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1. Barriers, Solutions, and Opportunities for Adapting Critical Care Clinical Trials in the COVID-19 Pandemic.

Author

Cook D, Taneja S, Krewulak K, Zytaruk N, Menon K, Fowler R, Lamontagne F, Kho ME, Rochwerg B, Masse MH, Lauzier F, O'Hearn K, Adhikari NKJ, Burns KEA, Bosma KJ, English S, McNally D, Turgeon AF, Brochard L, Parker M, Clayton L, Rishu A, Tuttle A, Daneman N, Fergusson D, McIntyre L, Kelly L, Orr S, Austin P, Mulligan S, and Fiest K

Subjects
Humans, Canada, Clinical Trials as Topic, Research Design, Randomized Controlled Trials as Topic methods, Focus Groups, Adult, COVID-19 epidemiology, Critical Care, SARS-CoV-2, Pandemics
Abstract

Importance: The COVID-19 pandemic created unprecedented challenges for clinical trials worldwide, threatening premature closure and trial integrity. Every phase of research operations was affected, often requiring modifications to protocol design and implementation., Objectives: To identify the barriers, solutions, and opportunities associated with continuing critical care trials that were interrupted during the pandemic, and to generate suggestions for future trials., Design, Setting, and Participants: This mixed-methods study performed an explanatory sequential analysis involving a self-administered electronic survey and focus groups of principal investigators (PIs) and project coordinators (PCs) conducting adult and pediatric individual-patient randomized trials of the Canadian Critical Care Trials Group during the COVID-19 pandemic. Eligible trials were actively enrolling patients on March 11, 2020. Data were analyzed between September 2023 and January 2024., Main Outcomes and Measures: Importance ratings of barriers to trial conduct and completion, solutions employed, opportunities arising, and suggested strategies for future trials. Quantitative data examining barriers were analyzed using descriptive statistics. Data addressing solutions, opportunities, and suggestions were analyzed by qualitative content analysis. Integration involved triangulation of data sources and perspectives about 13 trials, synthesized by an interprofessional team incorporating reflexivity and member-checking., Results: A total of 13 trials run by 29 PIs and PCs (100% participation rate) were included. The highest-rated barriers (on a 5-point scale) to ongoing conduct during the pandemic were decisions to pause all clinical research (mean [SD] score, 4.7 [0.8]), focus on COVID-19 studies (mean [SD] score, 4.6 [0.8]), and restricted family presence in hospitals (mean [SD] score, 4.1 [0.8]). Suggestions to enable trial progress and completion included providing scientific leadership, implementing technology for communication and data management, facilitating the informed consent process, adapting the protocol as necessary, fostering site engagement, initiating new sites, streamlining ethics and contract review, and designing nested studies. The pandemic necessitated new funding opportunities to sustain trial enrollment. It increased public awareness of critical illness and the importance of randomized trial evidence., Conclusions and Relevance: While underscoring the vital role of research in society and drawing the scientific community together with a common purpose, the pandemic signaled the need for innovation to ensure the rigor and completion of ongoing trials. Lessons learned to optimize research procedures will help to ensure a vibrant clinical trials enterprise in the future.

Published
2024
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2. Simvastatin in Critically Ill Patients with Covid-19.

Author

Hills TE, Lorenzi E, Berry LR, Shyamsundar M, Al-Beidh F, Annane D, Arabi Y, Aryal D, Au C, Beane A, Bhimani Z, Bonten M, Bradbury CA, Brunkhorst FM, Burrell A, Buxton M, Calfee CS, Cecconi M, Cheng AC, Cove ME, Detry MA, Estcourt LJ, Fitzgerald M, Goligher EC, Goossens H, Green C, Haniffa R, Harrison DA, Hashmi M, Higgins AM, Horvat C, Huang DT, Ichihara N, Jayakumar D, Kruger PS, Lamontagne F, Lampro L, Lawler PR, Marshall JC, Mason AJ, McGlothlin A, McGuinness S, McQuilten ZK, McVerry BJ, Mouncey PR, Murthy S, Neal MD, Nichol AD, O'Kane CM, Parke RL, Parker JC, Rabindrarajan E, Reyes LF, Rowan KM, Saito H, Santos M, Saunders CT, Seymour CW, Shankar-Hari M, Sinha P, Thompson BT, Turgeon AF, Turner AM, van de Veerdonk F, Weis S, Young IS, Zarychanski R, Lewis RJ, McArthur CJ, Angus DC, Berry SM, Derde LPG, Webb SA, Gordon AC, and McAuley DF

Subjects
Humans, Bayes Theorem, COVID-19 Drug Treatment, Hospital Mortality, Treatment Outcome, COVID-19 mortality, COVID-19 therapy, Critical Illness mortality, Critical Illness therapy, Hydroxymethylglutaryl-CoA Reductase Inhibitors therapeutic use, Simvastatin therapeutic use
Abstract

Background: The efficacy of simvastatin in critically ill patients with coronavirus disease 2019 (Covid-19) is unclear., Methods: In an ongoing international, multifactorial, adaptive platform, randomized, controlled trial, we evaluated simvastatin (80 mg daily) as compared with no statin (control) in critically ill patients with Covid-19 who were not receiving statins at baseline. The primary outcome was respiratory and cardiovascular organ support-free days, assessed on an ordinal scale combining in-hospital death (assigned a value of -1) and days free of organ support through day 21 in survivors; the analyis used a Bayesian hierarchical ordinal model. The adaptive design included prespecified statistical stopping criteria for superiority (>99% posterior probability that the odds ratio was >1) and futility (>95% posterior probability that the odds ratio was <1.2)., Results: Enrollment began on October 28, 2020. On January 8, 2023, enrollment was closed on the basis of a low anticipated likelihood that prespecified stopping criteria would be met as Covid-19 cases decreased. The final analysis included 2684 critically ill patients. The median number of organ support-free days was 11 (interquartile range, -1 to 17) in the simvastatin group and 7 (interquartile range, -1 to 16) in the control group; the posterior median adjusted odds ratio was 1.15 (95% credible interval, 0.98 to 1.34) for simvastatin as compared with control, yielding a 95.9% posterior probability of superiority. At 90 days, the hazard ratio for survival was 1.12 (95% credible interval, 0.95 to 1.32), yielding a 91.9% posterior probability of superiority of simvastatin. The results of secondary analyses were consistent with those of the primary analysis. Serious adverse events, such as elevated levels of liver enzymes and creatine kinase, were reported more frequently with simvastatin than with control., Conclusions: Although recruitment was stopped because cases had decreased, among critically ill patients with Covid-19, simvastatin did not meet the prespecified criteria for superiority to control. (REMAP-CAP ClinicalTrials.gov number, NCT02735707.)., (Copyright © 2023 Massachusetts Medical Society.)

Published
2023
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3. Intravenous Vitamin C for Patients Hospitalized With COVID-19: Two Harmonized Randomized Clinical Trials.

Author

Adhikari NKJ, Hashmi M, Tirupakuzhi Vijayaraghavan BK, Haniffa R, Beane A, Webb SA, Angus DC, Gordon AC, Cook DJ, Guyatt GH, Berry LR, Lorenzi E, Mouncey PR, Au C, Pinto R, Ménard J, Sprague S, Masse MH, Huang DT, Heyland DK, Nichol AD, McArthur CJ, de Man A, Al-Beidh F, Annane D, Anstey M, Arabi YM, Battista MC, Berry S, Bhimani Z, Bonten MJM, Bradbury CA, Brant EB, Brunkhorst FM, Burrell A, Buxton M, Cecconi M, Cheng AC, Cohen D, Cove ME, Day AG, Derde LPG, Detry MA, Estcourt LJ, Fagbodun EO, Fitzgerald M, Goossens H, Green C, Higgins AM, Hills TE, Horvat C, Ichihara N, Jayakumar D, Kanji S, Khoso MN, Lawler PR, Lewis RJ, Litton E, Marshall JC, McAuley DF, McGlothlin A, McGuinness SP, McQuilten ZK, McVerry BJ, Murthy S, Parke RL, Parker JC, Reyes LF, Rowan KM, Saito H, Salahuddin N, Santos MS, Saunders CT, Seymour CW, Shankar-Hari M, Tolppa T, Trapani T, Turgeon AF, Turner AM, Udy AA, van de Veerdonk FL, Zarychanski R, and Lamontagne F

Subjects
Humans, Female, Middle Aged, Male, Ascorbic Acid therapeutic use, Critical Illness therapy, Critical Illness mortality, Hospital Mortality, Bayes Theorem, Randomized Controlled Trials as Topic, Vitamins therapeutic use, COVID-19, Sepsis drug therapy
Abstract

Importance: The efficacy of vitamin C for hospitalized patients with COVID-19 is uncertain., Objective: To determine whether vitamin C improves outcomes for patients with COVID-19., Design, Setting, and Participants: Two prospectively harmonized randomized clinical trials enrolled critically ill patients receiving organ support in intensive care units (90 sites) and patients who were not critically ill (40 sites) between July 23, 2020, and July 15, 2022, on 4 continents., Interventions: Patients were randomized to receive vitamin C administered intravenously or control (placebo or no vitamin C) every 6 hours for 96 hours (maximum of 16 doses)., Main Outcomes and Measures: The primary outcome was a composite of organ support-free days defined as days alive and free of respiratory and cardiovascular organ support in the intensive care unit up to day 21 and survival to hospital discharge. Values ranged from -1 organ support-free days for patients experiencing in-hospital death to 22 organ support-free days for those who survived without needing organ support. The primary analysis used a bayesian cumulative logistic model. An odds ratio (OR) greater than 1 represented efficacy (improved survival, more organ support-free days, or both), an OR less than 1 represented harm, and an OR less than 1.2 represented futility., Results: Enrollment was terminated after statistical triggers for harm and futility were met. The trials had primary outcome data for 1568 critically ill patients (1037 in the vitamin C group and 531 in the control group; median age, 60 years [IQR, 50-70 years]; 35.9% were female) and 1022 patients who were not critically ill (456 in the vitamin C group and 566 in the control group; median age, 62 years [IQR, 51-72 years]; 39.6% were female). Among critically ill patients, the median number of organ support-free days was 7 (IQR, -1 to 17 days) for the vitamin C group vs 10 (IQR, -1 to 17 days) for the control group (adjusted proportional OR, 0.88 [95% credible interval {CrI}, 0.73 to 1.06]) and the posterior probabilities were 8.6% (efficacy), 91.4% (harm), and 99.9% (futility). Among patients who were not critically ill, the median number of organ support-free days was 22 (IQR, 18 to 22 days) for the vitamin C group vs 22 (IQR, 21 to 22 days) for the control group (adjusted proportional OR, 0.80 [95% CrI, 0.60 to 1.01]) and the posterior probabilities were 2.9% (efficacy), 97.1% (harm), and greater than 99.9% (futility). Among critically ill patients, survival to hospital discharge was 61.9% (642/1037) for the vitamin C group vs 64.6% (343/531) for the control group (adjusted OR, 0.92 [95% CrI, 0.73 to 1.17]) and the posterior probability was 24.0% for efficacy. Among patients who were not critically ill, survival to hospital discharge was 85.1% (388/456) for the vitamin C group vs 86.6% (490/566) for the control group (adjusted OR, 0.86 [95% CrI, 0.61 to 1.17]) and the posterior probability was 17.8% for efficacy., Conclusions and Relevance: In hospitalized patients with COVID-19, vitamin C had low probability of improving the primary composite outcome of organ support-free days and hospital survival., Trial Registration: ClinicalTrials.gov Identifiers: NCT04401150 (LOVIT-COVID) and NCT02735707 (REMAP-CAP).

Published
2023
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4. Frequency of screening and SBT Technique Trial-North American Weaning Collaboration (FAST-NAWC): an update to the protocol and statistical analysis plan.

Author

Burns KEA, Lafrienier-Roula M, Hill NS, Cook DJ, Seely AJE, Rochwerg B, Mayette M, D'Aragon F, Devlin JW, Dodek P, Tanios M, Gouskos A, Turgeon AF, Aslanian P, Sia YT, Beitler JR, Hyzy R, Criner GJ, Kassis EB, Tsang JLY, Meade MO, Liebler JM, Wong JTY, and Thorpe KE

Subjects
Adult, Humans, Critical Illness, Time Factors, North America, Respiration, Artificial, Randomized Controlled Trials as Topic, Multicenter Studies as Topic, Ventilator Weaning methods, COVID-19
Abstract

Background: This update summarizes key changes made to the protocol for the Frequency of Screening and Spontaneous Breathing Trial (SBT) Technique Trial-North American Weaning Collaborative (FAST-NAWC) trial since the publication of the original protocol. This multicenter, factorial design randomized controlled trial with concealed allocation, will compare the effect of both screening frequency (once vs. at least twice daily) to identify candidates to undergo a SBT and SBT technique [pressure support + positive end-expiratory pressure vs. T-piece] on the time to successful extubation (primary outcome) in 760 critically ill adults who are invasively ventilated for at least 24 h in 20 North American intensive care units., Methods/design: Protocols for the pilot, factorial design trial and the full trial were previously published in J Clin Trials ( https://doi.org/10.4172/2167-0870.1000284 ) and Trials (https://doi: 10.1186/s13063-019-3641-8). As planned, participants enrolled in the FAST pilot trial will be included in the report of the full FAST-NAWC trial. In response to the onset of the coronavirus disease of 2019 (COVID-19) pandemic when approximately two thirds of enrollment was complete, we revised the protocol and consent form to include critically ill invasively ventilated patients with COVID-19. We also refined the statistical analysis plan (SAP) to reflect inclusion and reporting of participants with and without COVID-19. This update summarizes the changes made and their rationale and provides a refined SAP for the FAST-NAWC trial. These changes have been finalized before completion of trial follow-up and the commencement of data analysis., Trial Registration: Clinical Trials.gov NCT02399267., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Published
2023
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5. Real-World Effectiveness of Nirmatrelvir/Ritonavir on Coronavirus Disease 2019-Associated Hospitalization Prevention: A Population-based Cohort Study in the Province of Quebec, Canada.

Author

Kaboré JL, Laffont B, Diop M, Tardif MR, Turgeon AF, Dumaresq J, Luong ML, Cauchon M, Chapdelaine H, Claveau D, Brosseau M, Haddad E, and Benigeri M

Subjects
Humans, Quebec epidemiology, Cohort Studies, Retrospective Studies, SARS-CoV-2, COVID-19 Drug Treatment, Hospitalization, Antiviral Agents therapeutic use, Ritonavir therapeutic use, COVID-19 prevention & control
Abstract

Background: Nirmatrelvir/ritonavir has shown to reduce COVID-19 hospitalization and death before Omicron, but updated real-world evidence studies are needed. This study aimed to assess whether nirmatrelvir/ritonavir reduces the risk of COVID-19-associated hospitalization among high-risk outpatients., Methods: A retrospective cohort study of outpatients with SARS-CoV-2 between March 15 and 15 October 2022, using data from the Quebec clinico-administrative databases. Outpatients treated with nirmatrelvir/ritonavir were compared with infected ones not receiving nirmatrelvir/ritonavir using propensity-score matching. Relative risk (RR) of COVID-19-associated hospitalization within 30 days was assessed using a Poisson regression., Results: A total of 8402 treated outpatients were matched to controls. Regardless of vaccination status, nirmatrelvir/ritonavir treatment was associated with a 69% reduced RR of hospitalization (RR: .31; 95% CI: .28; .36; number needed to treat [NNT] = 13). The effect was more pronounced in outpatients with incomplete primary vaccination (RR: .04; 95% CI: .03; .06; NNT = 8), while no benefit was found in those with a complete primary vaccination (RR: .93; 95% CI: .78; 1.08). Subgroups analysis among high-risk outpatients with a complete primary vaccination showed that nirmatrelvir/ritonavir treatment was associated with a significant decrease in the RR of hospitalization in severely immunocompromised outpatients (RR: .66; 95% CI: .50; .89; NNT = 16) and in high-risk outpatients aged ≥70 years (RR: .50; 95% CI: .34; .74; NNT = 10) when the last dose of the vaccine was received at least 6 months ago., Conclusions: Nirmatrelvir/ritonavir reduces the risk of COVID-19-associated hospitalization among incompletely vaccinated high-risk outpatients and among some subgroups of completely vaccinated high-risk outpatients., Competing Interests: Potential conflicts of interest. M. R. T. reports an issued or pending patent (US 11,359,010 B2) for humanized anti-S100A9 antibody and uses thereof (no royalties to date). A. F. T. is the chairholder of the Canada Research Chair in Critical Care Neurology and Trauma. M.-L. L. reports consulting fees from Takeda and Merck. H. C. reports grants or contracts from Novartis, Roche, Sanofi, and Merck for participation in COVID-19–related trials (paid to their institution) and unpaid participation on the medical board of an immunodeficient patient advocacy group (Quebec and Canada). M. Brosseau reports a grant from AstraZeneca as the local principal investigator for the Efficacy and Safety of Tozorakimab in Patients Hospitalised for Viral Lung Infection Requiring Supplemental Oxygen (TILIA) study (paid to their institution). E. H. reports an ongoing patent from Immune BioSolutions for an anti–SARS-CoV-2 monoclonal antibody, and an unpaid position as President Elect of the Clinical Immunology Society. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Published
2023
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6. Equity issues rarely addressed in the development of COVID-19 formal recommendations and good practice statements: a cross-sectional study.

Author

Dewidar O, Bondok M, Abdelrazeq L, Aliyeva K, Solo K, Welch V, Brignardello-Petersen R, Mathew JL, Hazlewood G, Pottie K, Hartling L, Khalifa DS, Duda S, Falavigna M, Khabsa J, Lotfi T, Petkovic J, Elliot S, Chi Y, Parker R, Kristjansson E, Riddle A, Darzi AJ, Magwood O, Saad A, Rada G, Neumann I, Loeb M, Reveiz L, Mertz D, Piggott T, Turgeon AF, Schünemann H, and Tugwell P

Subjects
Child, Humans, Cross-Sectional Studies, Social Class, Research Design, COVID-19 epidemiology, Health Equity
Abstract

Background and Objective: To identify COVID-19 actionable statements (e.g., recommendations) focused on specific disadvantaged populations in the living map of COVID-19 recommendations (eCOVIDRecMap) and describe how health equity was assessed in the development of the formal recommendations., Methods: We employed the place of residence, race or ethnicity or culture, occupation, gender or sex, religion, education, socio-economic status, and social capital-Plus framework to identify statements focused on specific disadvantaged populations. We assessed health equity considerations in the evidence to decision frameworks (EtD) of formal recommendations for certainty of evidence and impact on health equity criteria according to the Grading of Recommendations, Assessment, Development, and Evaluations criteria., Results: We identified 16% (124/758) formal recommendations and 24% (186/819) good practice statements (GPS) that were focused on specific disadvantaged populations. Formal recommendations (40%, 50/124) and GPS (25%, 47/186) most frequently focused on children. Seventy-six percent (94/124) of the recommendations were accompanied with EtDs. Over half (55%, 52/94) of those considered indirectness of the evidence for disadvantaged populations. Considerations in impact on health equity criterion most frequently involved implementation of the recommendation for disadvantaged populations (17%, 16/94)., Conclusion: Equity issues were rarely explicitly considered in the development COVID-19 formal recommendations focused on specific disadvantaged populations. Guidance is needed to support the consideration of health equity in guideline development during health emergencies., Competing Interests: Declaration of Competing Interest Several authors (L.R., M.L., G.H.) were involved in the development of guidelines that were included in the study. However, they did not participate in the evaluation of health equity considerations in the study. Authors hold sole responsibility for the views expressed in the manuscript, which may not necessarily reflect the opinion or policy of the Pan American Health Organization, Canadian Rheumatology Association. The remaining authors report no conflicts of interest., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Published
2023
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7. Good or best practice statements: proposal for the operationalisation and implementation of GRADE guidance.

Author

Dewidar O, Lotfi T, Langendam MW, Parmelli E, Saz Parkinson Z, Solo K, Chu DK, Mathew JL, Akl EA, Brignardello-Petersen R, Mustafa RA, Moja L, Iorio A, Chi Y, Canelo-Aybar C, Kredo T, Karpusheff J, Turgeon AF, Alonso-Coello P, Wiercioch W, Gerritsen A, Klugar M, Rojas MX, Tugwell P, Welch VA, Pottie K, Munn Z, Nieuwlaat R, Ford N, Stevens A, Khabsa J, Nasir Z, Leontiadis G, Meerpohl J, Piggott T, Qaseem A, Matthews M, and Schünemann HJ

Subjects
Humans, Research Design, Evidence-Based Medicine, COVID-19
Abstract

An evidence-based approach is considered the gold standard for health decision-making. Sometimes, a guideline panel might judge the certainty that the desirable effects of an intervention clearly outweigh its undesirable effects as high, but the body of supportive evidence is indirect. In such cases, the application of the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) approach for grading the strength of recommendations is inappropriate. Instead, the GRADE Working Group has recommended developing ungraded best or good practice statement (GPS) and developed guidance under which circumsances they would be appropriate.Through an evaluation of COVID-1- related recommendations on the eCOVID Recommendation Map (COVID-19.recmap.org), we found that recommendations qualifying a GPS were widespread. However, guideline developers failed to label them as GPS or transparently report justifications for their development. We identified ways to improve and facilitate the operationalisation and implementation of the GRADE guidance for GPS.Herein, we propose a structured process for the development of GPSs that includes applying a sequential order for the GRADE guidance for developing GPS. This operationalisation considers relevant evidence-to-decision criteria when assessing the net consequences of implementing the statement, and reporting information supporting judgments for each criterion. We also propose a standardised table to facilitate the identification of GPS and reporting of their development. This operationalised guidance, if endorsed by guideline developers, may palliate some of the shortcomings identified. Our proposal may also inform future updates of the GRADE guidance for GPS., Competing Interests: Competing interests: This work was supported by grants from Canadian Institutes of Health (FRN VR4-172741 and GA3-177732) and WHO during the conduct of the study. EA, HJS and PA-C report contribution to the development of the original five criteria for assessing the appropriateness of issuing good practice statements. The remaining authors have nothing else to declare., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Published
2023
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8. 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 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

Subjects
Female, Humans, Male, Middle Aged, Bayes Theorem, Hospitalization, Critical Illness, Receptors, Chemokine antagonists & inhibitors, Angiotensin Receptor Antagonists pharmacology, Angiotensin Receptor Antagonists therapeutic use, Angiotensin-Converting Enzyme Inhibitors pharmacology, Angiotensin-Converting Enzyme Inhibitors therapeutic use, COVID-19 therapy, Renin-Angiotensin System drug effects, COVID-19 Drug Treatment methods
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
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9. Long-term (180-Day) Outcomes in Critically Ill Patients With COVID-19 in the REMAP-CAP Randomized Clinical Trial.

