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Interventions for treatment of COVID-19: Second edition of a living systematic review with meta-analyses and trial sequential analyses (The LIVING Project).
Juul, Sophie; Nielsen, Emil Eik; Feinberg, Joshua; Siddiqui, Faiza; Jørgensen, Caroline Kamp; Barot, Emily; Holgersson, Johan; Nielsen, Niklas; Bentzer, Peter; Veroniki, Areti Angeliki; Thabane, Lehana; Bu, Fanlong; Klingenberg, Sarah; Gluud, Christian; Jakobsen, Janus Christian.
  • Juul S; Copenhagen Trial Unit-Centre for Clinical Intervention Research, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
  • Nielsen EE; Copenhagen Trial Unit-Centre for Clinical Intervention Research, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
  • Feinberg J; Department of Internal Medicine-Cardiology Section, Holbæk Hospital, Holbæk, Denmark.
  • Siddiqui F; Copenhagen Trial Unit-Centre for Clinical Intervention Research, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
  • Jørgensen CK; Copenhagen Trial Unit-Centre for Clinical Intervention Research, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
  • Barot E; Copenhagen Trial Unit-Centre for Clinical Intervention Research, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
  • Holgersson J; Copenhagen Trial Unit-Centre for Clinical Intervention Research, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
  • Nielsen N; Department of Clinical Sciences Lund, Anesthesia & Intensive Care, Helsingborg Hospital, Lund University, Lund, Sweden.
  • Bentzer P; Department of Clinical Sciences Lund, Anesthesia & Intensive Care, Helsingborg Hospital, Lund University, Lund, Sweden.
  • Veroniki AA; Department of Clinical Sciences Lund, Anesthesia & Intensive Care, Helsingborg Hospital, Lund University, Lund, Sweden.
  • Thabane L; Department of Primary Education, School of Education, University of Ioannina, Ioannina, Greece.
  • Bu F; Knowledge Translation Program, Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, Ontario, Canada.
  • Klingenberg S; Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, ON, Canada.
  • Gluud C; Centre for Evidence-based Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China.
  • Jakobsen JC; Copenhagen Trial Unit-Centre for Clinical Intervention Research, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
PLoS One ; 16(3): e0248132, 2021.
Article in English | MEDLINE | ID: covidwho-1127793
Preprint
This scientific journal article is probably based on a previously available preprint. It has been identified through a machine matching algorithm, human confirmation is still pending.
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Semantic information from SemMedBD (by NLM)
1. Intervention regimes TREATS COVID-19
Subject
Intervention regimes
Predicate
TREATS
Object
COVID-19
2. COVID-19 PROCESS_OF Human Age Group
Subject
COVID-19
Predicate
PROCESS_OF
Object
Human Age Group
3. Intervention regimes TREATS Participant
