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3. Long-term (180-Day) Outcomes in Critically Ill Patients With COVID-19 in the REMAP-CAP Randomized Clinical Trial.

Author

Higgins, A.M., Berry, L.R., Lorenzi, E., Murthy, S., McQuilten, Z., Mouncey, P.R., Al-Beidh, F., Annane, D., Arabi, Y.M., Beane, A., Bentum-Puijk, W. van, Bhimani, Z., Bonten, M.J.M., Bradbury, C.A., Brunkhorst, F.M., Burrell, A., Buzgau, A., Buxton, M., Charles, W.N., Cove, M., Detry, M.A., Estcourt, L.J., Fagbodun, E.O., Fitzgerald, M., Girard, T.D., Goligher, E.C., Goossens, H., Haniffa, R., Hills, T., Horvat, C.M., Huang, D.T., Ichihara, N., Lamontagne, F., Marshall, J.C., McAuley, D.F., McGlothlin, A., McGuinness, S.P., McVerry, B.J., Neal, M.D., Nichol, A.D., Parke, R.L., Parker, J.C., Parry-Billings, K., Peters, S.E.C., Reyes, L.F., Rowan, K.M., Saito, H., Santos, M.S., Saunders, C.T., Serpa-Neto, A., Seymour, C.W., Shankar-Hari, M., Stronach, L.M., Turgeon, A.F., Turner, A.M., Veerdonk, F.L. van de, Zarychanski, R., Green, C., Lewis, R.J., Angus, D.C., McArthur, C.J., Berry, S., Derde, L.P.G., Gordon, A.C., Webb, S.A., Lawler, P.R., Higgins, A.M., Berry, L.R., Lorenzi, E., Murthy, S., McQuilten, Z., Mouncey, P.R., Al-Beidh, F., Annane, D., Arabi, Y.M., Beane, A., Bentum-Puijk, W. van, Bhimani, Z., Bonten, M.J.M., Bradbury, C.A., Brunkhorst, F.M., Burrell, A., Buzgau, A., Buxton, M., Charles, W.N., Cove, M., Detry, M.A., Estcourt, L.J., Fagbodun, E.O., Fitzgerald, M., Girard, T.D., Goligher, E.C., Goossens, H., Haniffa, R., Hills, T., Horvat, C.M., Huang, D.T., Ichihara, N., Lamontagne, F., Marshall, J.C., McAuley, D.F., McGlothlin, A., McGuinness, S.P., McVerry, B.J., Neal, M.D., Nichol, A.D., Parke, R.L., Parker, J.C., Parry-Billings, K., Peters, S.E.C., Reyes, L.F., Rowan, K.M., Saito, H., Santos, M.S., Saunders, C.T., Serpa-Neto, A., Seymour, C.W., Shankar-Hari, M., Stronach, L.M., Turgeon, A.F., Turner, A.M., Veerdonk, F.L. van de, Zarychanski, R., Green, C., Lewis, R.J., Angus, D.C., McArthur, C.J., Berry, S., Derde, L.P.G., Gordon, A.C., Webb, S.A., and Lawler, P.R.

Abstract

Item does not contain fulltext, IMPORTANCE: The longer-term effects of therapies for the treatment of critically ill patients with COVID-19 are unknown. OBJECTIVE: To determine the effect of multiple interventions for critically ill adults with COVID-19 on longer-term outcomes. DESIGN, SETTING, AND PARTICIPANTS: Prespecified secondary analysis of an ongoing adaptive platform trial (REMAP-CAP) testing interventions within multiple therapeutic domains in which 4869 critically ill adult patients with COVID-19 were enrolled between March 9, 2020, and June 22, 2021, from 197 sites in 14 countries. The final 180-day follow-up was completed on March 2, 2022. INTERVENTIONS: Patients were randomized to receive 1 or more interventions within 6 treatment domains: immune modulators (n = 2274), convalescent plasma (n = 2011), antiplatelet therapy (n = 1557), anticoagulation (n = 1033), antivirals (n = 726), and corticosteroids (n = 401). MAIN OUTCOMES AND MEASURES: The main outcome was survival through day 180, analyzed using a bayesian piecewise exponential model. A hazard ratio (HR) less than 1 represented improved survival (superiority), while an HR greater than 1 represented worsened survival (harm); futility was represented by a relative improvement less than 20% in outcome, shown by an HR greater than 0.83. RESULTS: Among 4869 randomized patients (mean age, 59.3 years; 1537 [32.1%] women), 4107 (84.3%) had known vital status and 2590 (63.1%) were alive at day 180. IL-6 receptor antagonists had a greater than 99.9% probability of improving 6-month survival (adjusted HR, 0.74 [95% credible interval {CrI}, 0.61-0.90]) and antiplatelet agents had a 95% probability of improving 6-month survival (adjusted HR, 0.85 [95% CrI, 0.71-1.03]) compared with the control, while the probability of trial-defined statistical futility (HR >0.83) was high for therapeutic anticoagulation (99.9%; HR, 1.13 [95% CrI, 0.93-1.42]), convalescent plasma (99.2%; HR, 0.99 [95% CrI, 0.86-1.14]), and lopinavir-ritonavir (96.6%; HR, 1.06

Published
2023

4. Effect of Angiotensin-Converting Enzyme Inhibitor and Angiotensin Receptor Blocker Initiation on Organ Support-Free Days in Patients Hospitalized With COVID-19: A Randomized Clinical Trial.

Author

Lawler, P.R., Derde, L.P.G., Veerdonk, F.L. van de, McVerry, B.J., Huang, D.T., Berry, L.R., Lorenzi, E., Kimmenade, R.R.J. van, Gommans, F., Vaduganathan, M., Leaf, D.E., Baron, R.M., Kim, E.Y., Frankfurter, C., Epelman, S., Kwan, Y., Grieve, R., O'Neill, S., Sadique, Z., Puskarich, M., Marshall, J.C., Higgins, A.M., Mouncey, P.R., Rowan, K.M., Al-Beidh, F., Annane, D., Arabi, Y.M., Au, C., Beane, A., Bentum-Puijk, W. van, Bonten, M.J.M., Bradbury, C.A., Brunkhorst, F.M., Burrell, A., Buzgau, A., Buxton, M., Cecconi, M., Cheng, A.C., Cove, M., Detry, M.A., Estcourt, L.J., Ezekowitz, J., Fitzgerald, M., Gattas, D., Godoy, L.C., Goossens, H., Haniffa, R., Harrison, D.A., Hills, T., Horvat, C.M., Ichihara, N., Lamontagne, F., Linstrum, K.M., McAuley, D.F., McGlothlin, A., McGuinness, S.P., McQuilten, Z., Murthy, S., Nichol, A.D., Owen, D.R.J., Parke, R.L., Parker, J.C., Pollock, K.M., Reyes, L.F., Saito, H., Santos, M.S., Saunders, C.T., Seymour, C.W., Shankar-Hari, M., Singh, V., Turgeon, A.F., Turner, A.M., Zarychanski, R., Green, C., Lewis, R.J., Angus, D.C., Berry, S., Gordon, A.C., McArthur, C.J., Webb, S.A., Lawler, P.R., Derde, L.P.G., Veerdonk, F.L. van de, McVerry, B.J., Huang, D.T., Berry, L.R., Lorenzi, E., Kimmenade, R.R.J. van, Gommans, F., Vaduganathan, M., Leaf, D.E., Baron, R.M., Kim, E.Y., Frankfurter, C., Epelman, S., Kwan, Y., Grieve, R., O'Neill, S., Sadique, Z., Puskarich, M., Marshall, J.C., Higgins, A.M., Mouncey, P.R., Rowan, K.M., Al-Beidh, F., Annane, D., Arabi, Y.M., Au, C., Beane, A., Bentum-Puijk, W. van, Bonten, M.J.M., Bradbury, C.A., Brunkhorst, F.M., Burrell, A., Buzgau, A., Buxton, M., Cecconi, M., Cheng, A.C., Cove, M., Detry, M.A., Estcourt, L.J., Ezekowitz, J., Fitzgerald, M., Gattas, D., Godoy, L.C., Goossens, H., Haniffa, R., Harrison, D.A., Hills, T., Horvat, C.M., Ichihara, N., Lamontagne, F., Linstrum, K.M., McAuley, D.F., McGlothlin, A., McGuinness, S.P., McQuilten, Z., Murthy, S., Nichol, A.D., Owen, D.R.J., Parke, R.L., Parker, J.C., Pollock, K.M., Reyes, L.F., Saito, H., Santos, M.S., Saunders, C.T., Seymour, C.W., Shankar-Hari, M., Singh, V., Turgeon, A.F., Turner, A.M., Zarychanski, R., Green, C., Lewis, R.J., Angus, D.C., Berry, S., Gordon, A.C., McArthur, C.J., and Webb, S.A.

Abstract

Item does not contain fulltext, IMPORTANCE: Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. OBJECTIVE: To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS: In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non-critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS: Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES: The primary outcome was organ support-free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS: On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support-free days among critically ill patients was 10 (-1 to 16) in the ACE inhibitor group (n = 231), 8 (-1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support-free days compared with control were 94.9% and 95.4%, respectively. Hospital surv

Published
2023

6. Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support–free days in patients hospitalized with COVID-19

Author

Writing Committee for the REMAP-CAP Investigators, Lawler, PR, Derde, LPG, Van de Veerdonk, FL, McVerry, BJ, Huang, DT, Berry, LR, Lorenzi, E, Van Kimmenade, R, Gommans, F, Vaduganathan, M, Leaf, DE, Baron, RM, Kim, EY, Frankfurter, C, Epelman, S, Kwan, Y, Grieve, R, O'Neill, S, Sadique, Z, Puskarich, M, Marshall, JC, Higgins, AM, Mouncey, PR, Rowan, KM, Al-Beidh, F, Annane, D, Arabi, YM, Au, C, Beane, A, Van Bentum-Puijk, W, Bonten, MJM, Bradbury, CA, Brunkhorst, FM, Burrell, A, Buzgau, A, Buxton, M, Cecconi, M, Cheng, AC, Cove, M, Detry, MA, Estcourt, LJ, Ezekowitz, J, Fitzgerald, M, Gattas, D, Godoy, LC, Goossens, H, Haniffa, R, Harrison, DA, Hills, T, Horvat, CM, Ichihara, N, Lamontagne, F, Linstrum, KM, McAuley, DF, McGlothlin, A, McGuinness, SP, McQuilten, Z, Murthy, S, Nichol, AD, Owen, DRJ, Parke, RL, Parker, JC, Pollock, KM, Reyes, LF, Saito, H, Santos, MS, Saunders, CT, Seymour, CW, Shankar-Hari, M, Singh, V, Turgeon, AF, Turner, AM, Zarychanski, R, Green, C, Lewis, RJ, Angus, DC, Berry, S, Gordon, AC, McArthur, CJ, and Webb, SA

Abstract

IMPORTANCE: Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. OBJECTIVE: To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS: In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non-critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS: Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES: The primary outcome was organ support-free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS: On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support-free days among critically ill patients was 10 (-1 to 16) in the ACE inhibitor group (n = 231), 8 (-1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support-free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE: In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02735707.