Author

Higgins AM, Berry LR, Lorenzi E, Murthy S, McQuilten Z, Mouncey PR, Al-Beidh F, Annane D, Arabi YM, Beane A, van Bentum-Puijk W, Bhimani Z, Bonten MJM, Bradbury CA, Brunkhorst FM, Burrell A, Buzgau A, Buxton M, Charles WN, Cove M, Detry MA, Estcourt LJ, Fagbodun EO, Fitzgerald M, Girard TD, Goligher EC, Goossens H, Haniffa R, Hills T, Horvat CM, Huang DT, Ichihara N, Lamontagne F, Marshall JC, McAuley DF, McGlothlin A, McGuinness SP, McVerry BJ, Neal MD, Nichol AD, Parke RL, Parker JC, Parry-Billings K, Peters SEC, Reyes LF, Rowan KM, Saito H, Santos MS, Saunders CT, Serpa-Neto A, Seymour CW, Shankar-Hari M, Stronach LM, Turgeon AF, Turner AM, van de Veerdonk FL, Zarychanski R, Green C, Lewis RJ, Angus DC, McArthur CJ, Berry S, Derde LPG, Gordon AC, Webb SA, and Lawler PR

Subjects
Adult, Humans, Female, Middle Aged, Male, Lopinavir therapeutic use, Ritonavir therapeutic use, Follow-Up Studies, Hydroxychloroquine therapeutic use, SARS-CoV-2, Critical Illness therapy, Bayes Theorem, COVID-19 Serotherapy, Adrenal Cortex Hormones therapeutic use, Anticoagulants adverse effects, Receptors, Interleukin-6, COVID-19
Abstract

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 [95% CrI, 0.82-1.38]) and the probabilities of harm from hydroxychloroquine (96.9%; HR, 1.51 [95% CrI, 0.98-2.29]) and the combination of lopinavir-ritonavir and hydroxychloroquine (96.8%; HR, 1.61 [95% CrI, 0.97-2.67]) were high. The corticosteroid domain was stopped early prior to reaching a predefined statistical trigger; there was a 57.1% to 61.6% probability of improving 6-month survival across varying hydrocortisone dosing strategies., Conclusions and Relevance: Among critically ill patients with COVID-19 randomized to receive 1 or more therapeutic interventions, treatment with an IL-6 receptor antagonist had a greater than 99.9% probability of improved 180-day mortality compared with patients randomized to the control, and treatment with an antiplatelet had a 95.0% probability of improved 180-day mortality compared with patients randomized to the control. Overall, when considered with previously reported short-term results, the findings indicate that initial in-hospital treatment effects were consistent for most therapies through 6 months.

Published
2023
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10. Which actionable statements qualify as good practice statements In Covid-19 guidelines? A systematic appraisal.

Author

Dewidar O, Lotfi T, Langendam M, Parmelli E, Saz Parkinson Z, Solo K, Chu DK, Mathew JL, Akl EA, Brignardello-Petersen R, Mustafa RA, Moja L, Iorio A, Chi Y, Canelo-Aybar C, Kredo T, Karpusheff J, Turgeon AF, Alonso-Coello P, Wiercioch W, Gerritsen A, Klugar M, Rojas MX, Tugwell P, Welch VA, Pottie K, Munn Z, Nieuwlaat R, Ford N, Stevens A, Khabsa J, Nasir Z, Leontiadis GI, Meerpohl JJ, Piggott T, Qaseem A, Matthews M, and Schünemann HJ

Subjects
Humans, China, COVID-19
Abstract

Objectives: To evaluate the development and quality of actionable statements that qualify as good practice statements (GPS) reported in COVID-19 guidelines., Design and Setting: Systematic review . We searched MEDLINE, MedSci, China National Knowledge Infrastructure (CNKI), databases of Grading of Recommendations Assessment, Development and Evaluation (GRADE) Guidelines, NICE, WHO and Guidelines International Network (GIN) from March 2020 to September 2021. We included original or adapted recommendations addressing any COVID-19 topic., Main Outcome Measures: We used GRADE Working Group criteria for assessing the appropriateness of issuing a GPS: (1) clear and actionable; (2) rationale necessitating the message for healthcare practice; (3) practicality of systematically searching for evidence; (4) likely net positive consequences from implementing the GPS and (5) clear link to the indirect evidence. We assessed guideline quality using the Appraisal of Guidelines for Research and Evaluation II tool., Results: 253 guidelines from 44 professional societies issued 3726 actionable statements. We classified 2375 (64%) as GPS; of which 27 (1%) were labelled as GPS by guideline developers. 5 (19%) were labelled as GPS by their authors but did not meet GPS criteria. Of the 2375 GPS, 85% were clear and actionable; 59% provided a rationale necessitating the message for healthcare practice, 24% reported the net positive consequences from implementing the GPS. Systematic collection of evidence was deemed impractical for 13% of the GPS, and 39% explained the chain of indirect evidence supporting GPS development. 173/2375 (7.3%) statements explicitly satisfied all five criteria. The guidelines' overall quality was poor regardless of the appropriateness of GPS development and labelling., Conclusions: Statements that qualify as GPS are common in COVID-19 guidelines but are characterised by unclear designation and development processes, and methodological weaknesses., Competing Interests: Competing interests: HJS, AS, VAW report grants from Canadian Instituites of Health during the conduct of the study—FRN VR4-172741 & GA3-177732. RAM reports grants from WHO, grants from ASH, grants from ACR, other from Boehringer ingelheim international, grants from NIDDK, outside the submitted work. EA, PA-C and HJS report contribution to the development of the original five criteria for assessing the appropriateness of issuing good practice statements. The remaining authors have nothing else to declare., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Published
2022
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11. An evaluation of the COVID-19 recommendation map identified diverging clinical and public health guidance.

Author

Nasir ZH, Mertz D, Nieuwlaat R, Santesso N, Lotfi T, Motilall A, Moja L, Mbuagbaw L, Klugar M, Turgeon AF, Mathew JL, Canelo-Aybar C, Pottie K, Dewidar O, Langendam MW, Iorio A, Vist GE, Meerpohl JJ, Flottorp S, Kredo T, Piggott T, Mathews M, Qaseem A, Chu DK, Tugwell P, Klugarová J, Nelson H, Hussein H, Suvada J, Neumann I, and Schünemann HJ

Subjects
Humans, COVID-19 epidemiology, Public Health
Abstract

Objectives: To describe divergence between actionable statements issued by coronavirus disease 2019 (COVID-19) guideline developers cataloged on the "COVID-19 Recommendations and Gateway to Contextualization" platform., Study Design and Setting: We defined divergence as at least two comparable actionable statements with different explicit judgments of strength, direction, or subgroup consideration of the population or intervention. We applied a content analysis to compare guideline development methods for a sample of diverging statements and to evaluate factors associated with divergence., Results: Of the 138 guidelines evaluated, 85 (62%) contained at least one statement that diverged from another guideline. We identified 223 diverging statements in these 85 guidelines. We grouped statements into 66 clusters. Each cluster addressed the same population, intervention, and comparator group or just similar interventions. Clinical practice statements were more likely to diverge in an explicit judgment of strength or direction compared to public health statements. Statements were more likely to diverge in strength than direction. The date of publication, used evidence, interpretation of evidence, and contextualization considerations were associated with divergence., Conclusion: More than half of the assessed guidelines issued at least one diverging statement. This study helps in understanding the types of differences between guidelines issuing comparable statements and factors associated with their divergence., (Copyright © 2022. Published by Elsevier Inc.)

Published
2022
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12. Effect of Antiplatelet Therapy on Survival and Organ Support-Free Days in Critically Ill Patients With COVID-19: A Randomized Clinical Trial.

Author

Bradbury CA, Lawler PR, Stanworth SJ, McVerry BJ, McQuilten Z, Higgins AM, Mouncey PR, Al-Beidh F, Rowan KM, Berry LR, Lorenzi E, Zarychanski R, Arabi YM, Annane D, Beane A, van Bentum-Puijk W, Bhimani Z, Bihari S, Bonten MJM, Brunkhorst FM, Buzgau A, Buxton M, Carrier M, Cheng AC, Cove M, Detry MA, Estcourt LJ, Fitzgerald M, Girard TD, Goligher EC, Goossens H, Haniffa R, Hills T, Huang DT, Horvat CM, Hunt BJ, Ichihara N, Lamontagne F, Leavis HL, Linstrum KM, Litton E, Marshall JC, McAuley DF, McGlothlin A, McGuinness SP, Middeldorp S, Montgomery SK, Morpeth SC, Murthy S, Neal MD, Nichol AD, Parke RL, Parker JC, Reyes LF, Saito H, Santos MS, Saunders CT, Serpa-Neto A, Seymour CW, Shankar-Hari M, Singh V, Tolppa T, Turgeon AF, Turner AM, van de Veerdonk FL, Green C, Lewis RJ, Angus DC, McArthur CJ, Berry S, Derde LPG, Webb SA, and Gordon AC

Subjects
Adult, Anticoagulants adverse effects, Anticoagulants therapeutic use, Aspirin adverse effects, Aspirin therapeutic use, Bayes Theorem, Female, Hemorrhage chemically induced, Humans, Male, Middle Aged, Purinergic P2Y Receptor Antagonists adverse effects, Purinergic P2Y Receptor Antagonists therapeutic use, Respiration, Artificial, COVID-19 complications, COVID-19 mortality, COVID-19 therapy, Critical Illness mortality, Critical Illness therapy, Platelet Aggregation Inhibitors adverse effects, Platelet Aggregation Inhibitors therapeutic use, Venous Thromboembolism drug therapy, Venous Thromboembolism etiology, COVID-19 Drug Treatment
Abstract

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 criterion for futility was met for the pooled antiplatelet group compared with control. Among the 1557 critically ill patients randomized, 8 patients withdrew consent and 1549 completed the trial (median age, 57 years; 521 [33.6%] female). The median for organ support-free days was 7 (IQR, -1 to 16) in both the antiplatelet and control groups (median-adjusted OR, 1.02 [95% credible interval {CrI}, 0.86-1.23]; 95.7% posterior probability of futility). The proportions of patients surviving to hospital discharge were 71.5% (723/1011) and 67.9% (354/521) in the antiplatelet and control groups, respectively (median-adjusted OR, 1.27 [95% CrI, 0.99-1.62]; adjusted absolute difference, 5% [95% CrI, -0.2% to 9.5%]; 97% posterior probability of efficacy). Among survivors, the median for organ support-free days was 14 in both groups. Major bleeding occurred in 2.1% and 0.4% of patients in the antiplatelet and control groups (adjusted OR, 2.97 [95% CrI, 1.23-8.28]; adjusted absolute risk increase, 0.8% [95% CrI, 0.1%-2.7%]; 99.4% probability of harm)., Conclusions and Relevance: Among critically ill patients with COVID-19, treatment with an antiplatelet agent, compared with no antiplatelet agent, had a low likelihood of providing improvement in the number of organ support-free days within 21 days., Trial Registration: ClinicalTrials.gov Identifier: NCT02735707.

Published
2022
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13. A taxonomy and framework for identifying and developing actionable statements in guidelines suggests avoiding informal recommendations.

Author

Lotfi T, Hajizadeh A, Moja L, Akl EA, Piggott T, Kredo T, Langendam MW, Iorio A, Klugar M, Klugarová J, Neumann I, Wiercioch W, Leontiadis GI, Mbuagbaw L, Turgeon AF, Meerpohl J, Stevens A, Brozek J, Santesso N, Pottie K, Dewidar O, Flottorp SA, Karpusheff J, Saz-Parkinson Z, Rojas MX, Parmelli E, Chu DK, Tugwell P, Welch V, Avey MT, Brignardello-Petersen R, Mathew JL, Munn Z, Nieuwlaat R, Ford N, Qaseem A, Askie LM, and Schünemann HJ

Subjects
Humans, Publications, Research Design, World Health Organization, COVID-19 epidemiology
Abstract

Objective: To propose a taxonomy and framework that identifies and presents actionable statements in guidelines., Study Design and Setting: We took an iterative approach reviewing case studies of guidelines produced by the World Health Organization and the American Society of Hematology to develop an initial conceptual framework. We then tested it using randomly selected recommendations from published guidelines addressing COVID-19 from different organizations, evaluated its results, and refined it before retesting. The urgency and availability of evidence for development of these recommendations varied. We consulted with experts in research methodology and guideline developers to improve the final framework., Results: The resulting taxonomy and framework distinguishes five types of actional statements: formal recommendations; research recommendations; good practice statements; implementation considerations, tools and tips; and informal recommendations. These statements should respond to a priori established criteria and require a clear structure and recognizable presentation in a guideline. Most importantly, this framework identifies informal recommendations that differ from formal recommendations by how they consider evidence and in their development process., Conclusion: The identification, standardization and explicit labelling of actionable statements according to the framework may support guideline developers to create actionable statements with clear intent, avoid informal recommendations and improve their understanding and implementation by users., (Copyright © 2021. Published by Elsevier Inc.)

Published
2022
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14. Association between convalescent plasma treatment and mortality in COVID-19: a collaborative systematic review and meta-analysis of randomized clinical trials.

Author

Axfors C, Janiaud P, Schmitt AM, Van't Hooft J, Smith ER, Haber NA, Abayomi A, Abduljalil M, Abdulrahman A, Acosta-Ampudia Y, Aguilar-Guisado M, Al-Beidh F, Alejandria MM, Alfonso RN, Ali M, AlQahtani M, AlZamrooni A, Anaya JM, Ang MAC, Aomar IF, Argumanis LE, Averyanov A, Baklaushev VP, Balionis O, Benfield T, Berry S, Birocco N, Bonifacio LB, Bowen AC, Bown A, Cabello-Gutierrez C, Camacho B, Camacho-Ortiz A, Campbell-Lee S, Cao DH, Cardesa A, Carnate JM, Castillo GJJ, Cavallo R, Chowdhury FR, Chowdhury FUH, Ciccone G, Cingolani A, Climacosa FMM, Compernolle V, Cortez CFN, Costa Neto A, D'Antico S, Daly J, Danielle F, Davis JS, De Rosa FG, Denholm JT, Denkinger CM, Desmecht D, Díaz-Coronado JC, Díaz Ponce-Medrano JA, Donneau AF, Dumagay TE, Dunachie S, Dungog CC, Erinoso O, Escasa IMS, Estcourt LJ, Evans A, Evasan ALM, Fareli CJ, Fernandez-Sanchez V, Galassi C, Gallo JE, Garcia PJ, Garcia PL, Garcia JA, Garigliany M, Garza-Gonzalez E, Gauiran DTV, Gaviria García PA, Giron-Gonzalez JA, Gómez-Almaguer D, Gordon AC, Gothot A, Grass Guaqueta JS, Green C, Grimaldi D, Hammond NE, Harvala H, Heralde FM, Herrick J, Higgins AM, Hills TE, Hines J, Holm K, Hoque A, Hoste E, Ignacio JM, Ivanov AV, Janssen M, Jennings JH, Jha V, King RAN, Kjeldsen-Kragh J, Klenerman P, Kotecha A, Krapp F, Labanca L, Laing E, Landin-Olsson M, Laterre PF, Lim LL, Lim J, Ljungquist O, Llaca-Díaz JM, López-Robles C, López-Cárdenas S, Lopez-Plaza I, Lucero JAC, Lundgren M, Macías J, Maganito SC, Malundo AFG, Manrique RD, Manzini PM, Marcos M, Marquez I, Martínez-Marcos FJ, Mata AM, McArthur CJ, McQuilten ZK, McVerry BJ, Menon DK, Meyfroidt G, Mirasol MAL, Misset B, Molton JS, Mondragon AV, Monsalve DM, Moradi Choghakabodi P, Morpeth SC, Mouncey PR, Moutschen M, Müller-Tidow C, Murphy E, Najdovski T, Nichol AD, Nielsen H, Novak RM, O'Sullivan MVN, Olalla J, Osibogun A, Osikomaiya B, Oyonarte S, Pardo-Oviedo JM, Patel MC, Paterson DL, Peña-Perez CA, Perez-Calatayud AA, Pérez-Alba E, Perkina A, Perry N, Pouladzadeh M, Poyato I, Price DJ, Quero AKH, Rahman MM, Rahman MS, Ramesh M, Ramírez-Santana C, Rasmussen M, Rees MA, Rego E, Roberts JA, Roberts DJ, Rodríguez Y, Rodríguez-Baño J, Rogers BA, Rojas M, Romero A, Rowan KM, Saccona F, Safdarian M, Santos MCM, Sasadeusz J, Scozzari G, Shankar-Hari M, Sharma G, Snelling T, Soto A, Tagayuna PY, Tang A, Tatem G, Teofili L, Tong SYC, Turgeon AF, Veloso JD, Venkatesh B, Ventura-Enriquez Y, Webb SA, Wiese L, Wikén C, Wood EM, Yusubalieva GM, Zacharowski K, Zarychanski R, Khanna N, Moher D, Goodman SN, Ioannidis JPA, and Hemkens LG

Subjects
Humans, Immunization, Passive, Randomized Controlled Trials as Topic, SARS-CoV-2, Treatment Outcome, COVID-19 Serotherapy, COVID-19 therapy
Abstract

Background: Convalescent plasma has been widely used to treat COVID-19 and is under investigation in numerous randomized clinical trials, but results are publicly available only for a small number of trials. The objective of this study was to assess the benefits of convalescent plasma treatment compared to placebo or no treatment and all-cause mortality in patients with COVID-19, using data from all available randomized clinical trials, including unpublished and ongoing trials (Open Science Framework, https://doi.org/10.17605/OSF.IO/GEHFX )., Methods: In this collaborative systematic review and meta-analysis, clinical trial registries (ClinicalTrials.gov, WHO International Clinical Trials Registry Platform), the Cochrane COVID-19 register, the LOVE database, and PubMed were searched until April 8, 2021. Investigators of trials registered by March 1, 2021, without published results were contacted via email. Eligible were ongoing, discontinued and completed randomized clinical trials that compared convalescent plasma with placebo or no treatment in COVID-19 patients, regardless of setting or treatment schedule. Aggregated mortality data were extracted from publications or provided by investigators of unpublished trials and combined using the Hartung-Knapp-Sidik-Jonkman random effects model. We investigated the contribution of unpublished trials to the overall evidence., Results: A total of 16,477 patients were included in 33 trials (20 unpublished with 3190 patients, 13 published with 13,287 patients). 32 trials enrolled only hospitalized patients (including 3 with only intensive care unit patients). Risk of bias was low for 29/33 trials. Of 8495 patients who received convalescent plasma, 1997 died (23%), and of 7982 control patients, 1952 died (24%). The combined risk ratio for all-cause mortality was 0.97 (95% confidence interval: 0.92; 1.02) with between-study heterogeneity not beyond chance (I 2  = 0%). The RECOVERY trial had 69.8% and the unpublished evidence 25.3% of the weight in the meta-analysis., Conclusions: Convalescent plasma treatment of patients with COVID-19 did not reduce all-cause mortality. These results provide strong evidence that convalescent plasma treatment for patients with COVID-19 should not be used outside of randomized trials. Evidence synthesis from collaborations among trial investigators can inform both evidence generation and evidence application in patient care., (© 2021. The Author(s).)

Published
2021
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15. Effect of Convalescent Plasma on Organ Support-Free Days in Critically Ill Patients With COVID-19: A Randomized Clinical Trial.

Author

Estcourt LJ, Turgeon AF, McQuilten ZK, McVerry BJ, Al-Beidh F, Annane D, Arabi YM, Arnold DM, Beane A, Bégin P, van Bentum-Puijk W, Berry LR, Bhimani Z, Birchall JE, Bonten MJM, Bradbury CA, Brunkhorst FM, Buxton M, Callum JL, Chassé M, Cheng AC, Cove ME, Daly J, Derde L, Detry MA, De Jong M, Evans A, Fergusson DA, Fish M, Fitzgerald M, Foley C, Goossens H, Gordon AC, Gosbell IB, Green C, Haniffa R, Harvala H, Higgins AM, Hills TE, Hoad VC, Horvat C, Huang DT, Hudson CL, Ichihara N, Laing E, Lamikanra AA, Lamontagne F, Lawler PR, Linstrum K, Litton E, Lorenzi E, MacLennan S, Marshall J, McAuley DF, McDyer JF, McGlothlin A, McGuinness S, Miflin G, Montgomery S, Mouncey PR, Murthy S, Nichol A, Parke R, Parker JC, Priddee N, Purcell DFJ, Reyes LF, Richardson P, Robitaille N, Rowan KM, Rynne J, Saito H, Santos M, Saunders CT, Serpa Neto A, Seymour CW, Silversides JA, Tinmouth AA, Triulzi DJ, Turner AM, van de Veerdonk F, Walsh TS, Wood EM, Berry S, Lewis RJ, Menon DK, McArthur C, Zarychanski R, Angus DC, Webb SA, Roberts DJ, and Shankar-Hari M

Subjects
ABO Blood-Group System, Adult, Aged, Critical Illness therapy, Female, Hospital Mortality, Humans, Immunization, Passive, Length of Stay, Logistic Models, Male, Middle Aged, Respiration, Artificial statistics & numerical data, Treatment Failure, Vasoconstrictor Agents therapeutic use, COVID-19 Serotherapy, COVID-19 therapy
Abstract

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 thromboembolic events at 90 days; and serious adverse events., Results: Among the 2011 participants who were randomized (median age, 61 [IQR, 52 to 70] years and 645/1998 [32.3%] women), 1990 (99%) completed the trial. The convalescent plasma intervention was stopped after the prespecified criterion for futility was met. The median number of organ support-free days was 0 (IQR, -1 to 16) in the convalescent plasma group and 3 (IQR, -1 to 16) in the no convalescent plasma group. The in-hospital mortality rate was 37.3% (401/1075) for the convalescent plasma group and 38.4% (347/904) for the no convalescent plasma group and the median number of days alive and free of organ support was 14 (IQR, 3 to 18) and 14 (IQR, 7 to 18), respectively. The median-adjusted OR was 0.97 (95% credible interval, 0.83 to 1.15) and the posterior probability of futility (OR <1.2) was 99.4% for the convalescent plasma group compared with the no convalescent plasma group. The treatment effects were consistent across the primary outcome and the 11 secondary outcomes. Serious adverse events were reported in 3.0% (32/1075) of participants in the convalescent plasma group and in 1.3% (12/905) of participants in the no convalescent plasma group., Conclusions and Relevance: Among critically ill adults with confirmed COVID-19, treatment with 2 units of high-titer, ABO-compatible convalescent plasma had a low likelihood of providing improvement in the number of organ support-free days., Trial Registration: ClinicalTrials.gov Identifier: NCT02735707.

Published
2021
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16. Convalescent plasma for hospitalized patients with COVID-19: an open-label, randomized controlled trial.

