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Clinician Article

Interventions for treatment of COVID-19: Second edition of a living systematic review with meta-analyses and trial sequential analyses (The LIVING Project).



  • Juul S
  • Nielsen EE
  • Feinberg J
  • Siddiqui F
  • Jorgensen CK
  • Barot E, et al.
PLoS One. 2021 Mar 11;16(3):e0248132. doi: 10.1371/journal.pone.0248132. eCollection 2021. (Review)
PMID: 33705495
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Disciplines
  • Family Medicine (FM)/General Practice (GP)
    Relevance - 7/7
    Newsworthiness - 6/7
  • General Internal Medicine-Primary Care(US)
    Relevance - 7/7
    Newsworthiness - 6/7
  • Emergency Medicine
    Relevance - 6/7
    Newsworthiness - 5/7
  • Intensivist/Critical Care
    Relevance - 6/7
    Newsworthiness - 5/7
  • Respirology/Pulmonology
    Relevance - 6/7
    Newsworthiness - 5/7
  • Hospital Doctor/Hospitalists
    Relevance - 6/7
    Newsworthiness - 4/7
  • Internal Medicine
    Relevance - 6/7
    Newsworthiness - 4/7
  • Infectious Disease
    Relevance - 5/7
    Newsworthiness - 4/7

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 We searched relevant databases and websites for published and unpublished trials until November 2, 2020.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.


Clinical Comments

Emergency Medicine

In this systematic review/meta-analysis, no intervention was shown in certainty to improve outcomes in COVID-19 infection. Although there is some low-certainty evidence of possible benefit for certain interventions, more studies are needed (especially of higher quality) to guide evidence-based treatment for COVID-19 infection. It would be interesting to see with some of the newer data (i.e., past November 2020), especially with monoclonal antibodies and antivirals (e.g., remdesivir) showing benefit, how that changes the living document meta-analysis.

General Internal Medicine-Primary Care(US)

This is a long complex review of data on the usefulness of drugs to combat Covid-19 infection. Overall, the evidence quality was low and the unreliability high. They concluded that steroids probably reduced the risk of death and ventilator use. IVIG probably reduced death and ventilator use. Remdisivir and tocilizumamb probably reduced adverse events and ventilator use.

Infectious Disease

These types of combinations are potentially dangerous: it is not possible to give the same “very low certainty evidence” to corticosteroids and remdesivir, or to tociluzumab with intravenous immunoglobulin. On the other hand, just two trials with less than 100 patients in total and critical issues in validity, are almost absurd to mention.

Intensivist/Critical Care

This is a very comprehensive systematic review of treatments for COVID-19, one of several living SRs. It is well done but does not add much more to guide clinical practice. Most ICU physicians are probably already aware of these data.

Internal Medicine

I think this misses some of the important subgroup information from these trials - e.g. steroids seem to have huge benefits in those already intubated and probable harm in those who don't need oxygen at all.

Internal Medicine

It looks like the search ends in November. That is a long time ago for COVID evidence.

Internal Medicine

A living systematic review.

Respirology/Pulmonology

More extensive meta-analysis of numerous reported trials. As with many of these trials, the quality of the data is sketchy. No new information in this review.

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