Subject
Intervention regimes
Predicate
TREATS
Object
Participant
4. Intervention regimes TREATS Human Age Group
Subject
Intervention regimes
Predicate
TREATS
Object
Human Age Group
5. Validation USES Interventional procedure
Subject
Validation
Predicate
USES
Object
Interventional procedure
6. remdesivir DISRUPTS Cessation of life
Subject
remdesivir
Predicate
DISRUPTS
Object
Cessation of life
7. remdesivir TREATS Serious Adverse Event
Subject
remdesivir
Predicate
TREATS
Object
Serious Adverse Event
8. tocilizumab TREATS Serious Adverse Event
Subject
tocilizumab
Predicate
TREATS
Object
Serious Adverse Event
9. hydroxychloroquine DISRUPTS Cessation of life
Subject
hydroxychloroquine
Predicate
DISRUPTS
Object
Cessation of life
10. lopinavir / ritonavir DISRUPTS Cessation of life
Subject
lopinavir / ritonavir
Predicate
DISRUPTS
Object
Cessation of life
11. Adrenal Cortex Hormones DISRUPTS Cessation of life
Subject
Adrenal Cortex Hormones
Predicate
DISRUPTS
Object
Cessation of life
12. remdesivir INHIBITS Serious Adverse Event
Subject
remdesivir
Predicate
INHIBITS
Object
Serious Adverse Event
13. tocilizumab INHIBITS Serious Adverse Event
Subject
tocilizumab
Predicate
INHIBITS
Object
Serious Adverse Event
14. bromhexine INHIBITS Non-serious Adverse Event
Subject
bromhexine
Predicate
INHIBITS
Object
Non-serious Adverse Event
15. Intervention regimes TREATS COVID-19
Subject
Intervention regimes
Predicate
TREATS
Object
COVID-19
16. COVID-19 PROCESS_OF Human Age Group
Subject
COVID-19
Predicate
PROCESS_OF
Object
Human Age Group
17. Intervention regimes TREATS Participant
Subject
Intervention regimes
Predicate
TREATS
Object
Participant
18. Intervention regimes TREATS Human Age Group
Subject
Intervention regimes
Predicate
TREATS
Object
Human Age Group
19. Validation USES Interventional procedure
Subject
Validation
Predicate
USES
Object
Interventional procedure
20. remdesivir DISRUPTS Cessation of life
Subject
remdesivir
Predicate
DISRUPTS
Object
Cessation of life
21. remdesivir TREATS Serious Adverse Event
Subject
remdesivir
Predicate
TREATS
Object
Serious Adverse Event
22. tocilizumab TREATS Serious Adverse Event
Subject
tocilizumab
Predicate
TREATS
Object
Serious Adverse Event
23. hydroxychloroquine DISRUPTS Cessation of life
Subject
hydroxychloroquine
Predicate
DISRUPTS
Object
Cessation of life
24. lopinavir / ritonavir DISRUPTS Cessation of life
Subject
lopinavir / ritonavir
Predicate
DISRUPTS
Object
Cessation of life
25. Adrenal Cortex Hormones DISRUPTS Cessation of life
Subject
Adrenal Cortex Hormones
Predicate
DISRUPTS
Object
Cessation of life
26. remdesivir INHIBITS Serious Adverse Event
Subject
remdesivir
Predicate
INHIBITS
Object
Serious Adverse Event
27. tocilizumab INHIBITS Serious Adverse Event
Subject
tocilizumab
Predicate
INHIBITS
Object
Serious Adverse Event
28. bromhexine INHIBITS Non-serious Adverse Event
Subject
bromhexine
Predicate
INHIBITS
Object
Non-serious Adverse Event
ABSTRACT