Author

Bégin P, Callum J, Jamula E, Cook R, Heddle NM, Tinmouth A, Zeller MP, Beaudoin-Bussières G, Amorim L, Bazin R, Loftsgard KC, Carl R, Chassé M, Cushing MM, Daneman N, Devine DV, Dumaresq J, Fergusson DA, Gabe C, Glesby MJ, Li N, Liu Y, McGeer A, Robitaille N, Sachais BS, Scales DC, Schwartz L, Shehata N, Turgeon AF, Wood H, Zarychanski R, Finzi A, and Arnold DM

Subjects
Adult, Aged, Aged, 80 and over, Brazil epidemiology, COVID-19 epidemiology, Canada epidemiology, Female, Hospitalization statistics & numerical data, Humans, Immunization, Passive, Intention to Treat Analysis, Male, Middle Aged, SARS-CoV-2 immunology, Treatment Outcome, United States epidemiology, COVID-19 Serotherapy, COVID-19 therapy
Abstract

The efficacy of convalescent plasma for coronavirus disease 2019 (COVID-19) is unclear. Although most randomized controlled trials have shown negative results, uncontrolled studies have suggested that the antibody content could influence patient outcomes. We conducted an open-label, randomized controlled trial of convalescent plasma for adults with COVID-19 receiving oxygen within 12 d of respiratory symptom onset ( NCT04348656 ). Patients were allocated 2:1 to 500 ml of convalescent plasma or standard of care. The composite primary outcome was intubation or death by 30 d. Exploratory analyses of the effect of convalescent plasma antibodies on the primary outcome was assessed by logistic regression. The trial was terminated at 78% of planned enrollment after meeting stopping criteria for futility. In total, 940 patients were randomized, and 921 patients were included in the intention-to-treat analysis. Intubation or death occurred in 199/614 (32.4%) patients in the convalescent plasma arm and 86/307 (28.0%) patients in the standard of care arm-relative risk (RR) = 1.16 (95% confidence interval (CI) 0.94-1.43, P = 0.18). Patients in the convalescent plasma arm had more serious adverse events (33.4% versus 26.4%; RR = 1.27, 95% CI 1.02-1.57, P = 0.034). The antibody content significantly modulated the therapeutic effect of convalescent plasma. In multivariate analysis, each standardized log increase in neutralization or antibody-dependent cellular cytotoxicity independently reduced the potential harmful effect of plasma (odds ratio (OR) = 0.74, 95% CI 0.57-0.95 and OR = 0.66, 95% CI 0.50-0.87, respectively), whereas IgG against the full transmembrane spike protein increased it (OR = 1.53, 95% CI 1.14-2.05). Convalescent plasma did not reduce the risk of intubation or death at 30 d in hospitalized patients with COVID-19. Transfusion of convalescent plasma with unfavorable antibody profiles could be associated with worse clinical outcomes compared to standard care., (© 2021. The Author(s).)

Published
2021
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17. The Biobanque québécoise de la COVID-19 (BQC19)-A cohort to prospectively study the clinical and biological determinants of COVID-19 clinical trajectories.

Author

Tremblay K, Rousseau S, Zawati MH, Auld D, Chassé M, Coderre D, Falcone EL, Gauthier N, Grandvaux N, Gros-Louis F, Jabet C, Joly Y, Kaufmann DE, Laprise C, Larochelle C, Maltais F, Mes-Masson AM, Montpetit A, Piché A, Richards JB, Tse SM, Turgeon AF, Turecki G, Vinh DC, Wang HT, and Mooser V

Subjects
COVID-19 epidemiology, COVID-19 genetics, COVID-19 metabolism, Humans, Information Dissemination methods, Pandemics, Quebec epidemiology, SARS-CoV-2 isolation & purification, Biological Specimen Banks organization & administration, COVID-19 pathology
Abstract

SARS-CoV-2 infection causing the novel coronavirus disease 2019 (COVID-19) has been responsible for more than 2.8 million deaths and nearly 125 million infections worldwide as of March 2021. In March 2020, the World Health Organization determined that the COVID-19 outbreak is a global pandemic. The urgency and magnitude of this pandemic demanded immediate action and coordination between local, regional, national, and international actors. In that mission, researchers require access to high-quality biological materials and data from SARS-CoV-2 infected and uninfected patients, covering the spectrum of disease manifestations. The "Biobanque québécoise de la COVID-19" (BQC19) is a pan-provincial initiative undertaken in Québec, Canada to enable the collection, storage and sharing of samples and data related to the COVID-19 crisis. As a disease-oriented biobank based on high-quality biosamples and clinical data of hospitalized and non-hospitalized SARS-CoV-2 PCR positive and negative individuals. The BQC19 follows a legal and ethical management framework approved by local health authorities. The biosamples include plasma, serum, peripheral blood mononuclear cells and DNA and RNA isolated from whole blood. In addition to the clinical variables, BQC19 will provide in-depth analytical data derived from the biosamples including whole genome and transcriptome sequencing, proteome and metabolome analyses, multiplex measurements of key circulating markers as well as anti-SARS-CoV-2 antibody responses. BQC19 will provide the scientific and medical communities access to data and samples to better understand, manage and ultimately limit, the impact of COVID-19. In this paper we present BQC19, describe the process according to which it is governed and organized, and address opportunities for future research collaborations. BQC19 aims to be a part of a global communal effort addressing the challenges of COVID-19., Competing Interests: The authors have declared that no competing interests exist.

Published
2021
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18. Convalescent plasma for adults with acute COVID-19 respiratory illness (CONCOR-1): study protocol for an international, multicentre, randomized, open-label trial.

Author

Bégin P, Callum J, Heddle NM, Cook R, Zeller MP, Tinmouth A, Fergusson DA, Cushing MM, Glesby MJ, Chassé M, Devine DV, Robitalle N, Bazin R, Shehata N, Finzi A, McGeer A, Scales DC, Schwartz L, Turgeon AF, Zarychanski R, Daneman N, Carl R, Amorim L, Gabe C, Ellis M, Sachais BS, Loftsgard KC, Jamula E, Carruthers J, Duncan J, Lucier K, Li N, Liu Y, Armali C, Kron A, Modi D, Auclair MC, Cerro S, Avram M, and Arnold DM

Subjects
Adult, Bisoprolol, Humans, Immunization, Passive, Multicenter Studies as Topic, Randomized Controlled Trials as Topic, SARS-CoV-2, Treatment Outcome, COVID-19 Serotherapy, COVID-19 therapy, Coronavirus Infections
Abstract

Background: Convalescent plasma has been used for numerous viral diseases including influenza, severe acute respiratory syndrome, Middle East respiratory syndrome and Ebola virus; however, evidence to support its use is weak. SARS-CoV-2 is a novel coronavirus responsible for the 2019 global pandemic of COVID-19 community acquired pneumonia. We have undertaken a randomized controlled trial to assess the efficacy and safety of COVID-19 convalescent plasma (CCP) in patients with SARS-CoV-2 infection., Methods: CONCOR-1 is an open-label, multicentre, randomized trial. Inclusion criteria include the following: patients > 16 years, admitted to hospital with COVID-19 infection, receiving supplemental oxygen for respiratory complications of COVID-19, and availability of blood group compatible CCP. Exclusion criteria are : onset of respiratory symptoms more than 12 days prior to randomization, intubated or imminent plan for intubation, and previous severe reactions to plasma. Consenting patients are randomized 2:1 to receive either approximately 500 mL of CCP or standard of care. CCP is collected from donors who have recovered from COVID-19 and who have detectable anti-SARS-CoV-2 antibodies quantified serologically. The primary outcome is intubation or death at day 30. Secondary outcomes include ventilator-free days, length of stay in intensive care or hospital, transfusion reactions, serious adverse events, and reduction in SARS-CoV-2 viral load. Exploratory analyses include patients who received CCP containing high titre antibodies. A sample size of 1200 patients gives 80% power to detect a 25% relative risk reduction assuming a 30% baseline risk of intubation or death at 30 days (two-sided test; α = 0.05). An interim analysis and sample size re-estimation will be done by an unblinded independent biostatistician after primary outcome data are available for 50% of the target recruitment (n = 600)., Discussion: This trial will determine whether CCP will reduce intubation or death non-intubated adults with COVID-19. The trial will also provide information on the role of and thresholds for SARS-CoV-2 antibody titres and neutralization assays for donor qualification., Trial Registration: Clinicaltrials.gov NCT04348656 . Registered on 16 April 2020.

Published
2021
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19. Postoperative outcomes in surgical COVID-19 patients: a multicenter cohort study.

Author

Carrier FM, Amzallag É, Lecluyse V, Côté G, Couture ÉJ, D'Aragon F, Kandelman S, Turgeon AF, Deschamps A, Nitulescu R, Djade CD, Girard M, Beaulieu P, and Richebé P

Subjects
Cohort Studies, Female, Humans, Male, Middle Aged, Quebec epidemiology, Survival Analysis, COVID-19 epidemiology, COVID-19 surgery, Patient Outcome Assessment, Postoperative Complications epidemiology
Abstract

Background: Data on postoperative outcomes of the COVID-19 patient population is limited. We described COVID-19 patients who underwent a surgery and the pandemic impact on surgical activities., Methods: We conducted a multicenter cohort study between March 13 and June 192,020. We included all COVID-19 patients who underwent surgery in nine centres of the Province of Québec, the Canadian province most afflicted by the pandemic. We also included concomitant suspected COVID-19 (subsequently confirmed not to have COVID-19) patients and patients who had recovered from it. We collected data on baseline characteristics, postoperative complications and postoperative mortality. Our primary outcome was 30-day mortality. We also collected data on overall surgical activities during this first wave and during the same period in 2019., Results: We included 44 COVID-19 patients, 18 suspected patients, and 18 patients who had recovered from COVID-19 at time of surgery. Among the 44 COVID-19 patients, 31 surgeries (71%) were urgent and 16 (36%) were major. In these patients, pulmonary complications were frequent (25%) and 30-day mortality was high (15.9%). This mortality was higher in patients with symptoms (23.1%) compared to those without symptoms (5.6%), although not statistically significant (p = 0.118). Of the total 22,616 cases performed among participating centres during the study period, only 0.19% had COVID-19 at the time of surgery. Fewer procedures were performed during the study period compared to the same period in 2019 (44,486 cases)., Conclusion: In this Canadian cohort study, postoperative 30-day mortality in COVID-19 patients undergoing surgery was high (15.9%). Although few surgeries were performed on COVID-19 patients, the pandemic impact on surgical activity volume was important., Trial Registration: ClinicalTrials.gov Identifier: NCT04458337 .

Published
2021
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20. Post-exposure prophylaxis or pre-emptive therapy for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2): study protocol for a pragmatic randomized-controlled trial.

Author

Lother SA, Abassi M, Agostinis A, Bangdiwala AS, Cheng MP, Drobot G, Engen N, Hullsiek KH, Kelly LE, Lee TC, Lofgren SM, MacKenzie LJ, Marten N, McDonald EG, Okafor EC, Pastick KA, Pullen MF, Rajasingham R, Schwartz I, Skipper CP, Turgeon AF, Zarychanski R, and Boulware DR

Subjects
Humans, Double-Blind Method, SARS-CoV-2, Severity of Illness Index, Pragmatic Clinical Trials as Topic, Multicenter Studies as Topic, COVID-19 prevention & control, Hydroxychloroquine administration & dosage, Pandemics prevention & control, Post-Exposure Prophylaxis methods
Abstract

Background: The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in December 2019 causing the coronavirus disease (COVID-19) pandemic. Currently, there is a lack of evidence-based therapies to prevent COVID-19 following exposure to the virus, or to prevent worsening of symptoms following confirmed infection. We describe the design of a clinical trial of hydroxychloroquine for post-exposure prophylaxis (PEP) and pre-emptive therapy (PET) for COVID-19., Methods: We will conduct two nested multicentre international double-blind randomized placebo-controlled clinical trials of hydroxychloroquine for: 1) PEP of asymptomatic household contacts or healthcare workers exposed to COVID-19 within the past four days, and 2) PET for symptomatic outpatients with COVID-19 showing symptoms for less than four days. We will recruit 1,500 patients each for the PEP and PET trials. Participants will be randomized 1:1 to receive five days of hydroxychloroquine or placebo. The primary PEP trial outcome will be the incidence of symptomatic COVID-19. The primary PET trial outcome will be an ordinal scale of disease severity (not hospitalized, hospitalized without intensive care, hospitalization with intensive care, or death). Participant screening, informed consent, and follow-up will be exclusively internet-based with appropriate regulatory and research ethics board approvals in Canada and the United States., Discussion: These complementary randomized-controlled trials are innovatively designed and adequately powered to rapidly answer urgent questions regarding the effectiveness of hydroxychloroquine to reduce virus transmission and disease severity of COVID-19 during a pandemic. In-person participant follow-up will not be conducted to facilitate social distancing strategies and reduce risks of exposure to study personnel. Innovative trial approaches are needed to urgently assess therapeutic options to mitigate the global impact of this pandemic., Trials Registration: clinicaltrials.gov (NCT04308668); registered 16 March, 2020.

Published
2020
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21. Therapeutic Anticoagulation with Heparin in Critically Ill Patients with Covid-19

Author

Goligher, Ewan C, Bradbury, Charlotte A, McVerry, Bryan J, Lawler, Patrick R, Berger, Jeffrey S, Gong, Michelle N, Carrier, Marc, Reynolds, Harmony R, Kumar, Anand, Turgeon, Alexis F, Kornblith, Lucy Z, Kahn, Susan R, Marshall, John C, Kim, Keri S, Houston, Brett L, Derde, Lennie PG, Cushman, Mary, Tritschler, Tobias, Angus, Derek C, Godoy, Lucas C, McQuilten, Zoe, Kirwan, Bridget-Anne, Farkouh, Michael E, Brooks, Maria M, Lewis, Roger J, Berry, Lindsay R, Lorenzi, Elizabeth, Gordon, Anthony C, Ahuja, Tania, Al-Beidh, Farah, Annane, Djillali, Arabi, Yaseen M, Aryal, Diptesh, Baumann Kreuziger, Lisa, Beane, Abi, Bhimani, Zahra, Bihari, Shailesh, Billett, Henny H, Bond, Lindsay, Bonten, Marc, Brunkhorst, Frank, Buxton, Meredith, Buzgau, Adrian, Castellucci, Lana A, Chekuri, Sweta, Chen, Jen-Ting, Cheng, Allen C, Chkhikvadze, Tamta, Coiffard, Benjamin, Contreras, Aira, Costantini, Todd W, de Brouwer, Sophie, Detry, Michelle A, Duggal, Abhijit, Džavík, Vladimír, Effron, Mark B, Eng, Heather F, Escobedo, Jorge, Estcourt, Lise J, Everett, Brendan M, Fergusson, Dean A, Fitzgerald, Mark, Fowler, Robert A, Froess, Joshua D, Fu, Zhuxuan, Galanaud, Jean P, Galen, Benjamin T, Gandotra, Sheetal, Girard, Timothy D, Goodman, Andrew L, Goossens, Herman, Green, Cameron, Greenstein, Yonatan Y, Gross, Peter L, Haniffa, Rashan, Hegde, Sheila M, Hendrickson, Carolyn M, Higgins, Alisa M, Hindenburg, Alexander A, Hope, Aluko A, Horowitz, James M, Horvat, Christopher M, Huang, David T, Hudock, Kristin, Hunt, Beverley J, Husain, Mansoor, Hyzy, Robert C, Jacobson, Jeffrey R, Jayakumar, Devachandran, Keller, Norma M, Khan, Akram, Kim, Yuri, Kindzelski, Andrei, King, Andrew J, Knudson, M Margaret, Kornblith, Aaron E, Kutcher, Matthew E, Laffan, Michael A, Lamontagne, Francois, and Le Gal, Grégoire

Subjects
Clinical Trials and Supportive Activities, Clinical Research, Comparative Effectiveness Research, Cardiovascular, Good Health and Well Being, Aged, Anticoagulants, COVID-19, Critical Illness, Female, Hemorrhage, Heparin, Hospital Mortality, Humans, Logistic Models, Male, Middle Aged, Odds Ratio, Respiration, Artificial, Thrombosis, Treatment Failure, COVID-19 Drug Treatment, REMAP-CAP Investigators, ACTIV-4a Investigators, ATTACC Investigators, Medical and Health Sciences, General & Internal Medicine
Abstract

BackgroundThrombosis 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.MethodsIn 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.ResultsThe 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

Published
2021

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

Author

Lawler, Patrick R, Goligher, Ewan C, Berger, Jeffrey S, Neal, Matthew D, McVerry, Bryan J, Nicolau, Jose C, Gong, Michelle N, Carrier, Marc, Rosenson, Robert S, Reynolds, Harmony R, Turgeon, Alexis F, Escobedo, Jorge, Huang, David T, Bradbury, Charlotte A, Houston, Brett L, Kornblith, Lucy Z, Kumar, Anand, Kahn, Susan R, Cushman, Mary, McQuilten, Zoe, Slutsky, Arthur S, Kim, Keri S, Gordon, Anthony C, Kirwan, Bridget-Anne, Brooks, Maria M, Higgins, Alisa M, Lewis, Roger J, Lorenzi, Elizabeth, Berry, Scott M, Berry, Lindsay R, Aday, Aaron W, Al-Beidh, Farah, Annane, Djillali, Arabi, Yaseen M, Aryal, Diptesh, Baumann Kreuziger, Lisa, Beane, Abi, Bhimani, Zahra, Bihari, Shailesh, Billett, Henny H, Bond, Lindsay, Bonten, Marc, Brunkhorst, Frank, Buxton, Meredith, Buzgau, Adrian, Castellucci, Lana A, Chekuri, Sweta, Chen, Jen-Ting, Cheng, Allen C, Chkhikvadze, Tamta, Coiffard, Benjamin, Costantini, Todd W, de Brouwer, Sophie, Derde, Lennie PG, Detry, Michelle A, Duggal, Abhijit, Džavík, Vladimír, Effron, Mark B, Estcourt, Lise J, Everett, Brendan M, Fergusson, Dean A, Fitzgerald, Mark, Fowler, Robert A, Galanaud, Jean P, Galen, Benjamin T, Gandotra, Sheetal, García-Madrona, Sebastian, Girard, Timothy D, Godoy, Lucas C, Goodman, Andrew L, Goossens, Herman, Green, Cameron, Greenstein, Yonatan Y, Gross, Peter L, Hamburg, Naomi M, Haniffa, Rashan, Hanna, George, Hanna, Nicholas, Hegde, Sheila M, Hendrickson, Carolyn M, Hite, R Duncan, Hindenburg, Alexander A, Hope, Aluko A, Horowitz, James M, Horvat, Christopher M, Hudock, Kristin, Hunt, Beverley J, Husain, Mansoor, Hyzy, Robert C, Iyer, Vivek N, Jacobson, Jeffrey R, Jayakumar, Devachandran, Keller, Norma M, Khan, Akram, Kim, Yuri, Kindzelski, Andrei L, King, Andrew J, Knudson, M Margaret, Kornblith, Aaron E, and Krishnan, Vidya

Subjects
Cardiovascular, Clinical Trials and Supportive Activities, Clinical Research, Hematology, Transplantation, Good Health and Well Being, Adult, Aged, Anticoagulants, COVID-19, Female, Hemorrhage, Heparin, Heparin, Low-Molecular-Weight, Hospital Mortality, Humans, Male, Middle Aged, Survival Analysis, Thrombosis, COVID-19 Drug Treatment, ATTACC Investigators, ACTIV-4a Investigators, REMAP-CAP Investigators, Medical and Health Sciences, General & Internal Medicine
Abstract

BackgroundThrombosis 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.MethodsIn 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.ResultsThe 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 anticoagulation and in 0.9% of those receiving thromboprophylaxis.ConclusionsIn noncritically ill patients with Covid-19, an initial strategy of therapeutic-dose anticoagulation with heparin increased the probability of survival to hospital discharge with reduced use of cardiovascular or respiratory organ support as compared with usual-care thromboprophylaxis. (ATTACC, ACTIV-4a, and REMAP-CAP ClinicalTrials.gov numbers, NCT04372589, NCT04505774, NCT04359277, and NCT02735707.).

Published
2021

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

Author

REMAP-CAP Investigators, ACTIV-4a Investigators, ATTACC Investigators, Goligher, Ewan C, Bradbury, Charlotte A, McVerry, Bryan J, Lawler, Patrick R, Berger, Jeffrey S, Gong, Michelle N, Carrier, Marc, Reynolds, Harmony R, Kumar, Anand, Turgeon, Alexis F, Kornblith, Lucy Z, Kahn, Susan R, Marshall, John C, Kim, Keri S, Houston, Brett L, Derde, Lennie PG, Cushman, Mary, Tritschler, Tobias, Angus, Derek C, Godoy, Lucas C, McQuilten, Zoe, Kirwan, Bridget-Anne, Farkouh, Michael E, Brooks, Maria M, Lewis, Roger J, Berry, Lindsay R, Lorenzi, Elizabeth, Gordon, Anthony C, Ahuja, Tania, Al-Beidh, Farah, Annane, Djillali, Arabi, Yaseen M, Aryal, Diptesh, Baumann Kreuziger, Lisa, Beane, Abi, Bhimani, Zahra, Bihari, Shailesh, Billett, Henny H, Bond, Lindsay, Bonten, Marc, Brunkhorst, Frank, Buxton, Meredith, Buzgau, Adrian, Castellucci, Lana A, Chekuri, Sweta, Chen, Jen-Ting, Cheng, Allen C, Chkhikvadze, Tamta, Coiffard, Benjamin, Contreras, Aira, Costantini, Todd W, de Brouwer, Sophie, Detry, Michelle A, Duggal, Abhijit, Džavík, Vladimír, Effron, Mark B, Eng, Heather F, Escobedo, Jorge, Estcourt, Lise J, Everett, Brendan M, Fergusson, Dean A, Fitzgerald, Mark, Fowler, Robert A, Froess, Joshua D, Fu, Zhuxuan, Galanaud, Jean P, Galen, Benjamin T, Gandotra, Sheetal, Girard, Timothy D, Goodman, Andrew L, Goossens, Herman, Green, Cameron, Greenstein, Yonatan Y, Gross, Peter L, Haniffa, Rashan, Hegde, Sheila M, Hendrickson, Carolyn M, Higgins, Alisa M, Hindenburg, Alexander A, Hope, Aluko A, Horowitz, James M, Horvat, Christopher M, Huang, David T, Hudock, Kristin, Hunt, Beverley J, Husain, Mansoor, Hyzy, Robert C, Jacobson, Jeffrey R, Jayakumar, Devachandran, Keller, Norma M, Khan, Akram, Kim, Yuri, Kindzelski, Andrei, King, Andrew J, Knudson, M Margaret, Kornblith, Aaron E, and Kutcher, Matthew E

Subjects
REMAP-CAP Investigators, ACTIV-4a Investigators, ATTACC Investigators, Humans, Thrombosis, Critical Illness, Hemorrhage, Heparin, Anticoagulants, Treatment Failure, Respiration, Artificial, Hospital Mortality, Logistic Models, Odds Ratio, Aged, Middle Aged, Female, Male, COVID-19, Clinical Research, Cardiovascular, Clinical Trials and Supportive Activities, Comparative Effectiveness Research, General & Internal Medicine, Medical and Health Sciences
Abstract

BackgroundThrombosis 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.MethodsIn 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.ResultsThe 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

Published
2021

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

Author

ATTACC Investigators, ACTIV-4a Investigators, REMAP-CAP Investigators, Lawler, Patrick R, Goligher, Ewan C, Berger, Jeffrey S, Neal, Matthew D, McVerry, Bryan J, Nicolau, Jose C, Gong, Michelle N, Carrier, Marc, Rosenson, Robert S, Reynolds, Harmony R, Turgeon, Alexis F, Escobedo, Jorge, Huang, David T, Bradbury, Charlotte A, Houston, Brett L, Kornblith, Lucy Z, Kumar, Anand, Kahn, Susan R, Cushman, Mary, McQuilten, Zoe, Slutsky, Arthur S, Kim, Keri S, Gordon, Anthony C, Kirwan, Bridget-Anne, Brooks, Maria M, Higgins, Alisa M, Lewis, Roger J, Lorenzi, Elizabeth, Berry, Scott M, Berry, Lindsay R, Aday, Aaron W, Al-Beidh, Farah, Annane, Djillali, Arabi, Yaseen M, Aryal, Diptesh, Baumann Kreuziger, Lisa, Beane, Abi, Bhimani, Zahra, Bihari, Shailesh, Billett, Henny H, Bond, Lindsay, Bonten, Marc, Brunkhorst, Frank, Buxton, Meredith, Buzgau, Adrian, Castellucci, Lana A, Chekuri, Sweta, Chen, Jen-Ting, Cheng, Allen C, Chkhikvadze, Tamta, Coiffard, Benjamin, Costantini, Todd W, de Brouwer, Sophie, Derde, Lennie PG, Detry, Michelle A, Duggal, Abhijit, Džavík, Vladimír, Effron, Mark B, Estcourt, Lise J, Everett, Brendan M, Fergusson, Dean A, Fitzgerald, Mark, Fowler, Robert A, Galanaud, Jean P, Galen, Benjamin T, Gandotra, Sheetal, García-Madrona, Sebastian, Girard, Timothy D, Godoy, Lucas C, Goodman, Andrew L, Goossens, Herman, Green, Cameron, Greenstein, Yonatan Y, Gross, Peter L, Hamburg, Naomi M, Haniffa, Rashan, Hanna, George, Hanna, Nicholas, Hegde, Sheila M, Hendrickson, Carolyn M, Hite, R Duncan, Hindenburg, Alexander A, Hope, Aluko A, Horowitz, James M, Horvat, Christopher M, Hudock, Kristin, Hunt, Beverley J, Husain, Mansoor, Hyzy, Robert C, Iyer, Vivek N, Jacobson, Jeffrey R, Jayakumar, Devachandran, Keller, Norma M, Khan, Akram, Kim, Yuri, Kindzelski, Andrei L, and King, Andrew J

Subjects
ATTACC Investigators, ACTIV-4a Investigators, REMAP-CAP Investigators, Humans, Thrombosis, Hemorrhage, Heparin, Heparin, Low-Molecular-Weight, Anticoagulants, Hospital Mortality, Survival Analysis, Adult, Aged, Middle Aged, Female, Male, COVID-19, Hematology, Clinical Trials and Supportive Activities, Transplantation, Clinical Research, Cardiovascular, General & Internal Medicine, Medical and Health Sciences
Abstract

BackgroundThrombosis 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.MethodsIn 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.ResultsThe 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 anticoagulation and in 0.9% of those receiving thromboprophylaxis.ConclusionsIn noncritically ill patients with Covid-19, an initial strategy of therapeutic-dose anticoagulation with heparin increased the probability of survival to hospital discharge with reduced use of cardiovascular or respiratory organ support as compared with usual-care thromboprophylaxis. (ATTACC, ACTIV-4a, and REMAP-CAP ClinicalTrials.gov numbers, NCT04372589, NCT04505774, NCT04359277, and NCT02735707.).