Published
2023

7. Heterogeneous treatment effects of therapeutic-dose heparin in patients hospitalized for COVID-19

Author

Goligher, EC, Lawler, PR, Jensen, TP, Talisa, V, Berry, LR, Lorenzi, E, McVerry, BJ, Chang, C-CH, Leifer, E, Bradbury, C, Berger, J, Hunt, BJ, Castellucci, LA, Kornblith, LZ, Gordon, AC, McArthur, C, Webb, S, Hochman, J, Neal, MD, Zarychanski, R, Berry, S, Angus, DC, Aday, A, Ahuja, T, Al-Beidh, F, Annane, D, Arabi, YM, Aryal, D, Baumann Kreuziger, L, Beane, A, Berger, JS, Berry, SM, Bhimani, Z, Bihari, S, Billett, HH, Bond, L, Bonten, M, Bradbury, CA, Brooks, MM, Brunkhorst, F, Buxton, M, Buzgau, A, Carrier, M, Castelucci, LA, Chekuri, S, Chen, J-T, Cheng, AC, Chkhikvadze, T, Coiffard, B, Contreras, A, Costantini, TW, Cushman, M, De Brouwer, S, Derde, LPG, Detry, MA, Duggal, A, Džavík, V, Effron, MB, Eng, HF, Escobedo, J, Estcourt, LJ, Everett, BM, Farkough, ME, Fergusson, DA, Fitzgerald, M, Fowler, RA, Froess, JD, Fu, Z, Galanaud, J-P, Galen, BT, Gandotra, S, Girard, TD, Godoy, LD, Gong, MN, Goodman, AL, Goossens, H, Green, C, Greenstein, YY, Gross, PL, Guerrero, RM, Hamburg, N, Haniffa, R, Hanna, G, Hanna, N, Hedge, SM, Hendrickson, CM, Higgins, AM, Hindenburg, AA, Hite, RD, Hochman, JS, Hope, AA, Horowitz, JM, Horvat, CM, Houston, BL, Huang, DT, Hudock, K, Husain, M, Hyzy, RC, Iyer, V, Jacobson, JR, Jayakumar, D, Kahn, SR, Keller, NM, Khan, A, Kim, Y, Kim, KS, Kindzelski, A, King, AJ, Kirwan, B-A, Knudson, MM, Kornblith, AE, Krishnan, V, Kumar, A, Kutcher, ME, Laffan, MA, Lamontagne, F, Le Gal, G, Leeper, CM, Leifer, ES, Lewis, RJ, Lim, G, Lima, FG, Linstrum, K, Litton, E, Lopez-Sendon, J, Lopez-Sendon Moreno, JL, Lother, SA, Madrona, SG, Malhotra, S, Marcos Martin, M, Marshall, JC, Marten, N, Martinez, AS, Martinez, M, Mateos Garcia, E, Matthay, MA, Mavromichalis, S, McArthur, CJ, McAuley, DF, McDonald, EG, McGlothlin, A, McGuinness, SP, McQuilten, ZK, Middeldorp, S, Montgomery, SK, Moore, SC, Mouncey, PR, Murthy, S, Nair, GB, Nair, R, Nichol, AD, Nicolau, JC, Nunez-Garcia, B, Pandey, A, Park, JJ, Park, PK, Parke, RL, Parker, JC, Parnia, S, Paul, JD, Pompilio, M, Prekker, M, Quigley, JG, Reynolds, HR, Rosenson, RS, Rost, NS, Rowan, K, Santos, MO, Santos, FO, Santos, M, Satterwhite, L, Saunders, CT, Schreiber, J, Schutgens, REG, Seymour, CW, Shankar Hari, M, Sheehan, JP, Siegal, DM, Silva Jr., DG, Singhal, AB, Slutsky, AS, Solvason, D, Stanworth, SJ, Tritschler, T, Turgeon, AF, Turner, AM, Van Bentum-Puijk, W, Van de Veerdonk, FL, Van Diepen, S, Vazquez Grande, G, Wahid, L, Wareham, V, Webb, SA, Wells, B, Widmer, RJ, Wilson, JG, Yuriditsky, E, Zampieri, F, and Zhong, Y

Abstract

Importance Randomized clinical trials (RCTs) of therapeutic-dose heparin in patients hospitalized with COVID-19 produced conflicting results, possibly due to heterogeneity of treatment effect (HTE) across individuals. Better understanding of HTE could facilitate individualized clinical decision-making. Objective To evaluate HTE of therapeutic-dose heparin for patients hospitalized for COVID-19 and to compare approaches to assessing HTE. Design, Setting, and Participants Exploratory analysis of a multiplatform adaptive RCT of therapeutic-dose heparin vs usual care pharmacologic thromboprophylaxis in 3320 patients hospitalized for COVID-19 enrolled in North America, South America, Europe, Asia, and Australia between April 2020 and January 2021. Heterogeneity of treatment effect was assessed 3 ways: using (1) conventional subgroup analyses of baseline characteristics, (2) a multivariable outcome prediction model (risk-based approach), and (3) a multivariable causal forest model (effect-based approach). Analyses primarily used bayesian statistics, consistent with the original trial. Exposures Participants were randomized to therapeutic-dose heparin or usual care pharmacologic thromboprophylaxis. Main Outcomes and Measures Organ support–free days, assigning a value of −1 to those who died in the hospital and the number of days free of cardiovascular or respiratory organ support up to day 21 for those who survived to hospital discharge; and hospital survival. Results Baseline demographic characteristics were similar between patients randomized to therapeutic-dose heparin or usual care (median age, 60 years; 38% female; 32% known non-White race; 45% Hispanic). In the overall multiplatform RCT population, therapeutic-dose heparin was not associated with an increase in organ support–free days (median value for the posterior distribution of the OR, 1.05; 95% credible interval, 0.91-1.22). In conventional subgroup analyses, the effect of therapeutic-dose heparin on organ support–free days differed between patients requiring organ support at baseline or not (median OR, 0.85 vs 1.30; posterior probability of difference in OR, 99.8%), between females and males (median OR, 0.87 vs 1.16; posterior probability of difference in OR, 96.4%), and between patients with lower body mass index (BMI 90% for all comparisons). In risk-based analysis, patients at lowest risk of poor outcome had the highest propensity for benefit from heparin (lowest risk decile: posterior probability of OR >1, 92%) while those at highest risk were most likely to be harmed (highest risk decile: posterior probability of OR

Published
2023

9. La recherche biomédicale en médecine des forces

Author

D’AUBIGNY, H., primary, LABROUSSE, T., additional, MARTINEZ-LORENZI, E., additional, ANDRÉ, N., additional, BARTHES, N., additional, LE FLEM, F-X., additional, ENSARGUEIX, A-N., additional, BALMER, D., additional, OKRUTNY, M., additional, THOMAS, G., additional, BELLEOUD, D., additional, SIMON, F., additional, BRIOLANT, S., additional, and DE LAVAL, F., additional

Published
2017
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10. Effect of Antiplatelet Therapy on Survival and Organ Support-Free Days in Critically Ill Patients With COVID-19: A Randomized Clinical Trial.

Author

Bradbury C.A., Lawler P.R., Stanworth S.J., McVerry B.J., McQuilten Z., Higgins A.M., Mouncey P.R., Al-Beidh F., Rowan K.M., Berry L.R., Lorenzi E., Zarychanski R., Arabi Y.M., Annane D., Beane A., Van Bentum-Puijk W., Bhimani Z., Bihari S., Bonten M.J.M., Brunkhorst F.M., Buzgau A., Buxton M., Carrier M., Cheng A.C., Cove M., Detry M.A., Estcourt L.J., Fitzgerald M., Girard T.D., Goligher E.C., Goossens H., Haniffa R., Hills T., Huang D.T., Horvat C.M., Hunt B.J., Ichihara N., Lamontagne F., Leavis H.L., Linstrum K.M., Litton E., Marshall J.C., McAuley D.F., McGlothlin A., McGuinness S.P., Middeldorp S., Montgomery S.K., Morpeth S.C., Murthy S., Neal M.D., Nichol A.D., Parke R.L., Parker J.C., Reyes L., Saito H., Santos M.S., Saunders C.T., Serpa-Neto A., Seymour C.W., Shankar-Hari M., Singh V., Tolppa T., Turgeon A.F., Turner A.M., Van De Veerdonk F.L., Green C., Lewis R.J., Angus D.C., McArthur C.J., Berry S., Derde L.P.G., Webb S.A., Gordon A.C., Bradbury C.A., Lawler P.R., Stanworth S.J., McVerry B.J., McQuilten Z., Higgins A.M., Mouncey P.R., Al-Beidh F., Rowan K.M., Berry L.R., Lorenzi E., Zarychanski R., Arabi Y.M., Annane D., Beane A., Van Bentum-Puijk W., Bhimani Z., Bihari S., Bonten M.J.M., Brunkhorst F.M., Buzgau A., Buxton M., Carrier M., Cheng A.C., Cove M., Detry M.A., Estcourt L.J., Fitzgerald M., Girard T.D., Goligher E.C., Goossens H., Haniffa R., Hills T., Huang D.T., Horvat C.M., Hunt B.J., Ichihara N., Lamontagne F., Leavis H.L., Linstrum K.M., Litton E., Marshall J.C., McAuley D.F., McGlothlin A., McGuinness S.P., Middeldorp S., Montgomery S.K., Morpeth S.C., Murthy S., Neal M.D., Nichol A.D., Parke R.L., Parker J.C., Reyes L., Saito H., Santos M.S., Saunders C.T., Serpa-Neto A., Seymour C.W., Shankar-Hari M., Singh V., Tolppa T., Turgeon A.F., Turner A.M., Van De Veerdonk F.L., Green C., Lewis R.J., Angus D.C., McArthur C.J., Berry S., Derde L.P.G., Webb S.A., and Gordon A.C.