BACKGROUND:

COVID-19 is a rapidly spreading disease that has caused extensive burden to individuals, families, countries, and the world. Effective treatments of COVID-19 are urgently needed. This is the second edition of a living systematic review of randomized clinical trials assessing the effects of all treatment interventions for participants in all age groups with COVID-19. METHODS AND

FINDINGS:

We planned to conduct aggregate data meta-analyses, trial sequential analyses, network meta-analysis, and individual patient data meta-analyses. Our systematic review was based on PRISMA and Cochrane guidelines, and our eight-step procedure for better validation of clinical significance of meta-analysis results. We performed both fixed-effect and random-effects meta-analyses. Primary outcomes were all-cause mortality and serious adverse events. Secondary outcomes were admission to intensive care, mechanical ventilation, renal replacement therapy, quality of life, and non-serious adverse events. According to the number of outcome comparisons, we adjusted our threshold for significance to p = 0.033. We used GRADE to assess the certainty of evidence. We searched relevant databases and websites for published and unpublished trials until November 2, 2020. Two reviewers independently extracted data and assessed trial methodology. We included 82 randomized clinical trials enrolling a total of 40,249 participants. 81 out of 82 trials were at overall high risk of bias. Meta-analyses showed no evidence of a difference between corticosteroids versus control on all-cause mortality (risk ratio [RR] 0.89; 95% confidence interval [CI] 0.79 to 1.00; p = 0.05; I2 = 23.1%; eight trials; very low certainty), on serious adverse events (RR 0.89; 95% CI 0.80 to 0.99; p = 0.04; I2 = 39.1%; eight trials; very low certainty), and on mechanical ventilation (RR 0.86; 95% CI 0.55 to 1.33; p = 0.49; I2 = 55.3%; two trials; very low certainty). The fixed-effect meta-analyses showed indications of beneficial effects. Trial sequential analyses showed that the required information size for all three analyses was not reached. Meta-analysis (RR 0.93; 95% CI 0.82 to 1.07; p = 0.31; I2 = 0%; four trials; moderate certainty) and trial sequential analysis (boundary for futility crossed) showed that we could reject that remdesivir versus control reduced the risk of death by 20%. Meta-analysis (RR 0.82; 95% CI 0.68 to 1.00; p = 0.05; I2 = 38.9%; four trials; very low certainty) and trial sequential analysis (required information size not reached) showed no evidence of difference between remdesivir versus control on serious adverse events. Fixed-effect meta-analysis showed indications of a beneficial effect of remdesivir on serious adverse events. Meta-analysis (RR 0.40; 95% CI 0.19 to 0.87; p = 0.02; I2 = 0%; two trials; very low certainty) showed evidence of a beneficial effect of intravenous immunoglobulin versus control on all-cause mortality, but trial sequential analysis (required information size not reached) showed that the result was severely underpowered to confirm or reject realistic intervention effects. Meta-analysis (RR 0.63; 95% CI 0.35 to 1.14; p = 0.12; I2 = 77.4%; five trials; very low certainty) and trial sequential analysis (required information size not reached) showed no evidence of a difference between tocilizumab versus control on serious adverse events. Fixed-effect meta-analysis showed indications of a beneficial effect of tocilizumab on serious adverse events. Meta-analysis (RR 0.70; 95% CI 0.51 to 0.96; p = 0.02; I2 = 0%; three trials; very low certainty) showed evidence of a beneficial effect of tocilizumab versus control on mechanical ventilation, but trial sequential analysis (required information size not reached) showed that the result was severely underpowered to confirm of reject realistic intervention effects. Meta-analysis (RR 0.32; 95% CI 0.15 to 0.69; p < 0.00; I2 = 0%; two trials; very low certainty) showed evidence of a beneficial effect of bromhexine versus standard care on non-serious adverse events, but trial sequential analysis (required information size not reached) showed that the result was severely underpowered to confirm or reject realistic intervention effects. Meta-analyses and trial sequential analyses (boundary for futility crossed) showed that we could reject that hydroxychloroquine versus control reduced the risk of death and serious adverse events by 20%. Meta-analyses and trial sequential analyses (boundary for futility crossed) showed that we could reject that lopinavir-ritonavir versus control reduced the risk of death, serious adverse events, and mechanical ventilation by 20%. All remaining outcome comparisons showed that we did not have enough information to confirm or reject realistic intervention effects. Nine single trials showed statistically significant results on our outcomes, but were underpowered to confirm or reject realistic intervention effects. Due to lack of data, it was not relevant to perform network meta-analysis or possible to perform individual patient data meta-analyses.

CONCLUSIONS:

No evidence-based treatment for COVID-19 currently exists. Very low certainty evidence indicates that corticosteroids might reduce the risk of death, serious adverse events, and mechanical ventilation; that remdesivir might reduce the risk of serious adverse events; that intravenous immunoglobin might reduce the risk of death and serious adverse events; that tocilizumab might reduce the risk of serious adverse events and mechanical ventilation; and that bromhexine might reduce the risk of non-serious adverse events. More trials with low risks of bias and random errors are urgently needed. This review will continuously inform best practice in treatment and clinical research of COVID-19. SYSTEMATIC REVIEW REGISTRATION PROSPERO CRD42020178787.
Subject(s)

Full text: Available Collection: International databases Database: MEDLINE Main subject: COVID-19 Type of study: Controlled clinical trial / Clinical Practice Guide / Randomized controlled trials / Reviews / Systematic review Limits: Humans Language: English Journal: PLoS One Journal subject: Science / Medicine Year: 2021 Document Type: Article Affiliation country: Journal.pone.0248132

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Full text: Available Collection: International databases Database: MEDLINE Main subject: COVID-19 Type of study: Controlled clinical trial / Clinical Practice Guide / Randomized controlled trials / Reviews / Systematic review Limits: Humans Language: English Journal: PLoS One Journal subject: Science / Medicine Year: 2021 Document Type: Article Affiliation country: Journal.pone.0248132