Published
2021

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

Author

Arabi, Yaseen M, Gordon, Anthony C, Derde, Lennie PG, Nichol, Alistair D, Murthy, Srinivas, Beidh, Farah Al, Annane, Djillali, Swaidan, Lolowa Al, Beane, Abi, Beasley, Richard, Berry, Lindsay R, Bhimani, Zahra, Bonten, Marc JM, 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 YC, 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, and Webb, Steven A

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Comparative Effectiveness Research, Clinical Research, Clinical Trials and Supportive Activities, Good Health and Well Being, Adult, Antiviral Agents, Bayes Theorem, Critical Illness, Drug Combinations, Humans, Hydroxychloroquine, Lopinavir, Ritonavir, SARS-CoV-2, COVID-19 Drug Treatment, Adaptive platform trial, Intensive care, Pneumonia, Pandemic, COVID-19, Lopinavir-ritonavir, REMAP-CAP Investigators, Public Health and Health Services, Emergency & Critical Care Medicine, Clinical sciences
Abstract

PurposeTo study the efficacy of lopinavir-ritonavir and hydroxychloroquine in critically ill patients with coronavirus disease 2019 (COVID-19).MethodsCritically 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.ResultsWe 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).ConclusionAmong critically ill patients with COVID-19, lopinavir-ritonavir, hydroxychloroquine, or combination therapy worsened outcomes compared to no antiviral therapy.

Published
2021

26. Association of country income level with the characteristics and outcomes of critically ill patients hospitalized with acute kidney injury and COVID-19