Abstract

Importance: The efficacy of antiplatelet therapy in critically ill patients with COVID-19 is uncertain. Objective(s): To determine whether antiplatelet therapy improves outcomes for critically ill adults with COVID-19. Design, Setting, and Participant(s): In an ongoing adaptive platform trial (REMAP-CAP) testing multiple interventions within multiple therapeutic domains, 1557 critically ill adult patients with COVID-19 were enrolled between October 30, 2020, and June 23, 2021, from 105 sites in 8 countries and followed up for 90 days (final follow-up date: July 26, 2021). Intervention(s): Patients were randomized to receive either open-label aspirin (n = 565), a P2Y12 inhibitor (n = 455), or no antiplatelet therapy (control; n = 529). Interventions were continued in the hospital for a maximum of 14 days and were in addition to anticoagulation thromboprophylaxis. Main Outcomes and Measures: The primary end point was organ support-free days (days alive and free of intensive care unit-based respiratory or cardiovascular organ support) within 21 days, ranging from-1 for any death in hospital (censored at 90 days) to 22 for survivors with no organ support. There were 13 secondary outcomes, including survival to discharge and major bleeding to 14 days. The primary analysis was a bayesian cumulative logistic model. An odds ratio (OR) greater than 1 represented improved survival, more organ support-free days, or both. Efficacy was defined as greater than 99% posterior probability of an OR greater than 1. Futility was defined as greater than 95% posterior probability of an OR less than 1.2 vs control. Intervention equivalence was defined as greater than 90% probability that the OR (compared with each other) was between 1/1.2 and 1.2 for 2 noncontrol interventions. Result(s): The aspirin and P2Y12 inhibitor groups met the predefined criteria for equivalence at an adaptive analysis and were statistically pooled for further analysis. Enrollment was discontinued after the prespe

Published
2022

11. Effect of Antiplatelet Therapy on Survival and Organ Support-Free Days in Critically Ill Patients With COVID-19: A Randomized Clinical Trial

Author

Bradbury, C.A., Lawler, P.R., Stanworth, S.J., McVerry, B.J., McQuilten, Z., Higgins, A.M., Mouncey, P.R., Al-Beidh, F., Rowan, K.M., Berry, L.R., Lorenzi, E., Zarychanski, R., Arabi, Y.M., Annane, D., Beane, A., Bentum-Puijk, W. van, Bhimani, Z., Bihari, S., Bonten, M.J.M., Brunkhorst, F.M., Buzgau, A., Buxton, M., Carrier, M., Cheng, A.C., Cove, M., Detry, M.A., Estcourt, L.J., Fitzgerald, M., Girard, T.D., Goligher, E.C., Goossens, H., Haniffa, R., Hills, T., Huang, D.T., Horvat, C.M., Hunt, B.J., Ichihara, N., Lamontagne, F., Leavis, H.L., Linstrum, K.M., Litton, E., Marshall, J.C., McAuley, D.F., McGlothlin, A., McGuinness, S.P., Middeldorp, S., Montgomery, S.K., Morpeth, S.C., Murthy, S., Neal, M.D., Nichol, A.D., Parke, R.L., Parker, J.C., Reyes, L.F., Saito, H., Santos, M.S., Saunders, C.T., Serpa-Neto, A., Seymour, C.W., Shankar-Hari, M., Singh, V., Tolppa, T., Turgeon, A.F., Turner, A.M., Veerdonk, F.L. van de, Green, C., Lewis, R.J., Angus, D.C., McArthur, C.J., Berry, S., Derde, L.P.G., Pickkers, P., Schouten, J.A., Webb, S.A., Gordon, A.C., Bradbury, C.A., Lawler, P.R., Stanworth, S.J., McVerry, B.J., McQuilten, Z., Higgins, A.M., Mouncey, P.R., Al-Beidh, F., Rowan, K.M., Berry, L.R., Lorenzi, E., Zarychanski, R., Arabi, Y.M., Annane, D., Beane, A., Bentum-Puijk, W. van, Bhimani, Z., Bihari, S., Bonten, M.J.M., Brunkhorst, F.M., Buzgau, A., Buxton, M., Carrier, M., Cheng, A.C., Cove, M., Detry, M.A., Estcourt, L.J., Fitzgerald, M., Girard, T.D., Goligher, E.C., Goossens, H., Haniffa, R., Hills, T., Huang, D.T., Horvat, C.M., Hunt, B.J., Ichihara, N., Lamontagne, F., Leavis, H.L., Linstrum, K.M., Litton, E., Marshall, J.C., McAuley, D.F., McGlothlin, A., McGuinness, S.P., Middeldorp, S., Montgomery, S.K., Morpeth, S.C., Murthy, S., Neal, M.D., Nichol, A.D., Parke, R.L., Parker, J.C., Reyes, L.F., Saito, H., Santos, M.S., Saunders, C.T., Serpa-Neto, A., Seymour, C.W., Shankar-Hari, M., Singh, V., Tolppa, T., Turgeon, A.F., Turner, A.M., Veerdonk, F.L. van de, Green, C., Lewis, R.J., Angus, D.C., McArthur, C.J., Berry, S., Derde, L.P.G., Pickkers, P., Schouten, J.A., Webb, S.A., and Gordon, A.C.

Abstract

Item does not contain fulltext, IMPORTANCE: The efficacy of antiplatelet therapy in critically ill patients with COVID-19 is uncertain. OBJECTIVE: To determine whether antiplatelet therapy improves outcomes for critically ill adults with COVID-19. DESIGN, SETTING, AND PARTICIPANTS: In an ongoing adaptive platform trial (REMAP-CAP) testing multiple interventions within multiple therapeutic domains, 1557 critically ill adult patients with COVID-19 were enrolled between October 30, 2020, and June 23, 2021, from 105 sites in 8 countries and followed up for 90 days (final follow-up date: July 26, 2021). INTERVENTIONS: Patients were randomized to receive either open-label aspirin (n = 565), a P2Y12 inhibitor (n = 455), or no antiplatelet therapy (control; n = 529). Interventions were continued in the hospital for a maximum of 14 days and were in addition to anticoagulation thromboprophylaxis. MAIN OUTCOMES AND MEASURES: The primary end point was organ support-free days (days alive and free of intensive care unit-based respiratory or cardiovascular organ support) within 21 days, ranging from -1 for any death in hospital (censored at 90 days) to 22 for survivors with no organ support. There were 13 secondary outcomes, including survival to discharge and major bleeding to 14 days. The primary analysis was a bayesian cumulative logistic model. An odds ratio (OR) greater than 1 represented improved survival, more organ support-free days, or both. Efficacy was defined as greater than 99% posterior probability of an OR greater than 1. Futility was defined as greater than 95% posterior probability of an OR less than 1.2 vs control. Intervention equivalence was defined as greater than 90% probability that the OR (compared with each other) was between 1/1.2 and 1.2 for 2 noncontrol interventions. RESULTS: The aspirin and P2Y12 inhibitor groups met the predefined criteria for equivalence at an adaptive analysis and were statistically pooled for further analysis. Enrollment was discontinued after the prespecified c

Published
2022

13. Fungal endophytes and epiphytes in needles of Picea abies (L.) Karst. from natural and urban areas in northern Italy

Author

Lorenzi E, Lorando E, and Picco AM

Subjects
Fungi, Norway spruce, Conifers, Needles, Endophytes, Epiphytes, Pollution, Forestry, SD1-669.5
Abstract

The foliar fungal endophytes community inhabiting needles of Picea abies (Norway spruce) has not been well documented. In this study, carried out in Northern Italy, needles were collected in the years 2003 - 2004 in Bagni di Masino and Passo S. Marco (natural locations) and in Milano and Pavia (urban areas). Needles were plated and scored for hyphal outgrowth of endophytes to observe composition and distribution pattern. Both colonization percentage and number of taxa were higher in needles collected in natural locations. There was a large difference in the infection levels between natural and urban areas, portion of the needle (the distal portion showing the largest number of colonies) and among the different needle age classes, with the youngest needles being virtually endophytes free and the 5 and 6 age classes being the most colonized. Thus Norway spruce foliar endophytes population appears to be influenced by age and portion of the needle and location. In the year 2003 fungal epiphytes were also investigated to compare the two different populations. Results analisys show a different distribution of endophytic and ephyphitic taxa, some species being mostly isolated in the natural locations others in the urban ones, thus indicating the presence of different clusters. Zythiostroma pinastri and Tiarosporella parca were the most frequent endophytes in natural locations while Sphaeropsis sapinea was common in urban areas. Among the epiphytes Alternaria alternata, Aureobasidium, and Cladosporium were ubiquitous taxa, Phomopsis was mostly isolated in natural locations.

