[SUP] 19 [/SUP], Frank Leo Van de Veerdonk[SUP] 69 [/SUP], Ryan Zarychanski[SUP] 70 [/SUP], Cameron Green[SUP] 9 [/SUP], Scott Berry[SUP] 20 [/SUP], John C Marshall[SUP] 21 71 [/SUP], Colin McArthur[SUP] 72 [/SUP], Derek C Angus[SUP] 36 37 [/SUP], Steven A Webb[SUP] 9 50 [/SUP], REMAP-CAP Investigators
Collaborators, Affiliations
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.
Trial registration: ClinicalTrials.gov NCT02735707.
Keywords: Adaptive platform trial; COVID-19; Hydroxychloroquine; Intensive care; Lopinavir-ritonavir; Pandemic; Pneumonia.
. 2021 Jul 12.
doi: 10.1007/s00134-021-06448-5. Online ahead of print.
Lopinavir-ritonavir and hydroxychloroquine for critically ill patients with COVID-19: REMAP-CAP randomized controlled trial
Yaseen M Arabi[SUP] 1 2 3 [/SUP], Anthony C Gordon[SUP] 4 5 [/SUP], Lennie P G Derde[SUP] 6 7 [/SUP], Alistair D Nichol[SUP] 8 9 10 [/SUP], Srinivas Murthy[SUP] 11 [/SUP], Farah Al Beidh[SUP] 4 [/SUP], Djillali Annane[SUP] 12 13 14 [/SUP], Lolowa Al Swaidan[SUP] 15 16 17 [/SUP], Abi Beane[SUP] 18 [/SUP], Richard Beasley[SUP] 19 [/SUP], Lindsay R Berry[SUP] 20 [/SUP], Zahra Bhimani[SUP] 21 [/SUP], Marc J M Bonten[SUP] 7 22 [/SUP], Charlotte A Bradbury[SUP] 23 24 [/SUP], Frank M Brunkhorst[SUP] 25 [/SUP], Meredith Buxton[SUP] 26 [/SUP], Adrian Buzgau[SUP] 27 [/SUP], Allen Cheng[SUP] 27 28 [/SUP], Menno De Jong[SUP] 29 [/SUP], Michelle A Detry[SUP] 20 [/SUP], Eamon J Duffy[SUP] 30 [/SUP], Lise J Estcourt[SUP] 31 32 [/SUP], Mark Fitzgerald[SUP] 20 [/SUP], Rob Fowler[SUP] 33 34 35 [/SUP], Timothy D Girard[SUP] 36 37 [/SUP], Ewan C Goligher[SUP] 38 [/SUP], Herman Goossens[SUP] 39 [/SUP], Rashan Haniffa[SUP] 40 41 42 [/SUP], Alisa M Higgins[SUP] 9 [/SUP], Thomas E Hills[SUP] 19 43 [/SUP], Christopher M Horvat[SUP] 36 37 44 [/SUP], David T Huang[SUP] 36 37 [/SUP], Andrew J King[SUP] 37 [/SUP], Francois Lamontagne[SUP] 45 46 [/SUP], Patrick R Lawler[SUP] 33 38 47 [/SUP], Roger Lewis[SUP] 20 48 [/SUP], Kelsey Linstrum[SUP] 36 37 [/SUP], Edward Litton[SUP] 49 50 51 [/SUP], Elizabeth Lorenzi[SUP] 20 [/SUP], Salim Malakouti[SUP] 52 [/SUP], Daniel F McAuley[SUP] 53 54 [/SUP], Anna McGlothlin[SUP] 20 [/SUP], Shay Mcguinness[SUP] 19 27 55 [/SUP], Bryan J McVerry[SUP] 36 37 [/SUP], Stephanie K Montgomery[SUP] 36 37 [/SUP], Susan C Morpeth[SUP] 56 [/SUP], Paul R Mouncey[SUP] 57 [/SUP], Katrina Orr[SUP] 58 [/SUP], Rachael Parke[SUP] 19 55 59 [/SUP], Jane C Parker[SUP] 9 [/SUP], Asad E Patanwala[SUP] 60 61 [/SUP], Kathryn M Rowan[SUP] 62 [/SUP], Marlene S Santos[SUP] 21 [/SUP], Christina T Saunders[SUP] 20 [/SUP], Christopher W Seymour[SUP] 36 37 [/SUP], Manu Shankar-Hari[SUP] 63 64 [/SUP], Steven Y C Tong[SUP] 65 66 [/SUP], Alexis F Turgeon[SUP] 67 68 [/SUP], Anne M Turner[SUP] 19 [/SUP], Frank Leo Van de Veerdonk[SUP] 69 [/SUP], Ryan Zarychanski[SUP] 70 [/SUP], Cameron Green[SUP] 9 [/SUP], Scott Berry[SUP] 20 [/SUP], John C Marshall[SUP] 21 71 [/SUP], Colin McArthur[SUP] 72 [/SUP], Derek C Angus[SUP] 36 37 [/SUP], Steven A Webb[SUP] 9 50 [/SUP], REMAP-CAP Investigators
Collaborators, Affiliations
- PMID: 34251506
- DOI: 10.1007/s00134-021-06448-5
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.
Trial registration: ClinicalTrials.gov NCT02735707.
Keywords: Adaptive platform trial; COVID-19; Hydroxychloroquine; Intensive care; Lopinavir-ritonavir; Pandemic; Pneumonia.