Author

Wainstein, Marina, Spyrison, Nicholas, Dai, Danyang, Ghadimi, Moji, Chavez-Iniquez, Jonathan Samuel, Rizo Topete, Lilia María, Citarella, Barbara Wanjiru, Merson, Laura, Pole, Jason, Claure-Del Granado, Rolando, Johnson, David W., Shrapnel, Sally, Abdukahil, heryl Ann, Abdulkadir, Nurul Najmee, Abe, Ryuzo, Abel, Laurent, Abrous, Amal, Absil, Lara, Acker, Andrew, Adachi, Shingo, Adrião, Diana, Al Ageel, Saleh, Ahmed, Shakeel, Ainscough, Kate, Airlangga, Eka, Aisa, Tharwat, Hssain, Ali Ait, Tamlihat, Younes Ait, Akimoto, Takako, Akmal, Ernita, Akwani, Chika, Al Qasim, Eman, Alalqam, Razi, Alberti, Angela, Al-dabbous, Tala, Alegesan, Senthilkumar, Alessi, Marta, Alex, Beatrice, Alexandre, Kévin, Al-Fares, Abdulrahman, Alfoudri, Huda, Ali, Imran, Alidjnou, Kazali Enagnon, Aliudin, Jeffrey, Alkhafajee, Qabas, Allavena, Clotilde, Allou, Nathalie, Alves, João, Alves, Rita, Alves, João Melo, Cabrita, Joana Alves, Amaral, Maria, Amira, Nur, Ampaw, Phoebe, Andini, Roberto, Andréjak, Claire, Angheben, Andrea, Angoulvant, François, Ansart, Séverine, Anthonidass, Sivanesen, Antonelli, Massimo, Antunes de Brito, Carlos Alexandre, Apriyana, Ardiyan, Arabi, Yaseen, Aragao, Irene, Arancibia, Francisco, Araujo, Carolline, Arcadipane, Antonio, Archambault, Patrick, Arenz, Lukas, Arlet, Jean-Benoît, Arnold-Day, Christel, Arora, Lovkesh, Arora, Rakesh, Artaud-Macari, Elise, Aryal, Diptesh, Asensio, Angel, Ashraf, Muhammad, Assie, Jean Baptiste, Asyraf, Amirul, Atif, Minahel, Atique, Anika, Auchabie, Johann, Aumaitre, Hugues, Auvet, Adrien, Azemar, Laurène, Azoulay, Cecile, Bach, Benjamin, Bachelet, Delphine, Badr, Claudine, Baillie, J. Kenneth, Baird, J Kevin, Bak, Erica, Bakakos, Agamemnon, Bakar, Nazreen Abu, Bal, Andriy, Balakrishnan, Mohanaprasanth, Balan, Valeria, Bani-Sadr, Firouzé, Barbalho, Renata, Barbosa, Nicholas Yuri, Barclay, Wendy S., Barnett, Saef Umar, Barnikel, Michaela, Barrelet, Audrey, Barrigoto, Cleide, Bartoli, Marie, Baruch, Joaquín, Basmaci, Romain, Hassin Basri, Muhammad Fadhli, Battaglini, Denise, Bauer, Jules, Bautista Rincon, Diego Fernando, Beane, Abigail, Bedossa, Alexandra, Bee, Ker Hong, Begum, Husna, Behilill, Sylvie, Beishuizen, Albertus, Beljantsev, Aleksandr, Bellemare, David, Beltrame, Anna, Beltrão, Beatriz Amorim, Beluze, Marine, Benech, Nicolas, Benjiman, Lionel Eric, Benkerrou, Dehbia, Bennett, Suzanne, Benny, Binny, Bento, Luís, Berdal, Jan-Erik, Bergeaud, Delphine, Bergin, Hazel, Bernal Sobrino, José Luis, Bertoli, Giulia, Bertolino, Lorenzo, Bessis, Simon, Bevilcaqua, Sybille, Bezulier, Karine, Bhatt, Amar, Bhavsar, Krishna, Bianco, Claudia, Bidin, Farah Nadiah, Singh, Moirangthem Bikram, Humaid, Felwa Bin, Bin Kamarudin, Mohd Nazlin, Bisoffi, Zeno, Bissuel, François, Biston, Patrick, Bitker, Laurent, Bitton, Jonathan, Blanco-Schweizer, Pablo, Blier, Catherine, Bloos, Frank, Blot, Mathieu, Blumberg, Lucille, Boccia, Filomena, Bodenes, Laetitia, Bogaert, Debby, Boivin, Anne-Hélène, Bolaños, Isabela, Bolze, Pierre-Adrien, Bompart, François, Borges, Diogo, Borie, Raphaël, Botelho-Nevers, Elisabeth, Bouadma, Lila, Bouchaud, Olivier, Bouchez, Sabelline, Bouhmani, Dounia, Bouhour, Damien, Bouiller, Kévin, Bouillet, Laurence, Bouisse, Camile, Boureau, Anne-Sophie, Bourke, John, Bouscambert, Maude, Bousquet, Aurore, Bouziotis, Jason, Boxma, Bianca, Boyer-Besseyre, Marielle, Boylan, Maria, Bozza, Fernando Augusto, Braconnier, Axelle, Braga, Cynthia, Monteiro, Filipa Brás, Brazzi, Luca, Breen, Patrick, Breen, Dorothy, Brewster, David, Brickell, Kathy, Browne, Shaunagh, Brusse-Keizer, Marjolein, Bryda, Petra, Buchtele, Nina, Bugaeva, Polina, Buisson, Marielle, Burhan, Erlina, Burrell, Aidan, Bustos, Ingrid G., Butnaru, Denis, Cabie, André, Cabral, Susana, Caceres, Eder, Cadoz, Cyril, Garcês, Rui Caetano, Calligy, Kate, Calvache, Jose Andres, Camões, João, Campana, Valentine, Campbell, Paul, Campisi, Josie, Cantero, Mireia, Caraux-Paz, Pauline, Cardellino, Chiara Simona, Cardoso, Sofia, Cardoso, Filipe, Cardoso, Filipa, Cardoso, Nelson, Carelli, Simone, Carlier, Nicolas, Carmoi, Thierry, Carney, Gayle, Carqueja, Inês, Carret, Marie-Christine, Carrier, François Martin, Carroll, Ida, Carson, Gail, Casanova, Maire-Laure, Cascão, Mariana, Casey, Siobhan, Casimiro, José, Cassandra, Bailey, Castanheira, Nidyanara, Castor-Alexandre, Guylaine, Castro, Ivo, Catarino, Ana, Catherine, François-Xavier, Cattaneo, Paolo, Cavalin, Roberta, Cavayas, Alexandros, Cervantes-Gonzalez, Minerva, Chair, Anissa, Chakveatze, Catherine, Chan, Adrienne, Chand, Meera, Chantalat Auger, Christelle, Chapplain, Jean-Marc, Charpentier, Charlotte, Chas, Julie, Chávez Iñiguez, Jonathan Samuel, Chen, Anjellica, Chen, Yih-Sharng, Chenard, Léo, Cheng, Matthew Pellan, Cheret, Antoine, Chiarabini, Thibault, Chica, Julian, Chidambaram, Suresh Kumar, Tho, Leong Chin, Chirouze, Catherine, Chiumello, Davide, Cho, Sung-Min, Cholley, Bernard, Chopin, Marie-Charlotte, Chow, Ting Soo, Chow, Yock Ping, Chua, Hiu Jian, Chua, Jonathan, Cidade, Jose Pedro, Ciullo, Anna, Clarke, Jennifer, Clohisey, Sara, Cobb, Perren J., Codan, Cassidy, Cody, Caitriona, Coelho, Alexandra, Coles, Megan, Coles, Jennifer, Colin, Gwenhaël, Collins, Michael, Colombo, Sebastiano Maria, Combs, Pamela, Connolly, Jennifer, Connor, Marie, Conrad, Anne, Conway, Elaine, Cooke, Graham S., Copland, Mary, Cordel, Hugues, Corley, Amanda, Cornelis, Sabine, Cornet, Alexander Daniel, Corpuz, Arianne Joy, Cortegiani, Andrea, Corvaisier, Grégory, Couffignal, Camille, Couffin-Cadiergues, Sandrine, Courtois, Roxane, Cousse, Stéphanie, Croonen, Sabine, Crowl, Gloria, Crump, Jonathan, Cruz, Claudina, Cruz Bermúdez, Juan Luis, Rojo, Jaime Cruz, Csete, Marc, Cullen, Ailbhe, Curley, Gerard, Curlier, Elodie, Curran, Colleen, Custodio, Paula, da Silva Filipe, Ana, Da Silveira, Charlene, Dabaliz, Al-Awwab, Dagens, Andrew, Dahly, Darren, Dalton, Heidi, Dalton, Jo, Daly, Seamus, Damas, Juliana, Daneman, Nick, Daniel, Corinne, Dankwa, Emmanuelle A., Dantas, Jorge, de Loughry, Gillian, De Montmollin, Etienne, Freitas de Oliveira França, Rafael, De Rosa, Rosanna, de Silva, Thushan, de Vries, Peter, Dean, David, Debard, Alexa, DeBenedictis, Bianca, Debray, Marie-Pierre, DeCastro, Nathalie, Dechert, William, Deconninck, Lauren, Decours, Romain, Defous, Eve, Delacroix, Isabelle, Delaveuve, Eric, Delavigne, Karen, Dell'Amore, Andrea, Delmas, Christelle, Delobel, Pierre, Delsing, Corine, Demonchy, Elisa, Denis, Emmanuelle, Deplanque, Dominique, Depuydt, Pieter, Desai, Mehul, Descamps, Diane, Desvallées, Mathilde, Dewayanti, Santi, Dhanger, Pathik, Diallo, Alpha, Diamantis, Sylvain, Da Silva, Fernanda Dias, Diaz, 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Chan Chee, Engelmann, Ilka, Enouf, Vincent, Epaulard, Olivier, Escher, Martina, Esperatti, Mariano, Esperou, Hélène, Santo, Catarina Espírito, Esposito-Farese, Marina, Estevão, João, Etienne, Manuel, Ettalhaoui, Nadia, Everding, Anna Greti, Evers, Mirjam, Fabre, Marc, Fabre, Isabelle, Faheem, Amna, Fahy, Arabella, Fairfield, Cameron J., Faria, Pedro, Fateena, Hanan, Fatoni, Arie Zainul, Faure, Karine, Favory, Raphaël, Fayed, Mohamed, Feely, Niamh, Feeney, Laura, Fernandes, Jorge, Fernandes, Marília Andreia, Fernandes, Susana, Ferrand, François-Xavier, Devouge, Eglantine Ferrand, Ferrão, Joana, Ferraz, Mário, Ferreira, Sílvia, Ferreira, Bernardo, Ferreira, Benigno, Ferriere, Nicolas, Ficko, Céline, Figueiredo-Mello, Claudia, Fiorda, Juan, Flament, Thomas, Flanagan, Emily, Flateau, Clara, Fletcher, Tom, Florence, Aline-Marie, Florio, Letizia Lucia, Flynn, Deirdre, Foley, Jean, Fomin, Victor, Fonseca, Tatiana, Forsyth, Simon, Foster, Denise, Foti, Giuseppe, Fourn, Erwan, Fowler, Robert A., Fraher, Marianne, Franch-Llasat, Diego, Fraser, John F., Fraser, Christophe, Freire, Marcela Vieira, Ribeiro, Ana Freitas, Friedrich, Caren, Fritz, Ricardo, Fry, Stéphanie, Fuentes, Nora, Fukuda, Masahiro, G, Argin, Gaborieau, Valérie, Gaci, Rostane, Gagliardi, Massimo, Gagnard, Jean-Charles, Gagneux-Brunon, Amandine, Gaião, Sérgio, Skeie, Linda Gail, Gallagher, Phil, Gamble, Carrol, Gani, Yasmin, Garan, Arthur, Garcia, Rebekha, Barrio, Noelia García, Garcia-Gallo, Esteban, Garot, Denis, Garrait, Valérie, Gault, Nathalie, Gavin, Aisling, Gavrylov, Anatoliy, Gaymard, Alexandre, Gebauer, Johannes, Geraud, Eva, Morlaes, Louis Gerbaud, Germano, Nuno, Ghosn, Jade, Giani, Marco, Gibson, Jess, Gigante, Tristan, Gilg, Morgane, Gilroy, Elaine, Giordano, Guillermo, Girvan, Michelle, Gissot, Valérie, Glikman, Daniel, Glybochko, Petr, Gnall, Eric, Goehringer, François, Goffard, Jean-Christophe, Goh, Jin Yi, Golob, Jonathan, Gominet, Marie, Gonzalez, Alicia, Gordon, Patricia, Gorenne, Isabelle, 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José, Ramli, Ahmad Afiq, Rammaert, Blandine, Ramos, Grazielle Viana, Ranjan, Ritika, Rapp, Christophe, Rasmin, Menaldi, Rätsep, Indrek, Ravi, Tharmini, Real, Andre, Rebaudet, Stanislas, Redl, Sarah, Reeve, Brenda, Reid, Liadain, Reikvam, Dag Henrik, Reis, Renato, Remy, Martine, Ren, Hongru, Resseguier, Anne-Sophie, Revest, Matthieu, Rewa, Oleksa, Reyes, Tiago, Reyes, Luis Felipe, Ribeiro, Maria Ines, Richardson, David, Richardson, Denise, Richier, Laurent, Atikah Ahmad Ridzuan, Siti Nurul, Rios, Ana L., Rishu, Asgar, Rispal, Patrick, Risso, Karine, Rizer, Nicholas, Robba, Chiara, Roberto, André, Roberts, Stephanie, Robertson, David L., Robineau, Olivier, Roche-Campo, Ferran, Rodari, Paola, Rodeia, Simão, Roessler, Bernhard, Roger, Pierre-Marie, Rojek, Amanda, Romaru, Juliette, Roncon-Albuquerque, Roberto, Roriz, Mélanie, Rosa-Calatrava, Manuel, Rose, Michael, Rosenberger, Dorothea, Rossanese, Andrea, Rossetti, Matteo, Rossignol, Bénédicte, Rossignol, Patrick, Rousset, Stella, Roy, Carine, Roze, Benoît, Russell, Clark D., Ryan, Maria, Ryan, Maeve, Ryckaert, Steffi, Holten, Aleksander Rygh, Saba, Isabela, Sadat, Musharaf, Sahraei, Valla, Saint-Gilles, Maximilien, Sakiyalak, Pranya, Salazar, Leonardo, Sales, Gabriele, Sallaberry, Stéphane, Gandonniere, Charlotte Salmon, Salvator, Hélène, Sanchez, Emely, Sanchez, Olivier, Sanchez-Miralles, Angel, Sancho-Shimizu, Vanessa, Sandhu, Gyan, Sandhu, Zulfiqar, Sandrine, Pierre-François, Sandulescu, Oana, Santos, Marlene, Sarfo-Mensah, Shirley, Sarmiento, Iam Claire E., Sarton, Benjamine, Satyapriya, Sree, Satyawati, Rumaisah, Saviciute, Egle, Saw, Yen Tsen, Schaffer, Justin, Schermer, Tjard, Scherpereel, Arnaud, Schneider, Marion, Schroll, Stephan, Schwameis, Michael, Scott, Janet T., Scott-Brown, James, Sedillot, Nicholas, Seitz, Tamara, Selvarajoo, Mageswari, Semaille, Caroline, Semple, Malcolm G., Senian, Rasidah Bt, Senneville, Eric, Sepulveda, Claudia, Sequeira, Filipa, Sequeira, Tânia, Neto, Ary Serpa, Balazote, Pablo 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Stephanie-Susanne, Steinsvik, Trude, Stienstra, Ymkje, Stiksrud, Birgitte, Stolz, Eva, Stone, Amy, Streinu-Cercel, Adrian, Streinu-Cercel, Anca, Stuart, Ami, Stuart, David, Su, Richa, Subekti, Decy, Suen, Gabriel, Suen, Jacky Y., Sukumar, Prasanth, Sultana, Asfia, Summers, Charlotte, Supic, Dubravka, Suppiah, Deepashankari, Surovcová, Magdalena, Svistunov, Suwarti, Andrey, Syahrin, Sarah, Syrigos, Konstantinos, Sztajnbok, Jaques, Szuldrzynski, Konstanty, Tabrizi, Shirin, Taccone, Fabio S., Tagherset, Lysa, Taib, Shahdattul Mawarni, Taleb, Sara, Talsma, Jelmer, Tampubolon, Maria Lawrensia, Tan, Kim Keat, Tan, Yan Chyi, Tanaka, Hiroyuki, Tanaka, Taku, Taniguchi, Hayato, Tardivon, Coralie, Tattevin, Pierre, Taufik, M Azhari, Tawfik, Hassan, Tedder, Richard S., Tee, Tze Yuan, Teixeira, João, Tellier, Marie-Capucine, Teoh, Sze Kye, Teotonio, Vanessa, Téoulé, François, Terpstra, Pleun, Terrier, Olivier, Terzi, Nicolas, Tessier-Grenier, Hubert, Tey, Adrian, Mohd Thabit, Alif Adlan, Tham, Zhang Duan, Thangavelu, Suvintheran, Theron, Elmi, Thibault, Vincent, Thiberville, Simon-Djamel, Thill, Benoît, Thirumanickam, Jananee, Thompson, Shaun, Thomson, David, Thomson, Emma C., Thorpe, Mathew, Thanga Thurai, Surain Raaj, Thwaites, Ryan S., Tierney, Paul, Tieroshyn, Vadim, Timashev, Peter S., Timsit, Jean-François, Tissot, Noémie, Toal, Fiona, Yang Toh, Jordan Zhien, Toki, Maria, Tonby, Kristian, Tonnii, Sia Loong, Torre, Marta, Torres, Antoni, Torres-Zevallos, Hernando, Towers, Michael, Trapani, Tony, Tromeur, Cécile, Trontzas, Ioannis, Trouillon, Tiffany, Truong, Jeanne, Tual, Christelle, Tubiana, Sarah, Tuite, Helen, Turgeon, Alexis F., Turmel, Jean-Marie, Turtle, Lance C. 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Kenneth, Baird, J Kevin, Bak, Erica, Bakakos, Agamemnon, Bakar, Nazreen Abu, Bal, Andriy, Balakrishnan, Mohanaprasanth, Balan, Valeria, Bani-Sadr, Firouzé, Barbalho, Renata, Barbosa, Nicholas Yuri, Barclay, Wendy S., Barnett, Saef Umar, Barnikel, Michaela, Barrelet, Audrey, Barrigoto, Cleide, Bartoli, Marie, Baruch, Joaquín, Basmaci, Romain, Hassin Basri, Muhammad Fadhli, Battaglini, Denise, Bauer, Jule, Bautista Rincon, Diego Fernando, Beane, Abigail, Bedossa, Alexandra, Bee, Ker Hong, Begum, Husna, Behilill, Sylvie, Beishuizen, Albertu, Beljantsev, Aleksandr, Bellemare, David, Beltrame, Anna, Beltrão, Beatriz Amorim, Beluze, Marine, Benech, Nicola, Benjiman, Lionel Eric, Benkerrou, Dehbia, Bennett, Suzanne, Benny, Binny, Bento, Luí, Berdal, Jan-Erik, Bergeaud, Delphine, Bergin, Hazel, Bernal Sobrino, José Lui, Bertoli, Giulia, Bertolino, Lorenzo, Bessis, Simon, Bevilcaqua, Sybille, Bezulier, Karine, Bhatt, Amar, Bhavsar, Krishna, Bianco, Claudia, Bidin, Farah Nadiah, Singh, Moirangthem Bikram, Humaid, Felwa Bin, Bin Kamarudin, Mohd Nazlin, Bisoffi, Zeno, Bissuel, Françoi, Biston, Patrick, Bitker, Laurent, Bitton, Jonathan, Blanco-Schweizer, Pablo, Blier, Catherine, Bloos, Frank, Blot, Mathieu, Blumberg, Lucille, Boccia, Filomena, Bodenes, Laetitia, Bogaert, Debby, Boivin, Anne-Hélène, Bolaños, Isabela, Bolze, Pierre-Adrien, Bompart, Françoi, Borges, Diogo, Borie, Raphaël, Botelho-Nevers, Elisabeth, Bouadma, Lila, Bouchaud, Olivier, Bouchez, Sabelline, Bouhmani, Dounia, Bouhour, Damien, Bouiller, Kévin, Bouillet, Laurence, Bouisse, Camile, Boureau, Anne-Sophie, Bourke, John, Bouscambert, Maude, Bousquet, Aurore, Bouziotis, Jason, Boxma, Bianca, Boyer-Besseyre, Marielle, Boylan, Maria, Bozza, Fernando Augusto, Braconnier, Axelle, Braga, Cynthia, Monteiro, Filipa Brá, Brazzi, Luca, Breen, Patrick, Breen, Dorothy, Brewster, David, Brickell, Kathy, Browne, Shaunagh, Brusse-Keizer, Marjolein, Bryda, Petra, Buchtele, Nina, Bugaeva, Polina, Buisson, Marielle, Burhan, Erlina, Burrell, Aidan, Bustos, Ingrid G., Butnaru, Deni, Cabie, André, Cabral, Susana, Caceres, Eder, Cadoz, Cyril, Garcês, Rui Caetano, Calligy, Kate, Calvache, Jose Andre, Camões, João, Campana, Valentine, Campbell, Paul, Campisi, Josie, Cantero, Mireia, Caraux-Paz, Pauline, Cardellino, Chiara Simona, Cardoso, Sofia, Cardoso, Filipe, Cardoso, Filipa, Cardoso, Nelson, Carelli, Simone, Carlier, Nicola, Carmoi, Thierry, Carney, Gayle, Carqueja, Inê, Carret, Marie-Christine, Carrier, François Martin, Carroll, Ida, Carson, Gail, Casanova, Maire-Laure, Cascão, Mariana, Casey, Siobhan, Casimiro, José, Cassandra, Bailey, Castanheira, Nidyanara, Castor-Alexandre, Guylaine, Castro, Ivo, Catarino, Ana, Catherine, François-Xavier, Cattaneo, Paolo, Cavalin, Roberta, Cavayas, Alexandro, Cervantes-Gonzalez, Minerva, Chair, Anissa, Chakveatze, Catherine, Chan, Adrienne, Chand, Meera, Chantalat Auger, Christelle, Chapplain, Jean-Marc, Charpentier, Charlotte, Chas, Julie, Chávez Iñiguez, Jonathan Samuel, Chen, Anjellica, Chen, Yih-Sharng, Chenard, Léo, Cheng, Matthew Pellan, Cheret, Antoine, Chiarabini, Thibault, Chica, Julian, Chidambaram, Suresh Kumar, Tho, Leong Chin, Chirouze, Catherine, Chiumello, Davide, Cho, Sung-Min, Cholley, Bernard, Chopin, Marie-Charlotte, Chow, Ting Soo, Chow, Yock Ping, Chua, Hiu Jian, Chua, Jonathan, Cidade, Jose Pedro, Ciullo, Anna, Clarke, Jennifer, Clohisey, Sara, Cobb, Perren J., Codan, Cassidy, Cody, Caitriona, Coelho, Alexandra, Coles, Megan, Coles, Jennifer, Colin, Gwenhaël, Collins, Michael, Colombo, Sebastiano Maria, Combs, Pamela, Connolly, Jennifer, Connor, Marie, Conrad, Anne, Conway, Elaine, Cooke, Graham S., Copland, Mary, Cordel, Hugue, Corley, Amanda, Cornelis, Sabine, Cornet, Alexander Daniel, Corpuz, Arianne Joy, Cortegiani, Andrea, Corvaisier, Grégory, Couffignal, Camille, Couffin-Cadiergues, Sandrine, Courtois, Roxane, Cousse, Stéphanie, Croonen, Sabine, Crowl, Gloria, Crump, Jonathan, Cruz, Claudina, Cruz Bermúdez, Juan Lui, Rojo, Jaime Cruz, Csete, Marc, Cullen, Ailbhe, Curley, Gerard, Curlier, Elodie, Curran, Colleen, Custodio, Paula, da Silva Filipe, Ana, Da Silveira, Charlene, Dabaliz, Al-Awwab, Dagens, Andrew, Dahly, Darren, Dalton, Heidi, Dalton, Jo, Daly, Seamu, Damas, Juliana, Daneman, Nick, Daniel, Corinne, Dankwa, Emmanuelle A., Dantas, Jorge, de Loughry, Gillian, De Montmollin, Etienne, Freitas de Oliveira França, Rafael, De Rosa, Rosanna, de Silva, Thushan, de Vries, Peter, Dean, David, Debard, Alexa, DeBenedictis, Bianca, Debray, Marie-Pierre, DeCastro, Nathalie, Dechert, William, Deconninck, Lauren, Decours, Romain, Defous, Eve, Delacroix, Isabelle, Delaveuve, Eric, Delavigne, Karen, Dell'Amore, Andrea, Delmas, Christelle, Delobel, Pierre, Delsing, Corine, Demonchy, Elisa, Denis, Emmanuelle, Deplanque, Dominique, Depuydt, Pieter, Desai, Mehul, Descamps, Diane, Desvallées, Mathilde, Dewayanti, Santi, Dhanger, Pathik, Diallo, Alpha, Diamantis, Sylvain, Da Silva, Fernanda Dia, Diaz, Juan Jose, Diaz, Rodrigo, Didier, Kévin, Diehl, Jean-Luc, Dieperink, Wim, Dimet, Jérôme, Dinot, Vincent, Diop, Fara, Diouf, Alphonsine, Dishon, Yael, Djossou, Félix, Docherty, Annemarie B., Doherty, Helen, Donnelly, Maria, Donnelly, Christl A., Donohue, Sean, Donohue, Yoann, Donohue, Chloe, Doran, Peter, Dorival, Céline, D'Ortenzio, Eric, Douglas, James Joshua, Dournon, Nathalie, Downer, Triona, Downey, Joanne, Downing, Mark, Drake, Tom, Driscoll, Aoife, Dryden, Murray, Fonseca, Claudio Duarte, Dubee, Vincent, Dubos, Françoi, Ducancelle, Alexandre, Duculan, Toni, Dudman, Susanne, Duggal, Abhijit, Dunand, Paul, Dunning, Jake, Duplaix, Mathilde, Durante-Mangoni, Emanuele, Durham, Lucian, Dussol, Bertrand, Duthoit, Juliette, Duval, Xavier, Dyrhol-Riise, Anne Margarita, Ean, Sim Choon, Echeverria-Villalobos, Marco, Edwards, Eleanor, Egan, Siobhan, El Sanharawi, Mohammed, Elapavaluru, Subbarao, Elharrar, Brigitte, Eloy, Philippine, Elshazly, Tarek, Enderle, Isabelle, Endo, Tomoyuki, Eng, Chan Chee, Engelmann, Ilka, Enouf, Vincent, Epaulard, Olivier, Escher, Martina, Esperatti, Mariano, Esperou, Hélène, Santo, Catarina Espírito, Esposito-Farese, Marina, Estevão, João, Etienne, Manuel, Ettalhaoui, Nadia, Everding, Anna Greti, Evers, Mirjam, Fabre, Marc, Fabre, Isabelle, Faheem, Amna, Fahy, Arabella, Fairfield, Cameron J., Faria, Pedro, Fateena, Hanan, Fatoni, Arie Zainul, Faure, Karine, Favory, Raphaël, Fayed, Mohamed, Feely, Niamh, Feeney, Laura, Fernandes, Jorge, Fernandes, Marília Andreia, Fernandes, Susana, Ferrand, François-Xavier, Devouge, Eglantine Ferrand, Ferrão, Joana, Ferraz, Mário, Ferreira, Sílvia, Ferreira, Bernardo, Ferreira, Benigno, Ferriere, Nicola, Ficko, Céline, Figueiredo-Mello, Claudia, Fiorda, Juan, Flament, Thoma, Flanagan, Emily, Flateau, Clara, Fletcher, Tom, Florence, Aline-Marie, Florio, Letizia Lucia, Flynn, Deirdre, Foley, Jean, Fomin, Victor, Fonseca, Tatiana, Forsyth, Simon, Foster, Denise, Foti, Giuseppe, Fourn, Erwan, Fowler, Robert A., Fraher, Marianne, Franch-Llasat, Diego, Fraser, John F., Fraser, Christophe, Freire, Marcela Vieira, Ribeiro, Ana Freita, Friedrich, Caren, Fritz, Ricardo, Fry, Stéphanie, Fuentes, Nora, Fukuda, Masahiro, G, Argin, Gaborieau, Valérie, Gaci, Rostane, Gagliardi, Massimo, Gagnard, Jean-Charle, Gagneux-Brunon, Amandine, Gaião, Sérgio, Skeie, Linda Gail, Gallagher, Phil, Gamble, Carrol, Gani, Yasmin, Garan, Arthur, Garcia, Rebekha, Barrio, Noelia García, Garcia-Gallo, Esteban, Garot, Deni, Garrait, Valérie, Gault, Nathalie, Gavin, Aisling, Gavrylov, Anatoliy, Gaymard, Alexandre, Gebauer, Johanne, Geraud, Eva, Morlaes, Louis Gerbaud, Germano, Nuno, Ghosn, Jade, Giani, Marco, Gibson, Je, Gigante, Tristan, Gilg, Morgane, Gilroy, Elaine, Giordano, Guillermo, Girvan, Michelle, Gissot, Valérie, Glikman, Daniel, Glybochko, Petr, Gnall, Eric, Goehringer, Françoi, Goffard, Jean-Christophe, Goh, Jin Yi, Golob, Jonathan, Gominet, Marie, Gonzalez, Alicia, Gordon, Patricia, Gorenne, Isabelle, Gormley, Conor, Goubert, Laure, Goujard, Cécile, Goulenok, Tiphaine, Grable, Margarite, Grandin, Edward Wilson, Granier, Pascal, Grasselli, Giacomo, Green, Christopher A., Greenhalf, William, Greffe, Segolène, Grieco, Domenico Luca, Griffee, Matthew, Griffiths, Fiona, Grigoras, Ioana, Groenendijk, Albert, Gruner, Heidi, Gu, Yusing, Guedj, Jérémie, Guego, Martin, Guellec, Dewi, Guerreiro, Daniela, Guery, Romain, Guillaumot, Anne, Guilleminault, Laurent, Guimarães de Castro, Maisa, Guimard, Thoma, Haalboom, Marieke, Haber, Daniel, Habraken, Hannah, Hachemi, Ali, Hadri, Nadir, Hakak, Sheeba, Hall, Adam, Hall, Matthew, Halpin, Sophie, Hamer, Ansley, Hamers, Raph L., Hamidfar, Rebecca, Hammond, Terese, Hammond, Naomi, Han, Lim Yuen, Hao, Kok Wei, Hardwick, Hayley, Harrison, Ewen M., Harrison, Janet, Hartman, Alan, Hashmi, Junaid, Hayes, Ailbhe, Hays, Leanne, Heerman, Jan, Heggelund, Lar, Hendry, Ro, Hennessy, Martina, Hentzien, Maxime, Hernandez, Diana, Hershey, Andrew, Hesstvedt, Liv, Higgins, Eibhlin, Higgins, Dawn, Higgins, Rupert, Hinchion, Rita, Hinton, Samuel, Hiraiwa, Hiroaki, Hitoto, Hikombo, Ho, Antonia, Ho, Yi Bin, Hoctin, Alexandre, Hoffmann, Isabelle, Hoh, Wei Han, Hoiting, Oscar, Holt, Rebecca, Holter, Jan Cato, Horby, Peter, Hoshino, Kota, Houas, Ikram, Hough, Catherine L., Houltham, Stuart, Ming-Yang Hsu, Jimmy, Hulot, Jean-Sébastien, Hurd, Abby, Ijaz, Samreen, Ikram, M. Arfan, Illes, Hajnal-Gabriela, Imbert, Patrick, Inácio, Hugo, Ing, Yun Sii, Ippolito, Mariachiara, Isgett, Sarah, Isidoro, Tiago, Ismail, Nadiah, Isnard, Margaux, Itai, Junji, Ivulich, Daniel, Jaafar, Danielle, Jaafoura, Salma, Jabot, Julien, Jackson, Clare, Jaquet, Pierre, Jassat, Waasila, Jaud-Fischer, Coline, Jaureguiberry, Stéphane, Jego, Florence, Jelani, Anilawati Mat, Jenum, Synne, Joe, Ong Yiaw, Jorge García, Ruth N., Joseph, Mark, Joseph, Cédric, Jourdain, Mercé, Jouvet, Philippe, Jung, Anna, Juzar, Dafsah, Kafif, Ouifiya, Kaguelidou, Florentia, Kaisbain, Neerusha, Kaleesvran, Thavamany, Kali, Sabina, Kalomoiri, Smaragdi, Ayadi Kamaluddin, Muhammad Aisar, Che Kamaruddin, Zul Amali, Kamarudin, Nadiah, Kandamby, Darshana Hewa, Kandel, Chri, Kang, Kong Yeow, Karpayah, Pratap, Kartsonaki, Christiana, Kasugai, Daisuke, Kataria, Anant, Katz, Kevin, Kaur, Aasmine, Kay, Christy, Kayyali, Lamee, Keating, Seán, Kelly, Claire, Kelly, Yvelynne, Kelly, Andrea, Kelly, Niamh, Kelly, Aoife, Kelly, Sadie, Kelsey, Maeve, Kennedy, Ryan, Kennon, Kalynn, Kernan, Maeve, Kerroumi, Youne, Keshav, Sharma, Khalid, Imrana, Khalil, Antoine, Khan, Coralie, Khan, Irfan, Kho, Michelle E., Khoo, Saye, Khoo, Ryan, Khoo, Denisa, Kiat, Khor How, Kida, Yuri, Kiiza, Peter, Granerud, Beathe Kiland, Kildal, Anders Benjamin, Kim, Jae Burm, Kimmoun, Antoine, Kitamura, Nobuya, Klenerman, Paul, Klont, Rob, Bekken, Gry Kloumann, Knight, Stephen R., Komatsu, Mamoru, Korten, Volkan, Kpangon, Arsène, Krawczyk, Karolina, Krishnan, Sudhir, Krishnan, Vinothini, Kruglova, Oksana, Kumar, Deepali, Kumar, Ganesh, Tirupakuzhi Vijayaraghavan, Bharath Kumar, Vecham, Pavan Kumar, Kuriakose, Dinesh, Kurtzman, Ethan, Kutsogiannis, Demetrio, Kutsyna, Galyna, Kyriakoulis, Konstantino, Lachatre, Marie, Lacoste, Marie, Laffey, John G., Lafhej, Nadhem, Lagrange, Marie, Laine, Fabrice, Lairez, Olivier, Lalueza, Antonio, Lambert, Marc, Langelot-Richard, Marie, Langlois, Vincent, Lantang, Eka Yudha, Lanza, Marina, Laouénan, Cédric, Laribi, Samira, Lariviere, Delphine, Lasry, Stéphane, Launay, Odile, Laureillard, Didier, Lavie-Badie, Yoan, Law, Andy, Lawrence, Teresa, Lawrence, Cassie, Le, Minh, Le Bihan, Clément, Le Bris, Cyril, Le Falher, George, Le Fevre, Lucie, Le Hingrat, Quentin, Le Maréchal, Marion, Le Mestre, Soizic, Le Moal, Gwenaël, Le Moing, Vincent, Le Nagard, Hervé, Le Turnier, Paul, Lee, Todd C., Lee, Su Hwan, Lee, Jame, Lee, Jennifer, Lee, Heng Gee, Lee, Biing Horng, Lee, Yi Lin, Leeming, Gary, Lefebvre, Laurent, Lefebvre, Bénédicte, Lefèvre, Benjamin, LeGac, Sylvie, Lelievre, Jean-Daniel, Lellouche, Françoi, Lemaignen, Adrien, Lemee, Véronique, Lemeur, Anthony, Lemmink, Gretchen, Lene, Ha Sha, Leone, Michela, Leone, Marc, Lepiller, Quentin, Lescure, François-Xavier, Lesens, Olivier, Lesouhaitier, Mathieu, Lester-Grant, Amy, Letrou, Sophie, Levy, Yve, Levy, Bruno, Levy-Marchal, Claire, L'Her, Erwan, Bassi, Gianluigi Li, Liang, Janet, Liegeon, Geoffrey, Lim, Wei Shen, Lim, Kah Chuan, Lima, Chantre, Lina, Bruno, Lina, Lim, Lind, Andrea, Lingas, Guillaume, Lion-Daolio, Sylvie, Liu, Keibun, Livrozet, Marine, Lizotte, Patricia, Lolong, Navy, Loon, Leong Chee, Lopes, Diogo, Lopez-Colon, Dalia, Loschner, Anthony L., Loubet, Paul, Loufti, Bouchra, Louis, Guillame, Lourenco, Silvia, Low, Lee, Lowik, Marije, Loy, Jia Shyi, Lucet, Jean Christophe, Bermejo, Carlos Lumbrera, Luna, Carlos M., Lungu, Olguta, Lunn, Mile, Luong, Liem, Luque, Nestor, Luton, Dominique, Lyons, Ruth, Maasikas, Olavi, Mabiala, Oryane, Machado, Sara, Machado, Moïse, Macheda, Gabriel, Madiha, Hashmi, Maestro de la Calle, Guillermo, Mahieu, Rafael, Mahy, Sophie, Maier, Lars S., Maillet, Mylène, Maitre, Thoma, Malfertheiner, Maximilian, Malik, Nadia, Mallon, Paddy, Malvy, Deni, Manda, Victoria, Mandelbrot, Laurent, Manetta, Frank, Mankikian, Julie, Manning, Edmund, Manuel, Aldric, Sant`Ana Malaque, Ceila Maria, Marino, Flávio, Markowicz, Samuel, Marques, Ana, Marsh, Brian, Marsh, Laura, Marshal, Megan, Marshall, John, Martelli, Celina Turchi, Martin, Emily, Martin-Blondel, Guillaume, Martinez, F. Eduardo, Martin-Loeches, Ignacio, Martinot, Martin, Martins, João, Martins, Ana, Rego, Caroline Martin, Martucci, Gennaro, Martynenko, Olga, Marwali, Eva Miranda, Marzukie, Marsilla, Maslove, David, Mason, Sabina, Mat Nor, Mohd Basri, Matan, Moshe, Mathieu, Daniel, Mattei, Mathieu, Maulin, Laurence, Maxwell, Michael, Mazzoni, Thierry, Sweeney, Lisa Mc, McArthur, Colin, McCanny, Peter, McCarthy, Anne, McCarthy, Aine, McCloskey, Colin, McConnochie, Rachael, McDermott, Sherry, McDonald, Sarah E., McElroy, Aine, McElwee, Samuel, McEneany, Victoria, McEvoy, Natalie, McGeer, Allison, McKay, Chri, McKeown, Johnny, McLean, Kenneth A., McNicholas, Bairbre, McPartlan, Elaine, Meaney, Edel, Mear-Passard, Cécile, Mechlin, Maggie, Mehkri, Omar, Mele, Ferruccio, Menon, Kusum, Mentré, France, Mentzer, Alexander J., Mercier, Noémie, Mercier, Emmanuelle, Merckx, Antoine, Mergeay-Fabre, Mayka, Mergler, Blake, Mesquita, António, Metwally, Osama, Meybeck, Agnè, Meyer, Dan, Meynert, Alison M., Meysonnier, Vanina, Meziane, Amina, Mezidi, Mehdi, Michelanglei, Céline, Michelet, Isabelle, Mihelis, Efstathia, Mihnovit, Vladislav, Miller, Jennene, Misnan, Nor Arisah, Mohamed, Tahira Jamal, Eliza Mohamed, Nik Nur, Moin, Asma, Molinos, Elena, Molloy, Brenda, Monahan, Sinead, Mone, Mary, Monteiro, Agostinho, Montes, Claudia, Montrucchio, Giorgia, Moore, Shona C., Moore, Sarah, Cely, Lina Morale, Moro, Lucia, Motherway, Catherine, Motos, Ana, Mouquet, Hugo, Perrot, Clara Mouton, Moyet, Julien, Mudara, Caroline, Muh, Ng Yong, Muhamad, Dzawani, Mullaert, Jimmy, Müller, Fredrik, Müller, Karl Erik, Munblit, Daniel, Murphy, Aisling, Murphy, Lorna, Murray, Patrick, Murris, Marlène, Murthy, Sriniva, Musaab, Himed, Muyandy, Gugapriyaa, Myrodia, Dimitra Melia, Nagpal, Dave, Nagrebetsky, Alex, Narasimhan, Mangala, Narayanan, Nageswaran, Neant, Nadège, Necsoi, Coca, Nekliudov, Nikita, Neto, Raul, Neumann, Emily, Ng, Pauline Yeung, Ng, Wing Yiu, Nghi, Anthony, Nguyen, Duc, Choileain, Orna Ni, Leathlobhair, Niamh Ni, Nichol, Alistair D., Nitayavardhana, Prompak, Nonas, Stephanie, Mohd Noordin, Nurul Amani, Noret, Marion, Izzati Norharizam, Nurul Faten, Norman, Lisa, Notari, Alessandra, Noursadeghi, Mahdad, Nseir, Saad, Nusantara, Dwi Utomo, Nyamankolly, Elsa, Brien, Fionnuala O., Callaghan, Annmarie O., O'Callaghan, Annmarie, Occhipinti, Giovanna, OConnor, Derbrenn, Ogura, Takayuki, O'Halloran, Sophie, O'Hearn, Katie, Ohshimo, Shinichiro, Oliveira, João, Olliaro, Piero L., O'Neil, Conar, Ong, David S.Y., Ong, Jee Yan, Oosthuyzen, Wilna, Opavsky, Anne, Openshaw, Peter, Orozco-Chamorro, Claudia Milena, Ortoleva, Jamel, Osatnik, Javier, O'Shea, Linda, O'Sullivan, Miriam, Othman, Siti Zubaidah, Ouamara, Nadia, Ouissa, Rachida, Oziol, Eric, Pagadoy, Maïder, Pages, Justine, Palmarini, Massimo, Panarello, Giovanna, Panda, Prasan Kumar, Pang, Lai Hui, Panigada, Mauro, Pansu, Nathalie, Papadopoulos, Aurélie, Parke, Rachael, Pasquier, Jérémie, Pastene, Bruno, Patauner, Fabian, Pathmanathan, Mohan Da, Patricio, Patricia, Patrier, Juliette, Patterson, Lisa, Paul, Mical, Paul, Christelle, Paulos, Jorge, Paxton, William A., Payen, Jean-Françoi, Peake, Sandra L., Peariasamy, Kalaiarasu, Jiménez, Miguel Pedrera, Peek, Giles J., Peelman, Florent, Peiffer-Smadja, Nathan, Peigne, Vincent, Pejkovska, Mare, Pelosi, Paolo, Peltan, Ithan D., Pereira, Rui, Perez, Daniel, Periel, Lui, Perpoint, Thoma, Pesenti, Antonio, Pestre, Vincent, Petrou, Lenka, Petrovic, Michele, Petrov-Sanchez, Ventzislava, Pettersen, Frank Olav, Peytavin, Gille, Pharand, Scott, Piagnerelli, Michael, Picard, Walter, Picone, Olivier, Pierobon, Carola, Piersma, Djura, Pimentel, Carlo, Piquard, Valentine, Pires, Catarina, Pironneau, Isabelle, Piroth, Lionel, Pitaloka, Ayodhia, Piubelli, Chiara, Pius, Riinu, Plantier, Laurent, Png, Hon Shen, Poissy, Julien, Pokeerbux, Ryadh, Poli, Sergio, Pollakis, Georgio, Ponscarme, Diane, Porto, Diego Basto, Post, Andra-Mari, Postma, Douwe F., Povoa, Pedro, Póvoas, Diana, Powis, Jeff, Prapa, Sofia, Preau, Sébastien, Prebensen, Christian, Preiser, Jean-Charle, Prinssen, Anton, Proença, Lucia, Pudota, Sravya, Puéchal, Oriane, Semedi, Bambang Pujo, Purcell, Gregory, Quesada, Luisa, González, Víctor Quiró, Quist-Paulsen, Else, Quraishi, Mohammed, Qutishat, Fadi, Rabaud, Christian, Rafael, Aldo, Rafiq, Marie, Rahardjani, Mutia, Rahimi, Amir Kamel, Rahman, Rozanah Abd, Haji Ab Rahman, Ahmad Kashfi, Rainieri, Fernando, Rajahram, Giri Shan, Ramakrishnan, Nagarajan, Ramalho, José, Ramli, Ahmad Afiq, Rammaert, Blandine, Ramos, Grazielle Viana, Ranjan, Ritika, Rapp, Christophe, Rasmin, Menaldi, Rätsep, Indrek, Ravi, Tharmini, Real, Andre, Rebaudet, Stanisla, Redl, Sarah, Reeve, Brenda, Reid, Liadain, Reikvam, Dag Henrik, Reis, Renato, Remy, Martine, Ren, Hongru, Resseguier, Anne-Sophie, Revest, Matthieu, Rewa, Oleksa, Reyes, Tiago, Reyes, Luis Felipe, Ribeiro, Maria Ine, Richardson, David, Richardson, Denise, Richier, Laurent, Atikah Ahmad Ridzuan, Siti Nurul, Rios, Ana L., Rishu, Asgar, Rispal, Patrick, Risso, Karine, Rizer, Nichola, Robba, Chiara, Roberto, André, Roberts, Stephanie, Robertson, David L., Robineau, Olivier, Roche-Campo, Ferran, Rodari, Paola, Rodeia, Simão, Roessler, Bernhard, Roger, Pierre-Marie, Rojek, Amanda, Romaru, Juliette, Roncon-Albuquerque, Roberto, Roriz, Mélanie, Rosa-Calatrava, Manuel, Rose, Michael, Rosenberger, Dorothea, Rossanese, Andrea, Rossetti, Matteo, Rossignol, Bénédicte, Rossignol, Patrick, Rousset, Stella, Roy, Carine, Roze, Benoît, Russell, Clark D., Ryan, Maria, Ryan, Maeve, Ryckaert, Steffi, Holten, Aleksander Rygh, Saba, Isabela, Sadat, Musharaf, Sahraei, Valla, Saint-Gilles, Maximilien, Sakiyalak, Pranya, Salazar, Leonardo, Sales, Gabriele, Sallaberry, Stéphane, Gandonniere, Charlotte Salmon, Salvator, Hélène, Sanchez, Emely, Sanchez, Olivier, Sanchez-Miralles, Angel, Sancho-Shimizu, Vanessa, Sandhu, Gyan, Sandhu, Zulfiqar, Sandrine, Pierre-Françoi, Sandulescu, Oana, Santos, Marlene, Sarfo-Mensah, Shirley, Sarmiento, Iam Claire E., Sarton, Benjamine, Satyapriya, Sree, Satyawati, Rumaisah, Saviciute, Egle, Saw, Yen Tsen, Schaffer, Justin, Schermer, Tjard, Scherpereel, Arnaud, Schneider, Marion, Schroll, Stephan, Schwameis, Michael, Scott, Janet T., Scott-Brown, Jame, Sedillot, Nichola, Seitz, Tamara, Selvarajoo, Mageswari, Semaille, Caroline, Semple, Malcolm G., Senian, Rasidah Bt, Senneville, Eric, Sepulveda, Claudia, Sequeira, Filipa, Sequeira, Tânia, Neto, Ary Serpa, Balazote, Pablo Serrano, Shadowitz, Ellen, Shahidan, Syamin Asyraf, Shamsah, Mohammad, Shankar, Anuraj, Sharjeel, Shaikh, Sharma, Pratima, Shaw, Catherine A., Shaw, Victoria, Sheenan, John Robert, Shi, Haixia, Shime, Nobuaki, Shimizu, Hiroaki, Shimizu, Keiki, Shum, Hoi Ping, Mohammed, Nassima Si, Siang, Ng Yong, Sibiude, Jeanne, Siddiqui, Atif, Sigfrid, Louise, Sillaots, Piret, Silva, Catarina, Silva, Rogério, Silva, Maria Joao, Lim Heng, Benedict Sim, Sin, Wai Ching, Singh, Punam, Singh, Budha Charan, Sitompul, Pompini Agustina, Sivam, Karisha, Skogen, Vegard, Smith, Sue, Smood, Benjamin, Smyth, Coilin, Smyth, Michelle, Snacken, Morgane, So, Dominic, Soh, Tze Vee, Solomon, Joshua, Solomon, Tom, Somers, Emily, Sommet, Agnè, Song, Rima, Song, Myung Jin, Song, Tae, Chia, Jack Song, Sotto, Albert, Soum, Edouard, Sousa, Marta, Sousa, Ana Chora, Uva, Maria Sousa, Souza-Dantas, Vicente, Sperry, Alexandra, Spinuzza, Elisabetta, Sriskandan, Shiranee, Stabler, Sarah, Staudinger, Thoma, Stecher, Stephanie-Susanne, Steinsvik, Trude, Stienstra, Ymkje, Stiksrud, Birgitte, Stolz, Eva, Stone, Amy, Streinu-Cercel, Adrian, Streinu-Cercel, Anca, Stuart, Ami, Stuart, David, Su, Richa, Subekti, Decy, Suen, Gabriel, Suen, Jacky Y., Sukumar, Prasanth, Sultana, Asfia, Summers, Charlotte, Supic, Dubravka, Suppiah, Deepashankari, Surovcová, Magdalena, Svistunov, Suwarti, Andrey, Syahrin, Sarah, Syrigos, Konstantino, Sztajnbok, Jaque, Szuldrzynski, Konstanty, Tabrizi, Shirin, Taccone, Fabio S., Tagherset, Lysa, Taib, Shahdattul Mawarni, Taleb, Sara, Talsma, Jelmer, Tampubolon, Maria Lawrensia, Tan, Kim Keat, Tan, Yan Chyi, Tanaka, Hiroyuki, Tanaka, Taku, Taniguchi, Hayato, Tardivon, Coralie, Tattevin, Pierre, Taufik, M Azhari, Tawfik, Hassan, Tedder, Richard S., Tee, Tze Yuan, Teixeira, João, Tellier, Marie-Capucine, Teoh, Sze Kye, Teotonio, Vanessa, Téoulé, Françoi, Terpstra, Pleun, Terrier, Olivier, Terzi, Nicola, Tessier-Grenier, Hubert, Tey, Adrian, Mohd Thabit, Alif Adlan, Tham, Zhang Duan, Thangavelu, Suvintheran, Theron, Elmi, Thibault, Vincent, Thiberville, Simon-Djamel, Thill, Benoît, Thirumanickam, Jananee, Thompson, Shaun, Thomson, David, Thomson, Emma C., Thorpe, Mathew, Thanga Thurai, Surain Raaj, Thwaites, Ryan S., Tierney, Paul, Tieroshyn, Vadim, Timashev, Peter S., Timsit, Jean-Françoi, Tissot, Noémie, Toal, Fiona, Yang Toh, Jordan Zhien, Toki, Maria, Tonby, Kristian, Tonnii, Sia Loong, Torre, Marta, Torres, Antoni, Torres-Zevallos, Hernando, Towers, Michael, Trapani, Tony, Tromeur, Cécile, Trontzas, Ioanni, Trouillon, Tiffany, Truong, Jeanne, Tual, Christelle, Tubiana, Sarah, Tuite, Helen, Turgeon, Alexis F., Turmel, Jean-Marie, Turtle, Lance C.W., Tveita, Ander, Twardowski, Pawel, Udy, Andrew, Ullrich, Roman, Uribe, Alberto, Usman, Asad, Uyeki, Timothy M., Vajdovics, Cristinava, Val-Flores, Luí, Valran, Amélie, Van de Velde, Stijn, van den Berge, Marcel, van der Palen, Job, van der Valk, Paul, Van Der Vekens, Nicky, Van der Voort, Peter, Van Der Werf, Sylvie, van Gulik, Laura, Van Hattem, Jarne, van Netten, Carolien, van Veen, Ilonka, Vanel, Noémie, Vanoverschelde, Henk, Varghese, Pooja, Varrone, Michael, Vasudayan, Shoban Raj, Vauchy, Charline, Veeran, Shaminee, Veislinger, Aurélie, Vencken, Sebastian, Ventura, Sara, Verbon, Annelie, Vidal, José Ernesto, Vieira, César, Villanueva, Joy Ann, Villoldo, Andrea, Visseaux, Benoit, Vitiello, Chiara, Vonkeman, Harald, Vuotto, Fanny, Wahab, Noor Hidayu, Wahab, Suhaila Abdul, Wahid, Nadirah Abdul, Walsh, Laura, Wang, Chih-Hsien, Webb, Steve, Wei, Jia, Wen, Tan Pei, Wesselius, Sanne, Wham, Murray, Whelan, Bryan, White, Nicole, Wicky, Paul Henri, Wiedemann, Aurélie, Wijaya, Surya Otto, Wille, Keith, Willems, Sue, Williams, Bailey, Williams, Virginie, Williams, Patricia J., Wils, Evert-Jan, Wittman, Jessica, Wong, Calvin, Wong, Xin Ci, Wong, Yew Sing, Wong, Teck Fung, Xian, Gan Ee, Xian, Lim Saio, Kuan, Pei Xuan, Xynogalas, Ioanni, Binti Mohd Yakop, Siti Rohani, Yamazaki, Masaki, Yarad, Elizabeth, Yazdanpanah, Yazdan, Liang Hing, Nicholas Yee, Yelnik, Cécile, Yeoh, Chian Hui, Yerkovich, Stephanie, Yokoyama, Toshiki, Yonis, Hodane, Yousif, Obada, Zaaqoq, Akram, Zabbe, Marion, Zahid, Masliza, Zahran, Maram, Binti Zaidan, Nor Zaila, Zambon, Maria, Zambrano, Miguel, Zanella, Alberto, Zaynah, Nurul, Zayyad, Hiba, Zoufaly, Alexander, and Zucman, David