Published
2006

14. Association between tocilizumab, sarilumab and all-cause mortality at 28 days in hospitalized patients with COVID-19: A network meta-analysis

Author

Godolphin, P, Fisher, D, Berry, L, Derde, LPG, Diaz, J, Gordon, A, Lorenzi, E, Marshall, J, Murthy, S, Shankar-Hari, M, Sterne, JAC, Tierney, J, and Vale, C

Abstract

Objective: To estimate pairwise associations between administration of tocilizumab, sarilumab and usual care or placebo with 28-day mortality, in COVID-19 patients receiving concomitant corticosteroids and non-invasive or mechanical ventilation, based on all available direct and indirect evidence. Methods: Eligible trials randomized hospitalized patients with COVID-19 that compared either interleukin-6 receptor antagonist with usual care or placebo in a recent prospective meta-analysis (27 trials, 10930 patients) or that directly compared tocilizumab with sarilumab. Data were restricted to patients receiving corticosteroids and either non-invasive or invasive ventilation at randomization. Pairwise associations between tocilizumab, sarilumab and usual care or placebo for all-cause mortality 28 days after randomization were estimated using a frequentist contrast-based network meta-analysis of odds ratios (ORs), implementing multivariate fixed-effects models that assume consistency between the direct and indirect evidence. Results: One trial (REMAP-CAP) was identified that directly compared tocilizumab with sarilumab and supplied results on all-cause mortality at 28-days. This network meta-analysis was based on 898 eligible patients (278 deaths) from REMAP-CAP and 3710 eligible patients from 18 trials (1278 deaths) from the prospective meta-analysis. Summary ORs were similar for tocilizumab [0.82 [0.71-0.95, P=0.008]] and sarilumab [0.80 [0.61-1.04, P=0.09]] compared with usual care or placebo. The summary OR for 28-day mortality comparing tocilizumab with sarilumab was 1.03 [95%CI 0.81-1.32, P=0.80]. The P value for the global test for inconsistency was 0.28. Conclusion: Administration of either tocilizumab or sarilumab was associated with lower 28-day all-cause mortality compared with usual care or placebo. The association is not dependent on the choice of interleukin-6 receptor antagonist.

Published
2021

16. Reference Protocol to Assess Analytical Performance of Higher Order Structural Analysis Measurements: Results from an Interlaboratory Comparison

Author

Groves, K., primary, Ashcroft, A. E., additional, Cryar, A., additional, Sula, A., additional, Wallace, B. A., additional, Stocks, B. B., additional, Burns, C., additional, Cooper-Shepherd, D., additional, De Lorenzi, E., additional, Rodriguez, E., additional, Zhang, H., additional, Ault, J. R., additional, Ferguson, J., additional, Phillips, J. J., additional, Pacholarz, K., additional, Thalassinos, K., additional, Luckau, L., additional, Ashton, L., additional, Durrant, O., additional, Barran, P., additional, Dalby, P., additional, Vicedo, P., additional, Colombo, R., additional, Davis, R., additional, Parakra, R., additional, Upton, R., additional, Hill, S., additional, Wood, V., additional, Soloviev, Z., additional, and Quaglia, M., additional

Published
2021
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17. Interleukin-6 Receptor Antagonists in Critically Ill Patients with Covid-19

Author

Gordon, A.C., Mouncey, P.R., Al-Beidh, F., Rowan, K.M., Nichol, A.D., Arabi, Y.M., Annane, D., Beane, A., Bentum-Puijk, W. van, Berry, L.R., Bhimani, Z., Bonten, M.J.M., Bradbury, C.A., Brunkhorst, F.M., Buzgau, A., Cheng, A.C., Detry, M.A., Duffy, E.J., Estcourt, L.J., Fitzgerald, M., Goossens, H., Haniffa, R., Higgins, A.M., Hills, T.E., Horvat, C.M., Lamontagne, F., Lawler, P.R., Leavis, H.L., Linstrum, K.M., Litton, E., Lorenzi, E., Marshall, J.C., Mayr, F.B., McAuley, D.F., McGlothlin, A., McGuinness, S.P., McVerry, B.J., Montgomery, S.K., Morpeth, S.C., Murthy, S., Orr, K., Parke, R.L., Parker, J.C., Patanwala, A.E., Pettilä, V., Rademaker, E., Santos, M.S., Saunders, C.T., Seymour, C.W., Shankar-Hari, M., Sligl, W.I., Turgeon, A.F., Turner, A.M., Veerdonk, F.L. van de, Zarychanski, R., Green, C., Lewis, R.J., Angus, D.C., McArthur, C.J., Berry, S., Schouten, J.A., Pickkers, P., Webb, S.A., Derde, L.P.G., Université de Versailles Saint-Quentin-en-Yvelines - UFR Sciences de la santé Simone Veil (UVSQ Santé), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), REMAP-CAP Investigators, Pour la France: Bruno Megarbane, Inserm U1144, European Project: 602386,EC:FP7:HEALTH,FP7-HEALTH-2013-INNOVATION-1,CREDITS4HEALTH(2013), European Project: 602525,EC:FP7:HEALTH,FP7-HEALTH-2013-INNOVATION-1,PREPARE(2014), NIHR, National Institute for Health Research, Gordon, Anthony C [0000-0002-0419-547X], Mouncey, Paul R [0000-0002-8510-8517], Beane, Abi [0000-0001-7046-1580], Bradbury, Charlotte A [0000-0001-5248-8165], Detry, Michelle A [0000-0002-2794-1439], Duffy, Eamon J [0000-0002-4515-5116], Estcourt, Lise J [0000-0003-4309-9162], Haniffa, Rashan [0000-0002-8288-449X], Higgins, Alisa M [0000-0001-8295-7559], Hills, Thomas E [0000-0003-0322-5822], Horvat, Christopher M [0000-0002-1593-2252], Lawler, Patrick R [0000-0001-5155-5071], Litton, Edward [0000-0002-5125-6829], Mayr, Florian B [0000-0002-2298-9011], McVerry, Bryan J [0000-0002-1175-4874], Patanwala, Asad E [0000-0003-3999-4703], Saunders, Christina T [0000-0003-4325-9568], Shankar-Hari, Manu [0000-0002-5338-2538], Angus, Derek C [0000-0002-7026-5181], Derde, Lennie PG [0000-0002-3577-5629], Apollo - University of Cambridge Repository, Investigators, REMAP-CAP, HAL UVSQ, Équipe, Credits-based, people-centric approach for the adoption of healthy life-styles and balanced Mediterranean diet in the frame of social participation and innovation for health promotion. - CREDITS4HEALTH - - EC:FP7:HEALTH2013-09-01 - 2016-08-31 - 602386 - VALID, and Platform foR European Preparedness Against (Re-)emerging Epidemics - PREPARE - - EC:FP7:HEALTH2014-02-01 - 2019-01-31 - 602525 - VALID

Subjects
Male, [SDV]Life Sciences [q-bio], lnfectious Diseases and Global Health Radboud Institute for Molecular Life Sciences [Radboudumc 4], 030204 cardiovascular system & hematology, law.invention, chemistry.chemical_compound, 0302 clinical medicine, Randomized controlled trial, law, Interquartile range, middle aged, Credible interval, Odds Ratio, odds ratio, 030212 general & internal medicine, Hospital Mortality, humans, 11 Medical and Health Sciences, adult, Hazard ratio, Covid19, General Medicine, Middle Aged, Intensive care unit, 3. Good health, [SDV] Life Sciences [q-bio], aged, Intensive Care Units, Antibodies, Monoclonal, Humanized/adverse effects, COVID-19/complications, Original Article, Female, Adult, medicine.medical_specialty, Critical Care, Critical Illness, Antibodies, Monoclonal, Humanized, 03 medical and health sciences, Tocilizumab, male, Internal medicine, General & Internal Medicine, medicine, Humans, Aged, hospital mortality, business.industry, SARS-CoV-2, COVID-19, Odds ratio, Receptors, Interleukin-6, Respiration, Artificial, COVID-19 Drug Treatment, Coronavirus, Sarilumab, lnfectious Diseases and Global Health Radboud Institute for Health Sciences [Radboudumc 4], chemistry, Receptors, Interleukin-6/antagonists & inhibitors, REMAP-CAP Investigators, interleukin-6 receptor antagonists, coronavirus disease, business
Abstract

BACKGROUNDThe efficacy of interleukin-6 receptor antagonists in critically ill patients with coronavirus disease 2019 (Covid-19) is unclear.METHODSWe evaluated tocilizumab and sarilumab in an ongoing international, multifactorial, adaptive platform trial. Adult patients with Covid-19, within 24 hours after starting organ support in the intensive care unit (ICU), were randomly assigned to receive tocilizumab (8 mg per kilogram of body weight), sarilumab (400 mg), or standard care (control). The primary outcome was respiratory and cardiovascular organ support–free days, on an ordinal scale combining in-hospital death (assigned a value of −1) and days free of organ support to day 21. The trial uses a Bayesian statistical model with predefined criteria for superiority, efficacy, equivalence, or futility. An odds ratio greater than 1 represented improved survival, more organ support–free days, or both.RESULTSBoth tocilizumab and sarilumab met the predefined criteria for efficacy. At that time, 353 patients had been assigned to tocilizumab, 48 to sarilumab, and 402 to control. The median number of organ support–free days was 10 (interquartile range, −1 to 16) in the tocilizumab group, 11 (interquartile range, 0 to 16) in the sarilumab group, and 0 (interquartile range, −1 to 15) in the control group. The median adjusted cumulative odds ratios were 1.64 (95% credible interval, 1.25 to 2.14) for tocilizumab and 1.76 (95% credible interval, 1.17 to 2.91) for sarilumab as compared with control, yielding posterior probabilities of superiority to control of more than 99.9% and of 99.5%, respectively. An analysis of 90-day survival showed improved survival in the pooled interleukin-6 receptor antagonist groups, yielding a hazard ratio for the comparison with the control group of 1.61 (95% credible interval, 1.25 to 2.08) and a posterior probability of superiority of more than 99.9%. All secondary analyses supported efficacy of these interleukin-6 receptor antagonists.CONCLUSIONSIn critically ill patients with Covid-19 receiving organ support in ICUs, treatment with the interleukin-6 receptor antagonists tocilizumab and sarilumab improved outcomes, including survival. (REMAP-CAP ClinicalTrials.gov number, NCT02735707. opens in new tab.)