Subjects
acute kidney injury, covid-19, Nephrology
Abstract

Introduction Acute kidney injury (AKI) has been identified as one of the most common and significant problems in hospitalized patients with COVID-19. However, studies examining the relationship between COVID-19 and AKI in low- and low-middle income countries (LLMIC) are lacking. Given that AKI is known to carry a higher mortality rate in these countries, it is important to understand differences in this population. Methods This prospective, observational study examines the AKI incidence and characteristics of 32,210 patients with COVID-19 from 49 countries across all income levels who were admitted to an intensive care unit during their hospital stay. Results Among patients with COVID-19 admitted to the intensive care unit (ICU), AKI incidence was highest in patients in LLMIC, followed by patients in upper-middle income countries (UMIC) and high-income countries (HIC) (53%, 38%, and 30%, respectively), whereas dialysis rates were lowest among patients with AKI from LLMIC and highest among those from HIC (27% vs. 45%). Patients with AKI in LLMIC had the largest proportion of community-acquired AKI (CA-AKI) and highest rate of in-hospital death (79% vs. 54% in HIC and 66% in UMIC). The association between AKI, being from LLMIC and in-hospital death persisted even after adjusting for disease severity. Conclusions AKI is a particularly devastating complication of COVID-19 among patients from poorer nations where the gaps in accessibility and quality of healthcare delivery have a major impact on patient outcomes.

Published
2023

27. 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

Writing Committee for the REMAP-CAP Investigators, Lawler, Patrick R, Derde, Lennie PG, van de Veerdonk, Frank L, McVerry, Bryan J, Huang, David T, Berry, Lindsay R, Lorenzi, Elizabeth, van Kimmenade, Roland, Gommans, Frank, Vaduganathan, Muthiah, Leaf, David E, Baron, Rebecca M, Kim, Edy Y, Frankfurter, Claudia, Epelman, Slava, Kwan, Yvonne, Grieve, Richard, O'Neill, Stephen, Sadique, Zia, Puskarich, Michael, Marshall, John C, Higgins, Alisa M, Mouncey, Paul R, Rowan, Kathryn M, Al-Beidh, Farah, Annane, Djillali, Arabi, Yaseen M, Au, Carly, Beane, Abi, van Bentum-Puijk, Wilma, Bonten, Marc JM, Bradbury, Charlotte A, Brunkhorst, Frank M, Burrell, Aidan, Buzgau, Adrian, Buxton, Meredith, Cecconi, Maurizio, Cheng, Allen C, Cove, Matthew, Detry, Michelle A, Estcourt, Lise J, Ezekowitz, Justin, Fitzgerald, Mark, Gattas, David, Godoy, Lucas C, Goossens, Herman, Haniffa, Rashan, Harrison, David A, Hills, Thomas, Horvat, Christopher M, Ichihara, Nao, Lamontagne, Francois, Linstrum, Kelsey M, McAuley, Daniel F, McGlothlin, Anna, McGuinness, Shay P, McQuilten, Zoe, Murthy, Srinivas, Nichol, Alistair D, Owen, David RJ, Parke, Rachael L, Parker, Jane C, Pollock, Katrina M, Reyes, Luis Felipe, Saito, Hiroki, Santos, Marlene S, Saunders, Christina T, Seymour, Christopher W, Shankar-Hari, Manu, Singh, Vanessa, Turgeon, Alexis F, Turner, Anne M, Zarychanski, Ryan, Green, Cameron, Lewis, Roger J, Angus, Derek C, Berry, Scott, Gordon, Anthony C, McArthur, Colin J, Webb, Steve A, and Apollo - University of Cambridge Repository

Subjects
Male, Renin-Angiotensin System, Hospitalization, Angiotensin Receptor Antagonists, Critical Illness, Humans, COVID-19, Female, Angiotensin-Converting Enzyme Inhibitors, Bayes Theorem, Receptors, Chemokine, Middle Aged, COVID-19 Drug Treatment
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

28. Good or best practice statements: proposal for the operationalisation and implementation of GRADE guidance

Author

Dewidar, Omar, Lotfi, Tamara, Langendam, Miranda W, Parmelli, Elena, Saz-Parkinson, ZuleiKa, Solo, Karla, Chu, Derek K, Mathew, Joseph L, Akl, Elie A, Brignardello-Petersen, Romina, Mustafa, Reem A, Moja, Lorenzo, Iorio, Alfonso, Chi, Yuan, Canelo-Aybar, Carlos, Kredo, Tamara, Karpusheff, Justine, Turgeon, Alexis F, Alonso-Coello, Pablo, Wiercioch, Wojtek, Gerritsen, Annette, Klugar, Miloslav, Rojas, María Ximena, Tugwell, Peter, Welch, Vivian Andrea, Pottie, Kevin, Munn, Zachary, Nieuwlaat, Robby, Ford, Nathan, Stevens, Adrienne, Khabsa, Joanne, Nasir, Zil, Leontiadis, Grigorios, Meerpohl, Joerg, Piggott, Thomas, Qaseem, Amir, Matthews, Micayla, Schünemann, Holger J, eCOVID-19 recommendations map collaborators, Epidemiology and Data Science, APH - Methodology, Canadian Institutes of Health Research, and Canada Research Chairs

Subjects
Evidence-Based Medicine, Research Design, Evidence-Based Practice, education, Humans, COVID-19, General Medicine
Abstract

An evidence-based approach is considered the gold standard for health decision-making. Sometimes, a guideline panel might judge the certainty that the desirable effects of an intervention clearly outweigh its undesirable effects as high, but the body of supportive evidence is indirect. In such cases, the application of the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) approach for grading the strength of recommendations is inappropriate. Instead, the GRADE Working Group has recommended developing ungraded best or good practice statement (GPS) and developed guidance under which circumsances they would be appropriate.Through an evaluation of COVID-1- related recommendations on the eCOVID Recommendation Map (COVID-19.recmap.org), we found that recommendations qualifying a GPS were widespread. However, guideline developers failed to label them as GPS or transparently report justifications for their development. We identified ways to improve and facilitate the operationalisation and implementation of the GRADE guidance for GPS.Herein, we propose a structured process for the development of GPSs that includes applying a sequential order for the GRADE guidance for developing GPS. This operationalisation considers relevant evidence-to-decision criteria when assessing the net consequences of implementing the statement, and reporting information supporting judgments for each criterion. We also propose a standardised table to facilitate the identification of GPS and reporting of their development. This operationalised guidance, if endorsed by guideline developers, may palliate some of the shortcomings identified. Our proposal may also inform future updates of the GRADE guidance for GPS. CIHR (FRN VR4-172741 & GA3-177732) for COVID-19 recommendation mapping. AFT is the Chairholder of the Canada Research Chair in Critical Care Neurology and Trauma. Sí

Published
2022

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

Author

Writing Committee for the REMAP-CAP Investigators, Estcourt, Lise J, Turgeon, Alexis F, McQuilten, Zoe K, McVerry, Bryan J, Al-Beidh, Farah, Annane, Djillali, Arabi, Yaseen M, Arnold, Donald M, Beane, Abigail, Bégin, Philippe, van Bentum-Puijk, Wilma, Berry, Lindsay R, Bhimani, Zahra, Birchall, Janet E, Bonten, Marc JM, Bradbury, Charlotte A, Brunkhorst, Frank M, Buxton, Meredith, Callum, Jeannie L, Chassé, Michaël, Cheng, Allen C, Cove, Matthew E, Daly, James, Derde, Lennie, Detry, Michelle A, De Jong, Menno, Evans, Amy, Fergusson, Dean A, Fish, Matthew, Fitzgerald, Mark, Foley, Claire, Goossens, Herman, Gordon, Anthony C, Gosbell, Iain B, Green, Cameron, Haniffa, Rashan, Harvala, Heli, Higgins, Alisa M, Hills, Thomas E, Hoad, Veronica C, Horvat, Christopher, Huang, David T, Hudson, Cara L, Ichihara, Nao, Laing, Emma, Lamikanra, Abigail A, Lamontagne, François, Lawler, Patrick R, Linstrum, Kelsey, Litton, Edward, Lorenzi, Elizabeth, MacLennan, Sheila, Marshall, John, McAuley, Daniel F, McDyer, John F, McGlothlin, Anna, McGuinness, Shay, Miflin, Gail, Montgomery, Stephanie, Mouncey, Paul R, Murthy, Srinivas, Nichol, Alistair, Parke, Rachael, Parker, Jane C, Priddee, Nicole, Purcell, Damian FJ, Reyes, Luis F, Richardson, Peter, Robitaille, Nancy, Rowan, Kathryn M, Rynne, Jennifer, Saito, Hiroki, Santos, Marlene, Saunders, Christina T, Serpa Neto, Ary, Seymour, Christopher W, Silversides, Jon A, Tinmouth, Alan A, Triulzi, Darrell J, Turner, Anne M, van de Veerdonk, Frank, Walsh, Timothy S, Wood, Erica M, Berry, Scott, Lewis, Roger J, Menon, David K, McArthur, Colin, Zarychanski, Ryan, Angus, Derek C, Webb, Steve A, Roberts, David J, Shankar-Hari, Manu, Menon, David [0000-0002-3228-9692], Apollo - University of Cambridge Repository, Investigators, Writing Committee for the REMAP-CAP, Writing Comm REMAP-CAP Investigators, Hôpital Raymond Poincaré [AP-HP], Université de Versailles Saint-Quentin-en-Yvelines - UFR Sciences de la santé Simone Veil (UVSQ Santé), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), National Institutes of Health, NIH, National Institute of Child Health and Human Development, NICHD, Pittsburgh Foundation, Breast Cancer Research Foundation, BCRF, Bristol-Myers Squibb, BMS, GlaxoSmithKline, GSK, Medtronic, Baxter International, Manitoba Medical Service Foundation, MMSF, CancerCare Manitoba Foundation, CCMF, Wellcome Trust, WT, University of Manitoba, UM, Health Research Board, HRB: PHRC-20-0147, National Blood Authority, NBA, Llywodraeth Cymru, Translational Breast Cancer Research Consortium, TBCRC, Canadian Institutes of Health Research, IRSC: 158584, CTN 2014-012, Medical Research Council, MRC, National Institute for Health Research, NIHR, Department of Health and Social Care, DH, European Commission, EC: APP194811, National Heart and Lung Institute, NHLI, National Health and Medical Research Council, NHMRC: 2015-06-18, 2016-16-011, APP1101719, APP2002132, Health Research Council of New Zealand, HRC: 16/631, 447335, Monash University, MU, Ministère des Affaires Sociales et de la Santé: 215522, Seventh Framework Programme, FP7, Université Pierre et Marie Curie, UPMC, Innovate UK, Horizon 2020, Pharmaceuticals Bayer, Minderoo Foundation, Dr Fitzgerald reported receiving grants from the PREPARE Network and the European Commission. Dr Gordon reported receiving grants from the National Institute for Health Research and receiving personal fees from 30 Respiratory, GlaxoSmithKline, and Bristol Myers Squibb. Dr Gosbell reported receiving grants from the Australian Red Cross Lifeblood, which is funded by the Australian government. Dr Haniffa reported receiving grants from the Wellcome Trust Innovations Project, the Minderoo Foundation, and the UK Research and Innovation African Critical Care Registry Network. Dr Higgins reported receiving grants from the National Health and Medical Research Council, the Minderoo Foundation, and the National Blood Authority. Dr Hills reported receiving grants from the Health Research Council of New Zealand. Dr Hoad reported receiving grants from the Australian Red Cross Lifeblood, which is funded by the Australian government. Dr Horvat reported receiving grants from the National Institute of Child Health and Human Development. Dr Huang reported receiving grants from the Breast Cancer Research Foundation. Dr Lamontagne reported receiving grants from the Canadian Institutes of Health Research. Dr Lawler reported receiving consulting fees from Novartis, Coronna LLC, and Brigham and Women’s Hospital, receiving royalties from McGraw-Hill Publishing, and receiving grants from the Canadian Institutes of Health Research, the LifeArc Foundation, the National Institutes of Health, the Peter Munk Cardiac Centre, the Ted Rogers Centre for Heart Research, the Thistledown Foundation, and the province of Ontario. Dr Lorenzi reported receiving personal fees from Berry Consultants. Dr Marshall reported receiving personal fees from AM-Pharma (data and safety monitoring board chair) and Critical Care Medicine (associate editor). Dr McAuley reported receiving personal fees from Bayer, GlaxoSmithKline, Boehringer Ingelheim, Novartis, Eli Lilly, Vir Biotechnology, Faron Pharmaceuticals, and Sobi, receiving grants from the National Institute for Health Research, Wellcome Trust, Innovate UK, the Medical Research Council, and the Northern Ireland Health and Social Care Research and Development Division, and holding a patent for an anti-inflammatory treatment that was issued to Queen’s University Belfast. Dr McGlothlin reported receiving grants from the PREPARE Network, the European Commission, and the Global Coalition for Adapative Research. Mr Mouncey reported receiving grants from the European Union, the PREPARE Network, the National Institute for Health Research, and European Union Horizon 2020. Dr Nichol reported receiving grants from the Health Research Board of Ireland and Baxter and receiving personal fees from AM-Pharma. Dr Parke reported receiving grants from Fisher and Paykel Healthcare Ltd. Ms Parker reported receiving grants from Monash University. Mr Richardson reported receiving funding from the Welsh government. Dr Rowan reported receiving grants from the European Commission and the National Institute for Health Research. Dr Saunders reported receiving grants from the PREPARE Network, the European Commission, and the Global Coalition for Adapative Research. Dr Serpa Neto reported receiving personal fees from Drager and Endpoint Health. Dr Tinmouth reported receiving grants and personal fees from the Canadian Blood Services. Ms Turner reported receiving grants from the Health Research Council of New Zealand. Dr van de Veerdonk reported receiving personal fees from Gilead, Sobi, and GlaxoSmithKline. Dr Wood reported receiving grants from the Australian Medical Research Future Fund. Dr S. Berry reported being an employee of Berry Consultants with an ownership role. Dr Lewis reported being an employee of Berry Consultants. Dr Menon reported receiving grants from the National Institute for Health Research. Dr McArthur reported receiving grants from the Health Research Council of New Zealand. Dr Zarychanski reported receiving grants from the Canadian Institutes of Health Research, the University of Manitoba, LifeArc, the Thistledown Foundation, Research Manitoba, the CancerCare Manitoba Foundation, the Victoria General Hospital Foundation, the Peter Munk Cardiac Centre, and the Manitoba Medical Services Foundation. Dr Webb reported receiving grants from the National Health and Medical Research Council and the Minderoo Foundation. Dr Shankar-Hari reported receiving grants from the National Institute for Clinical Research. No other disclosures were reported., nonprofit sponsors: Monash University, Melbourne, Australia (Australasian sponsor), Utrecht Medical Center, Utrecht, the Netherlands (European sponsor), St Michael’s Hospital, Toronto, Ontario, Canada (Canadian sponsor), and the Global Coalition for Adaptive Research, San Francisco, California (US sponsor). This study was additionally funded by grant 602525 FP7-health-2013-innovation-1 from the European Union Platform for European Preparedness Against Reemerging Epidemics, grants APP1101719 and APP1116530 from the Australian National Health and Medical Research Council, grant APP2002132 from the Australian Medical Research Future Fund, grant 16/631 from the New Zealand Health Research Council, grant 447335 from the Canadian Institutes of Health Research COVID-19 Rapid Research, grant 158584 from the Canadian Institutes of Health Research Strategy for Patient-Oriented Research Innovative Clinical Trials Program, grant CTN 2014-012 from the Health Research Board of Ireland, grant PHRC-20-0147 from the French Ministry of Health, and grant 215522 from the Wellcome Trust Innovations Project and funding from the National Institute for Health Research, the Department of Health and Social Care, the EU Programme Emergency Support Instrument, the NHS Blood and Transplant Research and Development Programme, the National Institute for Health Research, the National Institute for Health Research Imperial Biomedical Research Centre, the UPMC Learning While Doing Program, the Translational Breast Cancer Research Consortium, the Pittsburgh Foundation, and the Minderoo Foundation. The Australian government funds the Australian Red Cross Lifeblood for the provision of blood products and services. The collection of plasma in the United Kingdom was funded by European Union SoHo grants from the Department of Health and Social Care. Dr Turgeon is the Canada Research Chair in Critical Care Neurology and Trauma. Dr McQuilten is supported by emerging leader fellowship APP194811 from the National Health and Medical Research Council. Dr Gordon is funded by research professorship 2015-06-18 from the National Institute for Health Research. Dr Shankar-Hari is funded by clinician scientist fellowship 2016-16-011 from the National Institute for Health Research., In Canada, the trial has been funded by the Canadian Institute of Health Research, Strategy for Patient-Oriented Research (CIHR-SPOR) Innovative Clinical Trials Program Grant (no. 158584) for CAD $1,497,200, for the recruitment of 300 patients., The Platform for European Preparedness Against (Re-)emerging Epidemics (PREPARE) consortium is funded by the European Union (FP7-HEALTH-2013-INNOVATION-1, grant number 602525). Within the PREPARE consortium, the trial has funding for the recruitment of approximately 4000 patients., REMAP-CAP was supported in the Netherlands by the Research Collaboration Critical Care the Netherlands (RCC-Net)., Funding sources for the REMAP-CAP trial are specified in the core protocol documents. This domain has received domain-specific funding from the Australian Medical Research Future Fund (MRFF)., reported receiving grants from the National Institute for Health Research and European Union Horizon 2020. Dr Turgeon reported receiving grants from the Canadian Institutes of Health Research. Dr McQuilten reported receiving grants from the Australian Medical Research Future Fund. Dr McVerry reported receiving grants from the Pittsburgh Foundation, the Translational Breast Cancer Research Consortium, UPMC Learning While Doing Program, National Heart, Lung, and Blood Institute, and Bayer Pharmaceuticals and receiving personal fees from Boehringer Ingelheim. Dr Annane reported receiving grants from the French Ministry of Health and Solidarity. Dr Arnold reported receiving grants from the Canadian Institutes of Health Research. Ms Beane reported receiving grants and salary support from Wellcome Trust. Ms Bentum-Puijk reported receiving grants from the European Commission and the European Union. Dr L. Berry reported receiving grants from Berry Consultants. Dr Bradbury reported receiving personal fees from Lilly, Bristol Myers Squibb, Pfizer, Bayer, Amgen, Novartis, Janssen, Portola Advisors, and Ablynx. Dr Buxton reported receiving personal fees from the Breast Cancer Research Foundation, Amgen, and Eisai. Dr Callum reported receiving grants from the Canadian Blood Services and Octapharma. Dr Cove reported receiving grants from National University Health System, receiving consulting fees from Medtronic and Baxter, and holding a US patent for removal of carbon dioxide via dialysis. Dr Daly reported receiving grants from the Australian Red Cross Lifeblood, which is funded by the Australian government. Dr Derde reported receiving grants from University Medical Center Utrecht, being a member of the COVID-19 guideline committee of the Surviving Sepsis Campaign/ European Society of Intensive Care Medicine and European Society of Intensive Care Medicine COVID-19 taskforce, and serving as chair of the Dutch intensivists taskforce acute infectious threats. Dr Detry reported receiving grants from the European Union Platform for European Preparedness Against Reemerging Epidemics (PREPARE) consortium, the Australian National Health and Medical Research Council, the Health Research Council of New Zealand, and the UPMC Learning While Doing Program. Dr De Jong reported receiving personal fees from Roche Scientific, Shionogi Scientific, and Janssen., The current regions are: x Europe, with funding from a European Union FP7 grant (FP7-HEALTH-2013-INNOVATION-1, grant number 602525), to support the enrollment of 4000 participants. This funding terminates in 2021. x Australia and New Zealand. In Australia the project has received funding from a NHMRC Project Grant (APP1101719), to support the enrollment of 2000 participants. This funding terminates in December 2021, although some extension may be feasible. In New Zealand the project has received funding from a HRC Programme Grant (16/631), to support the enrollment of 800 participants. This funding terminates in November 2021. x Canada. In Canada the project has received funding for a CIHR grant (158584), to support the enrollment of 300 participants. This funding terminates in 2022. x United States. In the US, funding has been received from UPMC health system for recruitment internally at all UPMC hospitals (>40) and to support a US regional coordinating center. Philanthropic support is being provided through GCAR. Additional funds are being pursued., The REMAP-CAP platform is supported by the Australian and New Zealand Intensive Care Society Clinical Trials Group, the Canadian Critical Care Trials Group, the Irish Critical Care, European Project: 602525,EC:FP7:HEALTH,FP7-HEALTH-2013-INNOVATION-1,PREPARE(2014), NIHR, National Institute for Health Research, Medical Microbiology and Infection Prevention, AII - Infectious diseases, and Intensive Care Medicine

Subjects
Male, medicine.medical_treatment, [SDV]Life Sciences [q-bio], lnfectious Diseases and Global Health Radboud Institute for Molecular Life Sciences [Radboudumc 4], 030204 cardiovascular system & hematology, Logistic regression, law.invention, 0302 clinical medicine, Randomized controlled trial, law, Critical Illness/therapy, Vasoconstrictor Agents, 030212 general & internal medicine, Hospital Mortality, Treatment Failure, 11 Medical and Health Sciences, Original Investigation, Mortality rate, General Medicine, Middle Aged, Intensive care unit, Writing Committee for the REMAP-CAP Investigators, 3. Good health, Female, Life Sciences & Biomedicine, COVID-19/therapy, Adult, medicine.medical_specialty, Randomization, Respiration, Artificial/statistics & numerical data, Critical Illness, ABO Blood-Group System, 03 medical and health sciences, Medicine, General & Internal, Internal medicine, General & Internal Medicine, medicine, Humans, Adverse effect, COVID-19 Serotherapy, Aged, Mechanical ventilation, Science & Technology, business.industry, Immunization, Passive, Vasoconstrictor Agents/therapeutic use, COVID-19, Odds ratio, Length of Stay, Respiration, Artificial, Logistic Models, Human medicine, business
Abstract

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 thromboembolic events at 90 days; and serious adverse events.Results Among the 2011 participants who were randomized (median age, 61 [IQR, 52 to 70] years and 645/1998 [32.3%] women), 1990 (99%) completed the trial. The convalescent plasma intervention was stopped after the prespecified criterion for futility was met. The median number of organ support–free days was 0 (IQR, –1 to 16) in the convalescent plasma group and 3 (IQR, –1 to 16) in the no convalescent plasma group. The in-hospital mortality rate was 37.3% (401/1075) for the convalescent plasma group and 38.4% (347/904) for the no convalescent plasma group and the median number of days alive and free of organ support was 14 (IQR, 3 to 18) and 14 (IQR, 7 to 18), respectively. The median-adjusted OR was 0.97 (95% credible interval, 0.83 to 1.15) and the posterior probability of futility (OR Conclusions and Relevance Among critically ill adults with confirmed COVID-19, treatment with 2 units of high-titer, ABO-compatible convalescent plasma had a low likelihood of providing improvement in the number of organ support–free days.Trial Registration ClinicalTrials.gov Identifier: NCT02735707

Published
2021

30. Interleukin-6 Receptor Antagonists in Critically Ill Patients with Covid-19 – Preliminary report

Author

Gordon, Anthony C., Mouncey, Paul R., Al-Beidh, Farah, Rowan, Kathryn M., Nichol, Alistair D., Arabi, Yaseen M., Annane, Djillali, Beane, Abi, van Bentum-Puijk, Wilma, Berry, Lindsay R., Bhimani, Zahra, Bonten, Marc J.M., Bradbury, Charlotte A., Brunkhorst, Frank M., Buzgau, Adrian, Cheng, Allen C., Detry, Michelle A., Duffy, Eamon J., Estcourt, Lise J., Fitzgerald, Mark, Goossens, Herman, Haniffa, Rashan, Higgins, Alisa M., Hills, Thomas E., Horvat, Christopher M., Lamontagne, Francois, Lawler, Patrick R., Leavis, Helen L., Linstrum, Kelsey M., Litton, Edward, Lorenzi, Elizabeth, Marshall, John C., Mayr, Florian B., McAuley, Danny, McGlothlin, Anna, McGuinness, Shay P, McVerry, Bryan J., Montgomery, Stephanie K., Morpeth, Susan C., Murthy, Srinivas, Orr, Katrina, Parke, Rachael L., Parker, Jane C., Patanwala, Asad E., Pettilä, Ville, Rademaker, Emma, Santos, Marlene S., Saunders, Christina T., Seymour, Christopher W., Shankar-Hari, Manu, Sligl, Wendy I., Turgeon, Alexis F., Turner, Anne M., van de Veerdonk, Frank L., Zarychanski, Ryan, Green, Cameron, Lewis, Roger J., Angus, Derek C., McArthur, Colin J., Berry, Scott, Webb, Steve A., and Derde, Lennie P.G.

Subjects
medicine.medical_specialty, Coronavirus disease 2019 (COVID-19), business.industry, COVID-19, Odds ratio, Intensive care unit, law.invention, Coronavirus, Sarilumab, chemistry.chemical_compound, Tocilizumab, chemistry, Interquartile range, law, Intensive care, Internal medicine, Interleukin-6 receptor, Medicine, 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 of commencing organ support in an intensive care unit, were randomized to receive either tocilizumab (8mg/kg) or sarilumab (400mg) or standard care (control). The primary outcome was an ordinal scale combining in-hospital mortality (assigned −1) and days free of organ support to day 21. The trial uses a Bayesian statistical model with pre-defined triggers to declare superiority, efficacy, equivalence or futility.ResultsTocilizumab and sarilumab both met the pre-defined triggers for efficacy. At the time of full analysis 353 patients had been assigned to tocilizumab, 48 to sarilumab and 402 to control. Median organ support-free days were 10 (interquartile range [IQR] −1, 16), 11 (IQR 0, 16) and 0 (IQR −1, 15) for tocilizumab, sarilumab and control, respectively. Relative to control, median adjusted odds ratios were 1.64 (95% credible intervals [CrI] 1.25, 2.14) for tocilizumab and 1.76 (95%CrI 1.17, 2.91) for sarilumab, yielding >99.9% and 99.5% posterior probabilities of superiority compared with control. Hospital mortality was 28.0% (98/350) for tocilizumab, 22.2% (10/45) for sarilumab and 35.8% (142/397) for control. All secondary outcomes and analyses supported efficacy of these IL-6 receptor antagonists.ConclusionsIn critically ill patients with Covid-19 receiving organ support in intensive care, treatment with the IL-6 receptor antagonists, tocilizumab and sarilumab, improved outcome, including survival. (ClinicalTrials.govnumber:NCT02735707)

Published
2021

31. Anti-Thrombotic Therapy to Ameliorate Complications of COVID-19 (ATTACC): Study design and methodology for an international, adaptive Bayesian randomized controlled trial.

Author

Houston, Brett L, Lawler, Patrick R, Goligher, Ewan C, Farkouh, Michael E, Bradbury, Charlotte, Carrier, Marc, Dzavik, Vlad, Fergusson, Dean A, Fowler, Robert A, Galanaud, Jean-Phillippe, Gross, Peter L, McDonald, Emily G, Husain, Mansoor, Kahn, Susan R, Kumar, Anand, Marshall, John, Murthy, Srinivas, Slutsky, Arthur S, Turgeon, Alexis F, and Berry, Scott M

Subjects
THERAPEUTIC use of fibrinolytic agents, THROMBOSIS risk factors, INFLAMMATION, ANTI-inflammatory agents, ARTIFICIAL respiration, BLOOD diseases, RANDOMIZED controlled trials, COVID-19, DISEASE risk factors
Abstract

Background: Mortality from COVID-19 is high among hospitalized patients and effective therapeutics are lacking. Hypercoagulability, thrombosis and hyperinflammation occur in COVID-19 and may contribute to severe complications. Therapeutic anticoagulation may improve clinical outcomes through anti-thrombotic, anti-inflammatory and anti-viral mechanisms. Our primary objective is to evaluate whether therapeutic-dose anticoagulation with low-molecular-weight heparin or unfractionated heparin prevents mechanical ventilation and/or death in patients hospitalized with COVID-19 compared to usual care. Methods: An international, open-label, adaptive randomized controlled trial. Using a Bayesian framework, the trial will declare results as soon as pre-specified posterior probabilities for superiority, futility, or harm are reached. The trial uses response-adaptive randomization to maximize the probability that patients will receive the more beneficial treatment approach, as treatment effect information accumulates within the trial. By leveraging a common data safety monitoring board and pooling data with a second similar international Bayesian adaptive trial (REMAP-COVID anticoagulation domain), treatment efficacy and safety will be evaluated as efficiently as possible. The primary outcome is an ordinal endpoint with three possible outcomes based on the worst status of each patient through day 30: no requirement for invasive mechanical ventilation, invasive mechanical ventilation or death. Conclusion: Using an adaptive trial design, the Anti-Thrombotic Therapy To Ameliorate Complications of COVID-19 trial will establish whether therapeutic anticoagulation can reduce mortality and/or avoid the need for mechanical ventilation in patients hospitalized with COVID-19. Leveraging existing networks to recruit sites will increase enrollment and mitigate enrollment risk in sites with declining COVID-19 cases. [ABSTRACT FROM AUTHOR]

Published
2020
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32. Association between convalescent plasma treatment and mortality in COVID-19: a collaborative systematic review and meta-analysis of randomized clinical trials

Author

Axfors, Cathrine, Janiaud, Perrine, Schmitt, Andreas M, Van't Hooft, Janneke, Smith, Emily R, Haber, Noah A, Abayomi, Akin, Abduljalil, Manal, Abdulrahman, Abdulkarim, Acosta-Ampudia, Yeny, Aguilar-Guisado, Manuela, Al-Beidh, Farah, Alejandria, Marissa M, Alfonso, Rachelle N, Ali, Mohammad, AlQahtani, Manaf, AlZamrooni, Alaa, Anaya, Juan-Manuel, Ang, Mark Angelo C, Aomar, Ismael F, Argumanis, Luis E, Averyanov, Alexander, Baklaushev, Vladimir P, Balionis, Olga, Benfield, Thomas, Berry, Scott, Birocco, Nadia, Bonifacio, Lynn B, Bowen, Asha C, Bown, Abbie, Cabello-Gutierrez, Carlos, Camacho, Bernardo, Camacho-Ortiz, Adrian, Campbell-Lee, Sally, Cao, Damon H, Cardesa, Ana, Carnate, Jose M, Castillo, German Jr J, Cavallo, Rossana, Chowdhury, Fazle R, Chowdhury, Forhad UH, Ciccone, Giovannino, Cingolani, Antonella, Climacosa, Fresthel Monica M, Compernolle, Veerle, Cortez, Carlo Francisco N, Costa Neto, Abel, D'Antico, Sergio, Daly, James, Danielle, Franca, Davis, Joshua S, De Rosa, Francesco Giuseppe, Denholm, Justin T, Denkinger, Claudia M, Desmecht, Daniel, Díaz-Coronado, Juan C, Díaz Ponce-Medrano, Juan A, Donneau, Anne-Françoise, Dumagay, Teresita E, Dunachie, Susanna, Dungog, Cecile C, Erinoso, Olufemi, Escasa, Ivy Mae S, Estcourt, Lise J, Evans, Amy, Evasan, Agnes LM, Fareli, Christian J, Fernandez-Sanchez, Veronica, Galassi, Claudia, Gallo, Juan E, Garcia, Patricia J, Garcia, Patricia L, Garcia, Jesus A, Garigliany, Mutien, Garza-Gonzalez, Elvira, Gauiran, Deonne Thaddeus V, Gaviria García, Paula A, Giron-Gonzalez, Jose-Antonio, Gómez-Almaguer, David, Gordon, Anthony C, Gothot, André, Grass Guaqueta, Jeser Santiago, Green, Cameron, Grimaldi, David, Hammond, Naomi E, Harvala, Heli, Heralde, Francisco M, Herrick, Jesica, Higgins, Alisa M, Hills, Thomas E, Hines, Jennifer, Holm, Karin, Hoque, Ashraful, Hoste, Eric, Ignacio, Jose M, Ivanov, Alexander V, Janssen, Maike, Jennings, Jeffrey H, Jha, Vivekanand, King, Ruby Anne N, Kjeldsen-Kragh, Jens, Klenerman, Paul, Kotecha, Aditya, Krapp, Fiorella, Labanca, Luciana, Laing, Emma, Landin-Olsson, Mona, Laterre, Pierre-François, Lim, Lyn-Li, Lim, Jodor, Ljungquist, Oskar, Llaca-Díaz, Jorge M, López-Robles, Concepción, López-Cárdenas, Salvador, Lopez-Plaza, Ileana, Lucero, Josephine Anne C, Lundgren, Maria, Macías, Juan, Maganito, Sandy C, Malundo, Anna Flor G, Manrique, Rubén D, Manzini, Paola M, Marcos, Miguel, Marquez, Ignacio, Martínez-Marcos, Francisco Javier, Mata, Ana M, McArthur, Colin J, McQuilten, Zoe K, McVerry, Bryan J, Menon, David K, Meyfroidt, Geert, Mirasol, Ma Angelina L, Misset, Benoît, Molton, James S, Mondragon, Alric V, Monsalve, Diana M, Moradi Choghakabodi, Parastoo, Morpeth, Susan C, Mouncey, Paul R, Moutschen, Michel, Müller-Tidow, Carsten, Murphy, Erin, Najdovski, Tome, Nichol, Alistair D, Nielsen, Henrik, Novak, Richard M, O'Sullivan, Matthew VN, Olalla, Julian, Osibogun, Akin, Osikomaiya, Bodunrin, Oyonarte, Salvador, Pardo-Oviedo, Juan M, Patel, Mahesh C, Paterson, David L, Peña-Perez, Carlos A, Perez-Calatayud, Angel A, Pérez-Alba, Eduardo, Perkina, Anastasia, Perry, Naomi, Pouladzadeh, Mandana, Poyato, Inmaculada, Price, David J, Quero, Anne Kristine H, Rahman, Md M, Rahman, Md S, Ramesh, Mayur, Ramírez-Santana, Carolina, Rasmussen, Magnus, Rees, Megan A, Rego, Eduardo, Roberts, Jason A, Roberts, David J, Rodríguez, Yhojan, Rodríguez-Baño, Jesús, Rogers, Benjamin A, Rojas, Manuel, Romero, Alberto, Rowan, Kathryn M, Saccona, Fabio, Safdarian, Mehdi, Santos, Maria Clariza M, Sasadeusz, Joe, Scozzari, Gitana, Shankar-Hari, Manu, Sharma, Gorav, Snelling, Thomas, Soto, Alonso, Tagayuna, Pedrito Y, Tang, Amy, Tatem, Geneva, Teofili, Luciana, Tong, Steven YC, Turgeon, Alexis F, Veloso, Januario D, Venkatesh, Balasubramanian, Ventura-Enriquez, Yanet, Webb, Steve A, Wiese, Lothar, Wikén, Christian, Wood, Erica M, Yusubalieva, Gaukhar M, Zacharowski, Kai, Zarychanski, Ryan, Khanna, Nina, Moher, David, Goodman, Steven N, Ioannidis, John PA, and Hemkens, Lars G

Subjects
Meta-analysis, Convalescent plasma, Treatment Outcome, SARS-CoV-2, Immunization, Passive, COVID-19, Humans, COVID-19 Serotherapy, 3. Good health, Randomized Controlled Trials as Topic
Abstract

Funder: laura and john arnold foundation, BACKGROUND: Convalescent plasma has been widely used to treat COVID-19 and is under investigation in numerous randomized clinical trials, but results are publicly available only for a small number of trials. The objective of this study was to assess the benefits of convalescent plasma treatment compared to placebo or no treatment and all-cause mortality in patients with COVID-19, using data from all available randomized clinical trials, including unpublished and ongoing trials (Open Science Framework, https://doi.org/10.17605/OSF.IO/GEHFX ). METHODS: In this collaborative systematic review and meta-analysis, clinical trial registries (ClinicalTrials.gov, WHO International Clinical Trials Registry Platform), the Cochrane COVID-19 register, the LOVE database, and PubMed were searched until April 8, 2021. Investigators of trials registered by March 1, 2021, without published results were contacted via email. Eligible were ongoing, discontinued and completed randomized clinical trials that compared convalescent plasma with placebo or no treatment in COVID-19 patients, regardless of setting or treatment schedule. Aggregated mortality data were extracted from publications or provided by investigators of unpublished trials and combined using the Hartung-Knapp-Sidik-Jonkman random effects model. We investigated the contribution of unpublished trials to the overall evidence. RESULTS: A total of 16,477 patients were included in 33 trials (20 unpublished with 3190 patients, 13 published with 13,287 patients). 32 trials enrolled only hospitalized patients (including 3 with only intensive care unit patients). Risk of bias was low for 29/33 trials. Of 8495 patients who received convalescent plasma, 1997 died (23%), and of 7982 control patients, 1952 died (24%). The combined risk ratio for all-cause mortality was 0.97 (95% confidence interval: 0.92; 1.02) with between-study heterogeneity not beyond chance (I2 = 0%). The RECOVERY trial had 69.8% and the unpublished evidence 25.3% of the weight in the meta-analysis. CONCLUSIONS: Convalescent plasma treatment of patients with COVID-19 did not reduce all-cause mortality. These results provide strong evidence that convalescent plasma treatment for patients with COVID-19 should not be used outside of randomized trials. Evidence synthesis from collaborations among trial investigators can inform both evidence generation and evidence application in patient care.