Published
2021
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18. Association Between Administration of IL-6 Antagonists and Mortality Among Patients Hospitalized for COVID-19 AMeta-analysis

Author

Shankar-Hari, M, Vale, CL, Godolphin, PJ, Fisher, D, Higgins, JPT, Spiga, F, Savovic, J, Tierney, J, Baron, G, Benbenishty, JS, Berry, LR, Broman, N, Cavalcanti, AB, Colman, R, De Buyser, SL, Derde, LPG, Domingo, P, Omar, SF, Fernandez-Cruz, A, Feuth, T, Garcia, F, Garcia-Vicuna, R, Gonzalez-Alvaro, I, Gordon, AC, Haynes, R, Hermine, O, Horby, PW, Horick, NK, Kumar, K, Lambrecht, BN, Landray, MJ, Leal, L, Lederer, DJ, Lorenzi, E, Mariette, X, Merchante, N, Misnan, NA, Mohan, SV, Nivens, MC, Oksi, J, Perez-Molina, JA, Pizov, R, Porcher, R, Postma, S, Rajasuriar, R, Ramanan, AV, Ravaud, P, Reid, PD, Rutgers, A, Sancho-Lopez, A, Seto, TB, Sivapalasingam, S, Soin, AS, Staplin, N, Stone, JH, Strohbehn, GW, Sunden-Cullberg, J, Torre-Cisneros, J, Tsai, LW, van Hoogstraten, H, van Meerten, T, Veiga, VC, Westerweel, PE, Murthy, S, Diaz, JV, Marshall, JC, Sterne, JAC, Pomar V., Benito N., and WHO Rapid Evidence Appraisal COVID

Abstract

IMPORTANCE Clinical trials assessing the efficacy of IL-6 antagonists in patients hospitalized for COVID-19 have variously reported benefit, no effect, and harm. OBJECTIVE To estimate the association between administration of IL-6 antagonists compared with usual care or placebo and 28-day all-cause mortality and other outcomes. DATA SOURCES Trials were identified through systematic searches of electronic databases between October 2020 and January 2021. Searches were not restricted by trial status or language. Additional trials were identified through contact with experts. STUDY SELECTION Eligible trials randomly assigned patients hospitalized for COVID-19 to a group in whom IL-6 antagonists were administered and to a group in whom neither IL-6 antagonists nor any other immunomodulators except corticosteroids were administered. Among 72 potentially eligible trials, 27 (37.5%) met study selection criteria. DATA EXTRACTION AND SYNTHESIS In this prospectivemeta-analysis, risk of biaswas assessed using the Cochrane Risk of Bias Assessment Tool. Inconsistency among trial results was assessed using the I-2 statistic. The primary analysis was an inverse variance-weighted fixed-effects meta-analysis of odds ratios (ORs) for 28-day all-cause mortality. MAIN OUTCOMES AND MEASURES The primary outcome measurewas all-cause mortality at 28 days after randomization. There were 9 secondary outcomes including progression to invasive mechanical ventilation or death and risk of secondary infection by 28 days. RESULTS A total of 10 930 patients (median age, 61 years [range of medians, 52-68 years]; 3560 [33%] were women) participating in 27 trials were included. By 28 days, there were 1407 deaths among 6449 patients randomized to IL-6 antagonists and 1158 deaths among 4481 patients randomized to usual care or placebo (summary OR, 0.86 [95% CI, 0.79-0.95]; P =.003 based on a fixed-effects meta-analysis). This corresponds to an absolute mortality risk of 22% for IL-6 antagonists compared with an assumed mortality risk of 25% for usual care or placebo. The corresponding summary ORs were 0.83 (95% CI, 0.74-0.92; P

Published
2021

19. Effect of Convalescent Plasma on Organ Support-Free Days in Critically Ill Patients With COVID-19: A Randomized Clinical Trial

Author

Estcourt, L.J., Turgeon, A.F., McQuilten, Z.K., McVerry, B.J., Al-Beidh, F., Annane, D., Arabi, Y.M., Arnold, D.M., Beane, A., Bégin, P., Bentum-Puijk, W. van, Berry, L.R., Bhimani, Z., Birchall, J.E., Bonten, M.J.M., Bradbury, C.A., Brunkhorst, F.M., Buxton, M., Callum, J.L., Chassé, M., Cheng, A.C., Cove, M.E., Daly, J., Derde, L., Detry, M.A., Jong, Menno de, Evans, A., Fergusson, D.A., Fish, M., Fitzgerald, M., Foley, C., Goossens, H., Gordon, A.C., Gosbell, I.B., Green, C., Haniffa, R., Harvala, H., Higgins, A.M., Hills, T.E., Hoad, V.C., Horvat, C., Huang, D.T., Hudson, C.L., Ichihara, N., Laing, E., Lamikanra, A.A., Lamontagne, F., Lawler, P.R., Linstrum, K., Litton, E., Lorenzi, E., MacLennan, S., Marshall, J., McAuley, D.F., McDyer, J.F., McGlothlin, A., McGuinness, S., Miflin, G., Montgomery, S., Mouncey, P.R., Murthy, S., Nichol, A., Parke, R., Parker, J.C., Priddee, N., Purcell, D.F.J., Reyes, L.F., Richardson, P., Robitaille, N., Rowan, K.M., Rynne, J., Saito, H., Santos, M., Saunders, C.T., Neto, A. Serpa, Seymour, C.W., Silversides, J.A., Tinmouth, A.A., Triulzi, D.J., Turner, A.M., Veerdonk, F.L. van de, Walsh, T.S., Wood, E.M., Berry, S., Lewis, R.J., Menon, D.K., McArthur, C., Zarychanski, R., Angus, D.C., Webb, S.A., Roberts, D.J., Shankar-Hari, M., Estcourt, L.J., Turgeon, A.F., McQuilten, Z.K., McVerry, B.J., Al-Beidh, F., Annane, D., Arabi, Y.M., Arnold, D.M., Beane, A., Bégin, P., Bentum-Puijk, W. van, Berry, L.R., Bhimani, Z., Birchall, J.E., Bonten, M.J.M., Bradbury, C.A., Brunkhorst, F.M., Buxton, M., Callum, J.L., Chassé, M., Cheng, A.C., Cove, M.E., Daly, J., Derde, L., Detry, M.A., Jong, Menno de, Evans, A., Fergusson, D.A., Fish, M., Fitzgerald, M., Foley, C., Goossens, H., Gordon, A.C., Gosbell, I.B., Green, C., Haniffa, R., Harvala, H., Higgins, A.M., Hills, T.E., Hoad, V.C., Horvat, C., Huang, D.T., Hudson, C.L., Ichihara, N., Laing, E., Lamikanra, A.A., Lamontagne, F., Lawler, P.R., Linstrum, K., Litton, E., Lorenzi, E., MacLennan, S., Marshall, J., McAuley, D.F., McDyer, J.F., McGlothlin, A., McGuinness, S., Miflin, G., Montgomery, S., Mouncey, P.R., Murthy, S., Nichol, A., Parke, R., Parker, J.C., Priddee, N., Purcell, D.F.J., Reyes, L.F., Richardson, P., Robitaille, N., Rowan, K.M., Rynne, J., Saito, H., Santos, M., Saunders, C.T., Neto, A. Serpa, Seymour, C.W., Silversides, J.A., Tinmouth, A.A., Triulzi, D.J., Turner, A.M., Veerdonk, F.L. van de, Walsh, T.S., Wood, E.M., Berry, S., Lewis, R.J., Menon, D.K., McArthur, C., Zarychanski, R., Angus, D.C., Webb, S.A., Roberts, D.J., and Shankar-Hari, M.

Abstract

Item does not contain fulltext, IMPORTANCE: The evidence for benefit of convalescent plasma for critically ill patients with COVID-19 is inconclusive. OBJECTIVE: To determine whether convalescent plasma would improve outcomes for critically ill adults with COVID-19. DESIGN, SETTING, AND PARTICIPANTS: The ongoing Randomized, Embedded, Multifactorial, Adaptive Platform Trial for Community-Acquired Pneumonia (REMAP-CAP) enrolled and randomized 4763 adults with suspected or confirmed COVID-19 between March 9, 2020, and January 18, 2021, within at least 1 domain; 2011 critically ill adults were randomized to open-label interventions in the immunoglobulin domain at 129 sites in 4 countries. Follow-up ended on April 19, 2021. INTERVENTIONS: The immunoglobulin domain randomized participants to receive 2 units of high-titer, ABO-compatible convalescent plasma (total volume of 550 mL ± 150 mL) within 48 hours of randomization (n = 1084) or no convalescent plasma (n = 916). MAIN OUTCOMES AND MEASURES: The primary ordinal end point was organ support-free days (days alive and free of intensive care unit-based organ support) up to day 21 (range, -1 to 21 days; patients who died were assigned -1 day). The primary analysis was an adjusted bayesian cumulative logistic model. Superiority was defined as the posterior probability of an odds ratio (OR) greater than 1 (threshold for trial conclusion of superiority >99%). Futility was defined as the posterior probability of an OR less than 1.2 (threshold for trial conclusion of futility >95%). An OR greater than 1 represented improved survival, more organ support-free days, or both. The prespecified secondary outcomes included in-hospital survival; 28-day survival; 90-day survival; respiratory support-free days; cardiovascular support-free days; progression to invasive mechanical ventilation, extracorporeal mechanical oxygenation, or death; intensive care unit length of stay; hospital length of stay; World Health Organization ordinal scale score at day 14; venous thromb

Published
2021

20. Therapeutic Anticoagulation with Heparin in Critically Ill Patients with Covid-19

Author

Goligher, E.C., Bradbury, C.A., McVerry, B.J., Lawler, P.R., Berger, J.S., Gong, M.N., Carrier, M., Reynolds, H.R., Kumar, A., Turgeon, A.F., Kornblith, L.Z., Kahn, S.R., Marshall, J.C., Kim, K.S., Houston, B.L., Derde, L.P.G., Cushman, M., Tritschler, T., Angus, D.C., Godoy, L.C., McQuilten, Z., Kirwan, B.A., Farkouh, M.E., Brooks, M.M., Lewis, R.J., Berry, L.R., Lorenzi, E., Gordon, A.C., Ahuja, T., Al-Beidh, F., Annane, D., Arabi, Y.M., Aryal, D., Kreuziger, L. Baumann, Beane, A., Bhimani, Z., Bihari, S., Billett, H.H., Bond, L., Bonten, M., Brunkhorst, F., Buxton, M., Buzgau, A., Castellucci, L.A., Chekuri, S., Chen, J.T., Cheng, A.C., Chkhikvadze, T., Coiffard, B., Contreras, A., Costantini, T.W., Brouwer, S., Detry, M.A., Duggal, A., Džavík, V., Effron, M.B., Eng, H.F., Escobedo, J., Estcourt, L.J., Everett, B.M., Fergusson, D.A., Fitzgerald, M., Fowler, R.A., Froess, J.D., Fu, Z., Galanaud, J.P., Galen, B.T., Gandotra, S., Girard, T.D., Goodman, A.L., Goossens, H., Green, C., Greenstein, Y.Y., Gross, P.L., Haniffa, R., Hegde, S.M., Hendrickson, C.M., Higgins, A.M., Hindenburg, A.A., Hope, A.A., Horowitz, J.M., Horvat, C.M., Huang, D.T., Hudock, K., Hunt, B.J., Husain, M., Hyzy, R.C., Jacobson, J.R., Jayakumar, D., Keller, N.M., Khan, A., Kim, Y., Kindzelski, A., King, A.J., Knudson, M.M., Kornblith, A.E., Kutcher, M.E., Laffan, M.A., Lamontagne, F., Gal, G. Le, Veerdonk, F.L. van de, Middeldorp, S., Schouten, J.A., Pickkers, P., Webb, S.A., Zarychanski, R., Goligher, E.C., Bradbury, C.A., McVerry, B.J., Lawler, P.R., Berger, J.S., Gong, M.N., Carrier, M., Reynolds, H.R., Kumar, A., Turgeon, A.F., Kornblith, L.Z., Kahn, S.R., Marshall, J.C., Kim, K.S., Houston, B.L., Derde, L.P.G., Cushman, M., Tritschler, T., Angus, D.C., Godoy, L.C., McQuilten, Z., Kirwan, B.A., Farkouh, M.E., Brooks, M.M., Lewis, R.J., Berry, L.R., Lorenzi, E., Gordon, A.C., Ahuja, T., Al-Beidh, F., Annane, D., Arabi, Y.M., Aryal, D., Kreuziger, L. Baumann, Beane, A., Bhimani, Z., Bihari, S., Billett, H.H., Bond, L., Bonten, M., Brunkhorst, F., Buxton, M., Buzgau, A., Castellucci, L.A., Chekuri, S., Chen, J.T., Cheng, A.C., Chkhikvadze, T., Coiffard, B., Contreras, A., Costantini, T.W., Brouwer, S., Detry, M.A., Duggal, A., Džavík, V., Effron, M.B., Eng, H.F., Escobedo, J., Estcourt, L.J., Everett, B.M., Fergusson, D.A., Fitzgerald, M., Fowler, R.A., Froess, J.D., Fu, Z., Galanaud, J.P., Galen, B.T., Gandotra, S., Girard, T.D., Goodman, A.L., Goossens, H., Green, C., Greenstein, Y.Y., Gross, P.L., Haniffa, R., Hegde, S.M., Hendrickson, C.M., Higgins, A.M., Hindenburg, A.A., Hope, A.A., Horowitz, J.M., Horvat, C.M., Huang, D.T., Hudock, K., Hunt, B.J., Husain, M., Hyzy, R.C., Jacobson, J.R., Jayakumar, D., Keller, N.M., Khan, A., Kim, Y., Kindzelski, A., King, A.J., Knudson, M.M., Kornblith, A.E., Kutcher, M.E., Laffan, M.A., Lamontagne, F., Gal, G. Le, Veerdonk, F.L. van de, Middeldorp, S., Schouten, J.A., Pickkers, P., Webb, S.A., and Zarychanski, R.

Abstract

Item does not contain fulltext, BACKGROUND: Thrombosis and inflammation may contribute to morbidity and mortality among patients with coronavirus disease 2019 (Covid-19). We hypothesized that therapeutic-dose anticoagulation would improve outcomes in critically ill patients with Covid-19. METHODS: In an open-label, adaptive, multiplatform, randomized clinical trial, critically ill patients with severe Covid-19 were randomly assigned to a pragmatically defined regimen of either therapeutic-dose anticoagulation with heparin or pharmacologic thromboprophylaxis in accordance with local usual care. The primary outcome was organ support-free days, evaluated on an ordinal scale that combined in-hospital death (assigned a value of -1) and the number of days free of cardiovascular or respiratory organ support up to day 21 among patients who survived to hospital discharge. RESULTS: The trial was stopped when the prespecified criterion for futility was met for therapeutic-dose anticoagulation. Data on the primary outcome were available for 1098 patients (534 assigned to therapeutic-dose anticoagulation and 564 assigned to usual-care thromboprophylaxis). The median value for organ support-free days was 1 (interquartile range, -1 to 16) among the patients assigned to therapeutic-dose anticoagulation and was 4 (interquartile range, -1 to 16) among the patients assigned to usual-care thromboprophylaxis (adjusted proportional odds ratio, 0.83; 95% credible interval, 0.67 to 1.03; posterior probability of futility [defined as an odds ratio <1.2], 99.9%). The percentage of patients who survived to hospital discharge was similar in the two groups (62.7% and 64.5%, respectively; adjusted odds ratio, 0.84; 95% credible interval, 0.64 to 1.11). Major bleeding occurred in 3.8% of the patients assigned to therapeutic-dose anticoagulation and in 2.3% of those assigned to usual-care pharmacologic thromboprophylaxis. CONCLUSIONS: In critically ill patients with Covid-19, an initial strategy of therapeutic-dose anticoagulati

Published
2021

21. Therapeutic Anticoagulation with Heparin in Noncritically Ill Patients with Covid-19

Author

Lawler, P.R., Goligher, E.C., Berger, J.S., Neal, M.D., McVerry, B.J., Nicolau, J.C., Gong, M.N., Carrier, M., Rosenson, R.S., Reynolds, H.R., Turgeon, A.F., Escobedo, J., Huang, D.T., Bradbury, C.A., Houston, B.L., Kornblith, L.Z., Kumar, A., Kahn, S.R., Cushman, M., McQuilten, Z., Slutsky, A.S., Kim, K.S., Gordon, A.C., Kirwan, B.A., Brooks, M.M., Higgins, A.M., Lewis, R.J., Lorenzi, E., Berry, S.M., Berry, L.R., Aday, A.W., Al-Beidh, F., Annane, D., Arabi, Y.M., Aryal, D., Kreuziger, L. Baumann, Beane, A., Bhimani, Z., Bihari, S., Billett, H.H., Bond, L., Bonten, M., Brunkhorst, F., Buxton, M., Buzgau, A., Castellucci, L.A., Chekuri, S., Chen, J.T., Cheng, A.C., Chkhikvadze, T., Coiffard, B., Costantini, T.W., Brouwer, S., Derde, L.P.G., Detry, M.A., Duggal, A., Džavík, V., Effron, M.B., Estcourt, L.J., Everett, B.M., Fergusson, D.A., Fitzgerald, M., Fowler, R.A., Galanaud, J.P., Galen, B.T., Gandotra, S., García-Madrona, S., Girard, T.D., Godoy, L.C., Goodman, A.L., Goossens, H., Green, C., Greenstein, Y.Y., Gross, P.L., Hamburg, N.M., Haniffa, R., Hanna, G., Hanna, N., Hegde, S.M., Hendrickson, C.M., Hite, R.D., Hindenburg, A.A., Hope, A.A., Horowitz, J.M., Horvat, C.M., Hudock, K., Hunt, B.J., Husain, M., Hyzy, R.C., Iyer, V.N., Jacobson, J.R., Jayakumar, D., Keller, N.M., Khan, A., Kim, Y., Kindzelski, A.L., King, A.J., Knudson, M.M., Kornblith, A.E., Krishnan, V., Veerdonk, F.L. van de, Schouten, J.A., Pickkers, P., Hochman, J.S., Zarychanski, R., Lawler, P.R., Goligher, E.C., Berger, J.S., Neal, M.D., McVerry, B.J., Nicolau, J.C., Gong, M.N., Carrier, M., Rosenson, R.S., Reynolds, H.R., Turgeon, A.F., Escobedo, J., Huang, D.T., Bradbury, C.A., Houston, B.L., Kornblith, L.Z., Kumar, A., Kahn, S.R., Cushman, M., McQuilten, Z., Slutsky, A.S., Kim, K.S., Gordon, A.C., Kirwan, B.A., Brooks, M.M., Higgins, A.M., Lewis, R.J., Lorenzi, E., Berry, S.M., Berry, L.R., Aday, A.W., Al-Beidh, F., Annane, D., Arabi, Y.M., Aryal, D., Kreuziger, L. Baumann, Beane, A., Bhimani, Z., Bihari, S., Billett, H.H., Bond, L., Bonten, M., Brunkhorst, F., Buxton, M., Buzgau, A., Castellucci, L.A., Chekuri, S., Chen, J.T., Cheng, A.C., Chkhikvadze, T., Coiffard, B., Costantini, T.W., Brouwer, S., Derde, L.P.G., Detry, M.A., Duggal, A., Džavík, V., Effron, M.B., Estcourt, L.J., Everett, B.M., Fergusson, D.A., Fitzgerald, M., Fowler, R.A., Galanaud, J.P., Galen, B.T., Gandotra, S., García-Madrona, S., Girard, T.D., Godoy, L.C., Goodman, A.L., Goossens, H., Green, C., Greenstein, Y.Y., Gross, P.L., Hamburg, N.M., Haniffa, R., Hanna, G., Hanna, N., Hegde, S.M., Hendrickson, C.M., Hite, R.D., Hindenburg, A.A., Hope, A.A., Horowitz, J.M., Horvat, C.M., Hudock, K., Hunt, B.J., Husain, M., Hyzy, R.C., Iyer, V.N., Jacobson, J.R., Jayakumar, D., Keller, N.M., Khan, A., Kim, Y., Kindzelski, A.L., King, A.J., Knudson, M.M., Kornblith, A.E., Krishnan, V., Veerdonk, F.L. van de, Schouten, J.A., Pickkers, P., Hochman, J.S., and Zarychanski, R.