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

Author

ATTACC Investigators, ACTIV-4a Investigators, REMAP-CAP Investigators, Lawler, Patrick R, Goligher, Ewan C, Berger, Jeffrey S, Neal, Matthew D, McVerry, Bryan J, Nicolau, Jose C, Gong, Michelle N, Carrier, Marc, Rosenson, Robert S, Reynolds, Harmony R, Turgeon, Alexis F, Escobedo, Jorge, Huang, David T, Bradbury, Charlotte A, Houston, Brett L, Kornblith, Lucy Z, Kumar, Anand, Kahn, Susan R, Cushman, Mary, McQuilten, Zoe, Slutsky, Arthur S, Kim, Keri S, Gordon, Anthony C, Kirwan, Bridget-Anne, Brooks, Maria M, Higgins, Alisa M, Lewis, Roger J, Lorenzi, Elizabeth, Berry, Scott M, Berry, Lindsay R, Aday, Aaron W, Al-Beidh, Farah, Annane, Djillali, Arabi, Yaseen M, Aryal, Diptesh, Baumann Kreuziger, Lisa, Beane, Abi, Bhimani, Zahra, Bihari, Shailesh, Billett, Henny H, Bond, Lindsay, Bonten, Marc, Brunkhorst, Frank, Buxton, Meredith, Buzgau, Adrian, Castellucci, Lana A, Chekuri, Sweta, Chen, Jen-Ting, Cheng, Allen C, Chkhikvadze, Tamta, Coiffard, Benjamin, Costantini, Todd W, De Brouwer, Sophie, Derde, Lennie PG, Detry, Michelle A, Duggal, Abhijit, Džavík, Vladimír, Effron, Mark B, Estcourt, Lise J, Everett, Brendan M, Fergusson, Dean A, Fitzgerald, Mark, Fowler, Robert A, Galanaud, Jean P, Galen, Benjamin T, Gandotra, Sheetal, García-Madrona, Sebastian, Girard, Timothy D, Godoy, Lucas C, Goodman, Andrew L, Goossens, Herman, Green, Cameron, Greenstein, Yonatan Y, Gross, Peter L, Hamburg, Naomi M, Haniffa, Rashan, Hanna, George, Hanna, Nicholas, Hegde, Sheila M, Hendrickson, Carolyn M, Hite, R Duncan, Hindenburg, Alexander A, Hope, Aluko A, Horowitz, James M, Horvat, Christopher M, Hudock, Kristin, Hunt, Beverley J, Husain, Mansoor, Hyzy, Robert C, Iyer, Vivek N, Jacobson, Jeffrey R, Jayakumar, Devachandran, Keller, Norma M, Khan, Akram, Kim, Yuri, Kindzelski, Andrei L, King, Andrew J, Knudson, M Margaret, Kornblith, Aaron E, Krishnan, Vidya, Kutcher, Matthew E, Laffan, Michael A, Lamontagne, Francois, Le Gal, Grégoire, Leeper, Christine M, Leifer, Eric S, Lim, George, Lima, Felipe Gallego, Linstrum, Kelsey, Litton, Edward, Lopez-Sendon, Jose, Lopez-Sendon Moreno, Jose L, Lother, Sylvain A, Malhotra, Saurabh, Marcos, Miguel, Saud Marinez, Andréa, Marshall, John C, Marten, Nicole, Matthay, Michael A, McAuley, Daniel F, McDonald, Emily G, McGlothlin, Anna, McGuinness, Shay P, Middeldorp, Saskia, Montgomery, Stephanie K, Moore, Steven C, Morillo Guerrero, Raquel, Mouncey, Paul R, Murthy, Srinivas, Nair, Girish B, Nair, Rahul, Nichol, Alistair D, Nunez-Garcia, Brenda, Pandey, Ambarish, Park, Pauline K, Parke, Rachael L, Parker, Jane C, Parnia, Sam, Paul, Jonathan D, Pérez González, Yessica S, Pompilio, Mauricio, Prekker, Matthew E, Quigley, John G, Rost, Natalia S, Rowan, Kathryn, Santos, Fernanda O, Santos, Marlene, Olombrada Santos, Mayler, Satterwhite, Lewis, Saunders, Christina T, Schutgens, Roger EG, Seymour, Christopher W, Siegal, Deborah M, Silva, Delcio G, Shankar-Hari, Manu, Sheehan, John P, Singhal, Aneesh B, Solvason, Dayna, Stanworth, Simon J, Tritschler, Tobias, Turner, Anne M, Van Bentum-Puijk, Wilma, Van De Veerdonk, Frank L, Van Diepen, Sean, Vazquez-Grande, Gloria, Wahid, Lana, Wareham, Vanessa, Wells, Bryan J, Widmer, R Jay, Wilson, Jennifer G, Yuriditsky, Eugene, Zampieri, Fernando G, Angus, Derek C, McArthur, Colin J, Webb, Steven A, Farkouh, Michael E, Hochman, Judith S, and Zarychanski, Ryan

Subjects
Adult, Male, Heparin, Anticoagulants, COVID-19, Hemorrhage, Thrombosis, Heparin, Low-Molecular-Weight, Middle Aged, Survival Analysis, 3. Good health, COVID-19 Drug Treatment, Humans, Female, Hospital Mortality, Aged
Abstract

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 anticoagulation and in 0.9% of those receiving thromboprophylaxis. CONCLUSIONS: In noncritically ill patients with Covid-19, an initial strategy of therapeutic-dose anticoagulation with heparin increased the probability of survival to hospital discharge with reduced use of cardiovascular or respiratory organ support as compared with usual-care thromboprophylaxis. (ATTACC, ACTIV-4a, and REMAP-CAP ClinicalTrials.gov numbers, NCT04372589, NCT04505774, NCT04359277, and NCT02735707.).

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

Author

REMAP-CAP Investigators, ACTIV-4a Investigators, ATTACC Investigators, Goligher, Ewan C, Bradbury, Charlotte A, McVerry, Bryan J, Lawler, Patrick R, Berger, Jeffrey S, Gong, Michelle N, Carrier, Marc, Reynolds, Harmony R, Kumar, Anand, Turgeon, Alexis F, Kornblith, Lucy Z, Kahn, Susan R, Marshall, John C, Kim, Keri S, Houston, Brett L, Derde, Lennie PG, Cushman, Mary, Tritschler, Tobias, Angus, Derek C, Godoy, Lucas C, McQuilten, Zoe, Kirwan, Bridget-Anne, Farkouh, Michael E, Brooks, Maria M, Lewis, Roger J, Berry, Lindsay R, Lorenzi, Elizabeth, Gordon, Anthony C, Ahuja, Tania, Al-Beidh, Farah, Annane, Djillali, Arabi, Yaseen M, Aryal, Diptesh, Baumann Kreuziger, Lisa, Beane, Abi, Bhimani, Zahra, Bihari, Shailesh, Billett, Henny H, Bond, Lindsay, Bonten, Marc, Brunkhorst, Frank, Buxton, Meredith, Buzgau, Adrian, Castellucci, Lana A, Chekuri, Sweta, Chen, Jen-Ting, Cheng, Allen C, Chkhikvadze, Tamta, Coiffard, Benjamin, Contreras, Aira, Costantini, Todd W, De Brouwer, Sophie, Detry, Michelle A, Duggal, Abhijit, Džavík, Vladimír, Effron, Mark B, Eng, Heather F, Escobedo, Jorge, Estcourt, Lise J, Everett, Brendan M, Fergusson, Dean A, Fitzgerald, Mark, Fowler, Robert A, Froess, Joshua D, Fu, Zhuxuan, Galanaud, Jean P, Galen, Benjamin T, Gandotra, Sheetal, Girard, Timothy D, Goodman, Andrew L, Goossens, Herman, Green, Cameron, Greenstein, Yonatan Y, Gross, Peter L, Haniffa, Rashan, Hegde, Sheila M, Hendrickson, Carolyn M, Higgins, Alisa M, Hindenburg, Alexander A, Hope, Aluko A, Horowitz, James M, Horvat, Christopher M, Huang, David T, Hudock, Kristin, Hunt, Beverley J, Husain, Mansoor, Hyzy, Robert C, Jacobson, Jeffrey R, Jayakumar, Devachandran, Keller, Norma M, Khan, Akram, Kim, Yuri, Kindzelski, Andrei, King, Andrew J, Knudson, M Margaret, Kornblith, Aaron E, Kutcher, Matthew E, Laffan, Michael A, Lamontagne, Francois, Le Gal, Grégoire, Leeper, Christine M, Leifer, Eric S, Lim, George, Gallego Lima, Felipe, Linstrum, Kelsey, Litton, Edward, Lopez-Sendon, Jose, Lother, Sylvain A, Marten, Nicole, Saud Marinez, Andréa, Martinez, Mary, Mateos Garcia, Eduardo, Mavromichalis, Stavroula, McAuley, Daniel F, McDonald, Emily G, McGlothlin, Anna, McGuinness, Shay P, Middeldorp, Saskia, Montgomery, Stephanie K, Mouncey, Paul R, Murthy, Srinivas, Nair, Girish B, Nair, Rahul, Nichol, Alistair D, Nicolau, Jose C, Nunez-Garcia, Brenda, Park, John J, Park, Pauline K, Parke, Rachael L, Parker, Jane C, Parnia, Sam, Paul, Jonathan D, Pompilio, Mauricio, Quigley, John G, Rosenson, Robert S, Rost, Natalia S, Rowan, Kathryn, Santos, Fernanda O, Santos, Marlene, Santos, Mayler O, Satterwhite, Lewis, Saunders, Christina T, Schreiber, Jake, Schutgens, Roger EG, Seymour, Christopher W, Siegal, Deborah M, Silva, Delcio G, Singhal, Aneesh B, Slutsky, Arthur S, Solvason, Dayna, Stanworth, Simon J, Turner, Anne M, Van Bentum-Puijk, Wilma, Van De Veerdonk, Frank L, Van Diepen, Sean, Vazquez-Grande, Gloria, Wahid, Lana, Wareham, Vanessa, Widmer, R Jay, Wilson, Jennifer G, Yuriditsky, Eugene, Zhong, Yongqi, Berry, Scott M, McArthur, Colin J, Neal, Matthew D, Hochman, Judith S, Webb, Steven A, and Zarychanski, Ryan

Subjects
Male, Heparin, Critical Illness, Anticoagulants, COVID-19, Hemorrhage, Thrombosis, Middle Aged, Respiration, Artificial, 3. Good health, COVID-19 Drug Treatment, Logistic Models, Odds Ratio, Humans, Female, Hospital Mortality, Treatment Failure, Aged
Abstract

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

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

Author

REMAP-CAP Investigators, Gordon, Anthony C, Mouncey, Paul R, Al-Beidh, Farah, Rowan, Kathryn M, Nichol, Alistair D, Arabi, Yaseen M, Annane, Djillali, Beane, Abi, Van Bentum-Puijk, Wilma, Berry, Lindsay R, Bhimani, Zahra, Bonten, Marc JM, Bradbury, Charlotte A, Brunkhorst, Frank M, Buzgau, Adrian, Cheng, Allen C, Detry, Michelle A, Duffy, Eamon J, Estcourt, Lise J, Fitzgerald, Mark, Goossens, Herman, Haniffa, Rashan, Higgins, Alisa M, Hills, Thomas E, Horvat, Christopher M, Lamontagne, Francois, Lawler, Patrick R, Leavis, Helen L, Linstrum, Kelsey M, Litton, Edward, Lorenzi, Elizabeth, Marshall, John C, Mayr, Florian B, McAuley, Daniel F, McGlothlin, Anna, McGuinness, Shay P, McVerry, Bryan J, Montgomery, Stephanie K, Morpeth, Susan C, Murthy, Srinivas, Orr, Katrina, Parke, Rachael L, Parker, Jane C, Patanwala, Asad E, Pettilä, Ville, Rademaker, Emma, Santos, Marlene S, Saunders, Christina T, Seymour, Christopher W, Shankar-Hari, Manu, Sligl, Wendy I, Turgeon, Alexis F, Turner, Anne M, Van De Veerdonk, Frank L, Zarychanski, Ryan, Green, Cameron, Lewis, Roger J, Angus, Derek C, McArthur, Colin J, Berry, Scott, Webb, Steve A, and Derde, Lennie PG

Subjects
Adult, Male, Critical Illness, COVID-19, Middle Aged, Antibodies, Monoclonal, Humanized, Receptors, Interleukin-6, Respiration, Artificial, 3. Good health, COVID-19 Drug Treatment, Intensive Care Units, Odds Ratio, Humans, Female, Hospital Mortality, Aged
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. CONCLUSIONS: In 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.).

36. Association between convalescent plasma treatment and mortality in COVID-19: a collaborative systematic review and meta-analysis of randomized clinical trials

Author

Axfors, Cathrine, Janiaud, Perrine, Schmitt, Andreas M, Van't Hooft, Janneke, Smith, Emily R, Haber, Noah A, Abayomi, Akin, Abduljalil, Manal, Abdulrahman, Abdulkarim, Acosta-Ampudia, Yeny, Aguilar-Guisado, Manuela, Al-Beidh, Farah, Alejandria, Marissa M, Alfonso, Rachelle N, Ali, Mohammad, AlQahtani, Manaf, AlZamrooni, Alaa, Anaya, Juan-Manuel, Ang, Mark Angelo C, Aomar, Ismael F, Argumanis, Luis E, Averyanov, Alexander, Baklaushev, Vladimir P, Balionis, Olga, Benfield, Thomas, Berry, Scott, Birocco, Nadia, Bonifacio, Lynn B, Bowen, Asha C, Bown, Abbie, Cabello-Gutierrez, Carlos, Camacho, Bernardo, Camacho-Ortiz, Adrian, Campbell-Lee, Sally, Cao, Damon H, Cardesa, Ana, Carnate, Jose M, Castillo, German Jr J, Cavallo, Rossana, Chowdhury, Fazle R, Chowdhury, Forhad UH, Ciccone, Giovannino, Cingolani, Antonella, Climacosa, Fresthel Monica M, Compernolle, Veerle, Cortez, Carlo Francisco N, Costa Neto, Abel, D'Antico, Sergio, Daly, James, Danielle, Franca, Davis, Joshua S, De Rosa, Francesco Giuseppe, Denholm, Justin T, Denkinger, Claudia M, Desmecht, Daniel, D��az-Coronado, Juan C, D��az Ponce-Medrano, Juan A, Donneau, Anne-Fran��oise, Dumagay, Teresita E, Dunachie, Susanna, Dungog, Cecile C, Erinoso, Olufemi, Escasa, Ivy Mae S, Estcourt, Lise J, Evans, Amy, Evasan, Agnes LM, Fareli, Christian J, Fernandez-Sanchez, Veronica, Galassi, Claudia, Gallo, Juan E, Garcia, Patricia J, Garcia, Patricia L, Garcia, Jesus A, Garigliany, Mutien, Garza-Gonzalez, Elvira, Gauiran, Deonne Thaddeus V, Gaviria Garc��a, Paula A, Giron-Gonzalez, Jose-Antonio, G��mez-Almaguer, David, Gordon, Anthony C, Gothot, Andr��, Grass Guaqueta, Jeser Santiago, Green, Cameron, Grimaldi, David, Hammond, Naomi E, Harvala, Heli, Heralde, Francisco M, Herrick, Jesica, Higgins, Alisa M, Hills, Thomas E, Hines, Jennifer, Holm, Karin, Hoque, Ashraful, Hoste, Eric, Ignacio, Jose M, Ivanov, Alexander V, Janssen, Maike, Jennings, Jeffrey H, Jha, Vivekanand, King, Ruby Anne N, Kjeldsen-Kragh, Jens, Klenerman, Paul, Kotecha, Aditya, Krapp, Fiorella, Labanca, Luciana, Laing, Emma, Landin-Olsson, Mona, Laterre, Pierre-Fran��ois, Lim, Lyn-Li, Lim, Jodor, Ljungquist, Oskar, Llaca-D��az, Jorge M, L��pez-Robles, Concepci��n, L��pez-C��rdenas, Salvador, Lopez-Plaza, Ileana, Lucero, Josephine Anne C, Lundgren, Maria, Mac��as, Juan, Maganito, Sandy C, Malundo, Anna Flor G, Manrique, Rub��n D, Manzini, Paola M, Marcos, Miguel, Marquez, Ignacio, Mart��nez-Marcos, Francisco Javier, Mata, Ana M, McArthur, Colin J, McQuilten, Zoe K, McVerry, Bryan J, Menon, David K, Meyfroidt, Geert, Mirasol, Ma Angelina L, Misset, Beno��t, Molton, James S, Mondragon, Alric V, Monsalve, Diana M, Moradi Choghakabodi, Parastoo, Morpeth, Susan C, Mouncey, Paul R, Moutschen, Michel, M��ller-Tidow, Carsten, Murphy, Erin, Najdovski, Tome, Nichol, Alistair D, Nielsen, Henrik, Novak, Richard M, O'Sullivan, Matthew VN, Olalla, Julian, Osibogun, Akin, Osikomaiya, Bodunrin, Oyonarte, Salvador, Pardo-Oviedo, Juan M, Patel, Mahesh C, Paterson, David L, Pe��a-Perez, Carlos A, Perez-Calatayud, Angel A, P��rez-Alba, Eduardo, Perkina, Anastasia, Perry, Naomi, Pouladzadeh, Mandana, Poyato, Inmaculada, Price, David J, Quero, Anne Kristine H, Rahman, Md M, Rahman, Md S, Ramesh, Mayur, Ram��rez-Santana, Carolina, Rasmussen, Magnus, Rees, Megan A, Rego, Eduardo, Roberts, Jason A, Roberts, David J, Rodr��guez, Yhojan, Rodr��guez-Ba��o, Jes��s, Rogers, Benjamin A, Rojas, Manuel, Romero, Alberto, Rowan, Kathryn M, Saccona, Fabio, Safdarian, Mehdi, Santos, Maria Clariza M, Sasadeusz, Joe, Scozzari, Gitana, Shankar-Hari, Manu, Sharma, Gorav, Snelling, Thomas, Soto, Alonso, Tagayuna, Pedrito Y, Tang, Amy, Tatem, Geneva, Teofili, Luciana, Tong, Steven YC, Turgeon, Alexis F, Veloso, Januario D, Venkatesh, Balasubramanian, Ventura-Enriquez, Yanet, Webb, Steve A, Wiese, Lothar, Wik��n, Christian, Wood, Erica M, Yusubalieva, Gaukhar M, Zacharowski, Kai, Zarychanski, Ryan, Khanna, Nina, Moher, David, Goodman, Steven N, Ioannidis, John PA, and Hemkens, Lars G

Subjects
Meta-analysis, Convalescent plasma, SARS-CoV-2, COVID-19, 3. Good health, Research Article
Abstract

Funder: laura and john arnold foundation; doi: http://dx.doi.org/10.13039/100009827, BACKGROUND: Convalescent plasma has been widely used to treat COVID-19 and is under investigation in numerous randomized clinical trials, but results are publicly available only for a small number of trials. The objective of this study was to assess the benefits of convalescent plasma treatment compared to placebo or no treatment and all-cause mortality in patients with COVID-19, using data from all available randomized clinical trials, including unpublished and ongoing trials (Open Science Framework, https://doi.org/10.17605/OSF.IO/GEHFX ). METHODS: In this collaborative systematic review and meta-analysis, clinical trial registries (ClinicalTrials.gov, WHO International Clinical Trials Registry Platform), the Cochrane COVID-19 register, the LOVE database, and PubMed were searched until April 8, 2021. Investigators of trials registered by March 1, 2021, without published results were contacted via email. Eligible were ongoing, discontinued and completed randomized clinical trials that compared convalescent plasma with placebo or no treatment in COVID-19 patients, regardless of setting or treatment schedule. Aggregated mortality data were extracted from publications or provided by investigators of unpublished trials and combined using the Hartung-Knapp-Sidik-Jonkman random effects model. We investigated the contribution of unpublished trials to the overall evidence. RESULTS: A total of 16,477 patients were included in 33 trials (20 unpublished with 3190 patients, 13 published with 13,287 patients). 32 trials enrolled only hospitalized patients (including 3 with only intensive care unit patients). Risk of bias was low for 29/33 trials. Of 8495 patients who received convalescent plasma, 1997 died (23%), and of 7982 control patients, 1952 died (24%). The combined risk ratio for all-cause mortality was 0.97 (95% confidence interval: 0.92; 1.02) with between-study heterogeneity not beyond chance (I2 = 0%). The RECOVERY trial had 69.8% and the unpublished evidence 25.3% of the weight in the meta-analysis. CONCLUSIONS: Convalescent plasma treatment of patients with COVID-19 did not reduce all-cause mortality. These results provide strong evidence that convalescent plasma treatment for patients with COVID-19 should not be used outside of randomized trials. Evidence synthesis from collaborations among trial investigators can inform both evidence generation and evidence application in patient care.

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