Abstract

Item does not contain fulltext, BACKGROUND: Thrombosis and inflammation may contribute to the risk of death and complications among patients with coronavirus disease 2019 (Covid-19). We hypothesized that therapeutic-dose anticoagulation may improve outcomes in noncritically ill patients who are hospitalized with Covid-19. METHODS: In this open-label, adaptive, multiplatform, controlled trial, we randomly assigned patients who were hospitalized with Covid-19 and who were not critically ill (which was defined as an absence of critical care-level organ support at enrollment) to receive pragmatically defined regimens of either therapeutic-dose anticoagulation with heparin or usual-care pharmacologic thromboprophylaxis. The primary outcome was organ support-free days, evaluated on an ordinal scale that combined in-hospital death (assigned a value of -1) and the number of days free of cardiovascular or respiratory organ support up to day 21 among patients who survived to hospital discharge. This outcome was evaluated with the use of a Bayesian statistical model for all patients and according to the baseline d-dimer level. RESULTS: The trial was stopped when prespecified criteria for the superiority of therapeutic-dose anticoagulation were met. Among 2219 patients in the final analysis, the probability that therapeutic-dose anticoagulation increased organ support-free days as compared with usual-care thromboprophylaxis was 98.6% (adjusted odds ratio, 1.27; 95% credible interval, 1.03 to 1.58). The adjusted absolute between-group difference in survival until hospital discharge without organ support favoring therapeutic-dose anticoagulation was 4.0 percentage points (95% credible interval, 0.5 to 7.2). The final probability of the superiority of therapeutic-dose anticoagulation over usual-care thromboprophylaxis was 97.3% in the high d-dimer cohort, 92.9% in the low d-dimer cohort, and 97.3% in the unknown d-dimer cohort. Major bleeding occurred in 1.9% of the patients receiving therapeutic-dose anticoagul

Published
2021

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

Author

Arabi, Y.M., Gordon, A.C., Derde, L.P.G., Nichol, A.D., Murthy, S., Beidh, F.A., Annane, D., Swaidan, L.A., Beane, A., Beasley, R., Berry, L.R., Bhimani, Z., Bonten, M.J.M., Bradbury, C.A., Brunkhorst, F.M., Buxton, M., Buzgau, A., Cheng, A., Jong, Menno de, Detry, M.A., Duffy, E.J., Estcourt, L.J., Fitzgerald, M., Fowler, R., Girard, T.D., Goligher, E.C., Goossens, H., Haniffa, R., Higgins, A.M., Hills, T.E., Horvat, C.M., Huang, D.T., King, A.J., Lamontagne, F., Lawler, P.R., Lewis, R., Linstrum, K., Litton, E., Lorenzi, E., Malakouti, S., McAuley, D.F., McGlothlin, A., McGuinness, S., McVerry, B.J., Montgomery, S.K., Morpeth, S.C., Mouncey, P.R., Orr, K., Parke, R., Parker, J.C., Patanwala, A.E., Rowan, K.M., Santos, M.S., Saunders, C.T., Seymour, C.W., Shankar-Hari, M., Tong, S.Y.C., Turgeon, A.F., Turner, A.M., Veerdonk, F.L. van de, Zarychanski, R., Green, C., Berry, S., Marshall, J.C., McArthur, C., Schouten, J.A., Angus, D.C., Webb, S.A., Arabi, Y.M., Gordon, A.C., Derde, L.P.G., Nichol, A.D., Murthy, S., Beidh, F.A., Annane, D., Swaidan, L.A., Beane, A., Beasley, R., Berry, L.R., Bhimani, Z., Bonten, M.J.M., Bradbury, C.A., Brunkhorst, F.M., Buxton, M., Buzgau, A., Cheng, A., Jong, Menno de, Detry, M.A., Duffy, E.J., Estcourt, L.J., Fitzgerald, M., Fowler, R., Girard, T.D., Goligher, E.C., Goossens, H., Haniffa, R., Higgins, A.M., Hills, T.E., Horvat, C.M., Huang, D.T., King, A.J., Lamontagne, F., Lawler, P.R., Lewis, R., Linstrum, K., Litton, E., Lorenzi, E., Malakouti, S., McAuley, D.F., McGlothlin, A., McGuinness, S., McVerry, B.J., Montgomery, S.K., Morpeth, S.C., Mouncey, P.R., Orr, K., Parke, R., Parker, J.C., Patanwala, A.E., Rowan, K.M., Santos, M.S., Saunders, C.T., Seymour, C.W., Shankar-Hari, M., Tong, S.Y.C., Turgeon, A.F., Turner, A.M., Veerdonk, F.L. van de, Zarychanski, R., Green, C., Berry, S., Marshall, J.C., McArthur, C., Schouten, J.A., Angus, D.C., and Webb, S.A.

Abstract

Item does not contain fulltext, 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.

Published
2021

23. Effect of Convalescent Plasma on Organ Support-Free Days in Critically Ill Patients with COVID-19: A Randomized Clinical Trial.

Author

Estcourt L.J., Turgeon A.F., McQuilten Z.K., McVerry B.J., Al-Beidh F., Annane D., Arabi Y.M., Arnold D.M., Beane A., Begin P., Van Bentum-Puijk W., Berry L.R., Bhimani Z., Birchall J.E., Bonten M.J.M., Bradbury C.A., Brunkhorst F.M., Buxton M., Callum J.L., Chasse M., Cheng A.C., Cove M.E., Daly J., Derde L., Detry M.A., De Jong M., Evans A., Fergusson D.A., Fish M., Fitzgerald M., Foley C., Goossens H., Gordon A.C., Gosbell I.B., Green C., Haniffa R., Harvala H., Higgins A.M., Hills T.E., Hoad V.C., Horvat C., Huang D.T., Hudson C.L., Ichihara N., Laing E., Lamikanra A.A., Lamontagne F., Lawler P.R., Linstrum K., Litton E., Lorenzi E., Maclennan S., Marshall J., McAuley D.F., McDyer J.F., McGlothlin A., McGuinness S., Miflin G., Montgomery S., Mouncey P.R., Murthy S., Nichol A., Parke R., Parker J.C., Priddee N., Purcell D.F.J., Reyes L.F., Richardson P., Robitaille N., Rowan K.M., Rynne J., Saito H., Santos M., Saunders C.T., Serpa Neto A., Seymour C.W., Silversides J.A., Tinmouth A.A., Triulzi D.J., Turner A.M., Van De Veerdonk F., Walsh T.S., Wood E.M., Berry S., Lewis R.J., Menon D.K., McArthur C., Zarychanski R., Angus D.C., Webb S.A., Roberts D.J., Shankar-Hari M., Estcourt L.J., Turgeon A.F., McQuilten Z.K., McVerry B.J., Al-Beidh F., Annane D., Arabi Y.M., Arnold D.M., Beane A., Begin P., Van Bentum-Puijk W., Berry L.R., Bhimani Z., Birchall J.E., Bonten M.J.M., Bradbury C.A., Brunkhorst F.M., Buxton M., Callum J.L., Chasse M., Cheng A.C., Cove M.E., Daly J., Derde L., Detry M.A., De Jong M., Evans A., Fergusson D.A., Fish M., Fitzgerald M., Foley C., Goossens H., Gordon A.C., Gosbell I.B., Green C., Haniffa R., Harvala H., Higgins A.M., Hills T.E., Hoad V.C., Horvat C., Huang D.T., Hudson C.L., Ichihara N., Laing E., Lamikanra A.A., Lamontagne F., Lawler P.R., Linstrum K., Litton E., Lorenzi E., Maclennan S., Marshall J., McAuley D.F., McDyer J.F., McGlothlin A., McGuinness S., Miflin G., Montgomery S., Mouncey P.R., Murthy S., Nichol A., Parke R., Parker J.C., Priddee N., Purcell D.F.J., Reyes L.F., Richardson P., Robitaille N., Rowan K.M., Rynne J., Saito H., Santos M., Saunders C.T., Serpa Neto A., Seymour C.W., Silversides J.A., Tinmouth A.A., Triulzi D.J., Turner A.M., Van De Veerdonk F., Walsh T.S., Wood E.M., Berry S., Lewis R.J., Menon D.K., McArthur C., Zarychanski R., Angus D.C., Webb S.A., Roberts D.J., and Shankar-Hari M.

Abstract

Importance: The evidence for benefit of convalescent plasma for critically ill patients with COVID-19 is inconclusive. Objective(s): To determine whether convalescent plasma would improve outcomes for critically ill adults with COVID-19. Design, Setting, and Participant(s): The ongoing Randomized, Embedded, Multifactorial, Adaptive Platform Trial for Community-Acquired Pneumonia (REMAP-CAP) enrolled and randomized 4763 adults with suspected or confirmed COVID-19 between March 9, 2020, and January 18, 2021, within at least 1 domain; 2011 critically ill adults were randomized to open-label interventions in the immunoglobulin domain at 129 sites in 4 countries. Follow-up ended on April 19, 2021. Intervention(s): The immunoglobulin domain randomized participants to receive 2 units of high-titer, ABO-compatible convalescent plasma (total volume of 550 mL +/- 150 mL) within 48 hours of randomization (n = 1084) or no convalescent plasma (n = 916). Main Outcomes and Measures: The primary ordinal end point was organ support-free days (days alive and free of intensive care unit-based organ support) up to day 21 (range, -1 to 21 days; patients who died were assigned -1 day). The primary analysis was an adjusted bayesian cumulative logistic model. Superiority was defined as the posterior probability of an odds ratio (OR) greater than 1 (threshold for trial conclusion of superiority >99%). Futility was defined as the posterior probability of an OR less than 1.2 (threshold for trial conclusion of futility >95%). An OR greater than 1 represented improved survival, more organ support-free days, or both. The prespecified secondary outcomes included in-hospital survival; 28-day survival; 90-day survival; respiratory support-free days; cardiovascular support-free days; progression to invasive mechanical ventilation, extracorporeal mechanical oxygenation, or death; intensive care unit length of stay; hospital length of stay; World Health Organization ordinal scale score at day 14; veno

Published
2021

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

Author

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, Orford, Neil, 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, and Orford, Neil

Published
2021

25. Interleukin-6 Receptor Antagonists in Critically Ill Patients with Covid-19

Author

Gordon, AC, Al-Beidh, F, Rowan, KM, Nichol, AD, Arabi, YM, Annane, D, Beane, A, Van Bentum-Puijk, W, Berry, LR, Bhimani, Z, Bonten, MJM, Bradbury, CA, Brunkhorst, FM, Buzgau, A, Cheng, AC, Detry, MA, Duffy, EJ, Estcourt, LJ, Fitzgerald, M, Goossens, H, Haniffa, R, Higgins, AM, Hills, TE, Horvat, CM, Lamontagne, F, Lawler, PR, Leavis, HL, Linstrum, KM, Litton, E, Lorenzi, E, Marshall, JC, Mayr, FB, McAuley, DF, McGlothlin, A, McGuinness, SP, McVerry, BJ, Montgomery, SK, Morpeth, SC, Murthy, S, Orr, K, Parke, RL, Parker, JC, Patanwala, AE, Pettill, V, Rademaker, E, Santos, MS, Saunders, CT, Seymour, CW, Shankar-Hari, M, Sligl, WL, Turgeon, AF, Turner, AM, van de Veerdonk, FL, Zarychanski, R, Green, C, Lewis, RJ, Angus, DC, McArthur, CJ, Berry, S, Webb, SA, Derde, LPG, Gordon, AC, Al-Beidh, F, Rowan, KM, Nichol, AD, Arabi, YM, Annane, D, Beane, A, Van Bentum-Puijk, W, Berry, LR, Bhimani, Z, Bonten, MJM, Bradbury, CA, Brunkhorst, FM, Buzgau, A, Cheng, AC, Detry, MA, Duffy, EJ, Estcourt, LJ, Fitzgerald, M, Goossens, H, Haniffa, R, Higgins, AM, Hills, TE, Horvat, CM, Lamontagne, F, Lawler, PR, Leavis, HL, Linstrum, KM, Litton, E, Lorenzi, E, Marshall, JC, Mayr, FB, McAuley, DF, McGlothlin, A, McGuinness, SP, McVerry, BJ, Montgomery, SK, Morpeth, SC, Murthy, S, Orr, K, Parke, RL, Parker, JC, Patanwala, AE, Pettill, V, Rademaker, E, Santos, MS, Saunders, CT, Seymour, CW, Shankar-Hari, M, Sligl, WL, Turgeon, AF, Turner, AM, van de Veerdonk, FL, Zarychanski, R, Green, C, Lewis, RJ, Angus, DC, McArthur, CJ, Berry, S, Webb, SA, and Derde, LPG

Abstract

BACKGROUND: The efficacy of interleukin-6 receptor antagonists in critically ill patients with coronavirus disease 2019 (Covid-19) is unclear. METHODS: We evaluated tocilizumab and sarilumab in an ongoing international, multifactorial, adaptive platform trial. Adult patients with Covid-19, within 24 hours after starting organ support in the intensive care unit (ICU), were randomly assigned to receive tocilizumab (8 mg per kilogram of body weight), sarilumab (400 mg), or standard care (control). The primary outcome was respiratory and cardiovascular organ support-free days, on an ordinal scale combining in-hospital death (assigned a value of -1) and days free of organ support to day 21. The trial uses a Bayesian statistical model with predefined criteria for superiority, efficacy, equivalence, or futility. An odds ratio greater than 1 represented improved survival, more organ support-free days, or both. RESULTS: Both tocilizumab and sarilumab met the predefined criteria for efficacy. At that time, 353 patients had been assigned to tocilizumab, 48 to sarilumab, and 402 to control. The median number of organ support-free days was 10 (interquartile range, -1 to 16) in the tocilizumab group, 11 (interquartile range, 0 to 16) in the sarilumab group, and 0 (interquartile range, -1 to 15) in the control group. The median adjusted cumulative odds ratios were 1.64 (95% credible interval, 1.25 to 2.14) for tocilizumab and 1.76 (95% credible interval, 1.17 to 2.91) for sarilumab as compared with control, yielding posterior probabilities of superiority to control of more than 99.9% and of 99.5%, respectively. An analysis of 90-day survival showed improved survival in the pooled interleukin-6 receptor antagonist groups, yielding a hazard ratio for the comparison with the control group of 1.61 (95% credible interval, 1.25 to 2.08) and a posterior probability of superiority of more than 99.9%. All secondary analyses supported efficacy of these interleukin-6 receptor antagonists. CO

Published
2021

26. Reference Protocol to Assess Analytical Performance of Higher Order Structural Analysis Measurements:Results from an Interlaboratory Comparison

Author

Groves, K., Ashcroft, A.E., Cryar, A., Sula, A., Wallace, B.A., Stocks, B.B., Burns, C., Cooper-Shepherd, D., De Lorenzi, E., Rodriguez, E., Zhang, H., Ault, J.R., Ferguson, J., Phillips, J.J., Pacholarz, K., Thalassinos, K., Luckau, L., Ashton, L., Durrant, O., Barran, P., Dalby, P., Vicedo, P., Colombo, R., Davis, R., Parakra, R., Upton, R., Hill, S., Wood, V., Soloviev, Z., Quaglia, M., Groves, K., Ashcroft, A.E., Cryar, A., Sula, A., Wallace, B.A., Stocks, B.B., Burns, C., Cooper-Shepherd, D., De Lorenzi, E., Rodriguez, E., Zhang, H., Ault, J.R., Ferguson, J., Phillips, J.J., Pacholarz, K., Thalassinos, K., Luckau, L., Ashton, L., Durrant, O., Barran, P., Dalby, P., Vicedo, P., Colombo, R., Davis, R., Parakra, R., Upton, R., Hill, S., Wood, V., Soloviev, Z., and Quaglia, M.

Abstract

Measurements of protein higher order structure (HOS) provide important information on stability, potency, efficacy, immunogenicity, and biosimilarity of biopharmaceuticals, with a significant number of techniques and methods available to perform these measurements. The comparison of the analytical performance of HOS methods and the standardization of the results is, however, not a trivial task, due to the lack of reference protocols and reference measurement procedures. Here, we developed a protocol to structurally alter and compare samples of somatropin, a recombinant biotherapeutic, and describe the results obtained by using a number of techniques, methods and in different laboratories. This, with the final aim to provide tools and generate a pool of data to compare and benchmark analytical platforms and define method sensitivity to structural changes. Changes in somatropin HOS, induced by the presence of zinc at increasing concentrations, were observed, both globally and at more localized resolution, across many of the methods utilized in this study and with different sensitivities, suggesting the suitability of the protocol to improve understanding of inter- and cross-platform measurement comparability and assess analytical performance as appropriate. © 2021 The Authors. Published by American Chemical Society.

Published
2021

27. Effect of hydrocortisone on mortality and organ support in patients with severe COVID-19: the REMAP-CAP COVID-19 corticosteroid domain randomized clinical trial

Author

Angus, DC, Derde, L, Al-Beidh, F, Annane, D, Arabi, Y, Beane, A, Van Bentum-Puijk, W, Berry, L, Bhimani, Z, Bonten, M, Bradbury, C, Brunkhorst, F, Buxton, M, Buzgau, A, Cheng, AC, De Jong, M, Detry, M, Estcourt, L, Fitzgerald, M, Goossens, H, Green, C, Haniffa, R, Higgins, AM, Horvat, C, Hullegie, SJ, Kruger, P, Lamontagne, F, Lawler, PR, Linstrum, K, Litton, E, Lorenzi, E, Marshall, J, McAuley, D, McGlothin, A, McGuinness, S, McVerry, B, Montgomery, S, Mouncey, P, Murthy, S, Nichol, A, Parke, R, Parker, J, Rowan, K, Sanil, A, Santos, M, Saunders, C, Seymour, C, Turner, A, Van De Veerdonk, F, Venkatesh, B, Zarychanski, R, Berry, S, Lewis, RJ, McArthur, C, Webb, SA, Gordon, AC, Orford, Neil, Angus, DC, Derde, L, Al-Beidh, F, Annane, D, Arabi, Y, Beane, A, Van Bentum-Puijk, W, Berry, L, Bhimani, Z, Bonten, M, Bradbury, C, Brunkhorst, F, Buxton, M, Buzgau, A, Cheng, AC, De Jong, M, Detry, M, Estcourt, L, Fitzgerald, M, Goossens, H, Green, C, Haniffa, R, Higgins, AM, Horvat, C, Hullegie, SJ, Kruger, P, Lamontagne, F, Lawler, PR, Linstrum, K, Litton, E, Lorenzi, E, Marshall, J, McAuley, D, McGlothin, A, McGuinness, S, McVerry, B, Montgomery, S, Mouncey, P, Murthy, S, Nichol, A, Parke, R, Parker, J, Rowan, K, Sanil, A, Santos, M, Saunders, C, Seymour, C, Turner, A, Van De Veerdonk, F, Venkatesh, B, Zarychanski, R, Berry, S, Lewis, RJ, McArthur, C, Webb, SA, Gordon, AC, and Orford, Neil

Published
2020

45. Mismatch repair deficiency (MMRd) in glioma patients (PTS): Frequency and correlation with clinical, histological and molecular characteristics

Author

Lombardi, G., primary, Caccese, M., additional, Simonelli, M., additional, Fassan, M., additional, Persico, P., additional, Lorenzi, E., additional, Bertorelle, R., additional, Gardiman, M.P., additional, Bellu, L., additional, Pambuku, A., additional, Santoro, A., additional, and Zagonel, V., additional

Published
2018
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50. Spécificités clinico-biologiques comparées à la dengue d’une arbovirose guyanaise méconnue : le virus Tonate. TROP-12

Author

Mutricy, Rémi, Epelboin, Loïc, Martinez-Lorenzi, E., Calciatti, E., Matheus, Severine, Blanchet, Denis, Djossou, Félix, Rousset, Dominique, Matillon, Mirlène, Unité des Maladies Infectieuses et Tropicales (UMIT), Centre Hospitalier Andrée Rosemon [Cayenne, Guyane Française], Unité des Maladies Infectieuses et Tropicales [Cayenne, Guyane Française], Université de Guyane (UG), Institut Pasteur de la Guyane, Réseau International des Instituts Pasteur (RIIP), Ecosystemes Amazoniens et Pathologie Tropicale (EPat), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Guyane (UG)

Subjects
[SDV] Life Sciences [q-bio], [SDV]Life Sciences [q-bio], ComputingMilieux_MISCELLANEOUS
Abstract

International audience

Published
2016

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