2020

DOI: 10.21203/rs.3.rs-66909/v1

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Evaluation of the Efficacy of Methylprednisolone Pulse Therapy in Treatment of Covid-19 Adult Patients with Severe Respiratory Failure: Randomized, Clinical Trial

Ramin Hamidi Farahani

¹

,

²

,

Amir Nezami-Asl

³

et al.

Abstract: Background: Covid-19 is now global concern and widely spread to the world due to high mortality among the nations we tried to evaluate the efficacy of methylprednisolone pulse in COVID-19 patients with severe respiratory failure.Methods: This study was phase2, double-blind, randomized, clinical trial in adults with COVID-19 (aged ≥18 years old) admitted to the intensive care unit (ICU) of *. Patients with intermediate or severe COVID-19 with PaO2/FiO2 less than 300 and progressive disease unresponsive to stand… Show more

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Cited by 13 publications

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“…The identified trials compared the following interventions: 10 trials compared corticosteroids versus standard care [52,56,87,89,96–99] or placebo [68, 88]; four trials compared remdesivir versus standard care [86, 110] or placebo [43, 65]; 13 trials compared hydroxychloroquine versus standard care [34,35,42,48,54,55,58,59,105,110], or placebo [53, 108]; five trials compared lopinavir-ritonavir versus standard care [32,40,106,110] or a co-intervention alone [45]; two trials compared interferon beta-1a versus standard care [36, 110]; four trials compared convalescent plasma versus standard care [39,51,78,91]; three trials compared azithromycin versus standard care [83] or co-interventions with standard care [54] or without standard care [82]; three trials compared colchicine versus standard care [49], placebo plus standard care [92], or placebo plus a co-intervention [107]; two trials compared immunoglobulin versus standard care [57] or placebo [95]; six trials compared tocilizumab versus standard care [93,111–113], placebo with standard care [90] or favipiravir alone as co-intervention [114];two trials compared bromhexine versus standard care [94, 104]; and three trials compared favipiravir versus standard care [41, 67] or a co-intervention alone [114].…”

Section: Resultsmentioning

confidence: 99%

“…We identified 10 trials (11 comparisons) randomizing 7,918 participants to corticosteroids versus standard care [52,56,87,89,96–99] or placebo [68, 88]. One trial was assessed at low risk of bias [88].…”

Section: Resultsmentioning

confidence: 99%

“…The remaining trials were assessed at high risk of bias ( S3 Table ). Five trials assessed the effects of methylprednisolone [56,68,96–98], three trials assessed the effects of dexamethasone [52,87,99], and two trials (three comparisons) assessed the effects of hydrocortisone [88, 89]. One trial assessing the effects of methylprednisolone was not eligible for meta-analysis, as approximately half of the participants in the experimental group were non-randomized [56].…”

Section: Resultsmentioning

confidence: 99%

“…We contacted the trial authors and asked for separate data for all randomized participants, but did not receive any response. Another trial assessing the effects of methylprednisolone was not eligible for meta-analysis, as the trial did not report on any of our review outcomes [96]. We requested data for our review outcomes from the trial authors but did not receive a response.…”

Section: Resultsmentioning

confidence: 99%

“…Two trials did not report the results in a usable way; one trial reported results of the experimental group with a proportion of participants being non-randomized [56], and the second trial reported the results as per-protocol, and there was participant crossover [42]. Seven trials did not report on our review outcomes [44,62,63,67,71,96,101]. We have contacted all corresponding authors, but we have not been able to obtain outcomes for our analyses from the trialists yet.…”

Section: Resultsmentioning

confidence: 99%

See 4 more Smart Citations

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

¹

,

²

,

³

et al. 2020

Preprint

View full text Add to dashboard Cite

BackgroundCOVID-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 findingsWe 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 bromhexidine 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.ConclusionsNo 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 intraveneous 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 bromhexidine 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 CRD42020178787Author summaryWhy was this study done?Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has spread rapidly worldwide, causing an international outbreak of the corona virus disease 2019 (COVID-19).There is a need for a living systematic review evaluating the beneficial and harmful effects of all possible interventions for treatment of COVID-19.What did the researchers do and find?We conducted the second edition of our living systematic review with meta-analyses and Trial sequential analyses to compare the effects of all treatment interventions for COVID-19.Very low certainty evidence indicated 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 intraveneous 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 bromhexidine might reduce the risk of non-serious adverse events.Nine single trials showed statistically significant results on our predefined outcomes but were underpowered to confirm or reject realistic intervention effects.None of the remaining trials showed evidence of a difference of the experimental interventions on our predefined outcomes.What do these findings mean?No evidence-based treatment for COVID-19 currently existsMore high quality, low risk of bias randomized clinical trials are urgently needed.

“…The identified trials compared the following interventions: 10 trials compared corticosteroids versus standard care [52,56,87,89,96–99] or placebo [68, 88]; four trials compared remdesivir versus standard care [86, 110] or placebo [43, 65]; 13 trials compared hydroxychloroquine versus standard care [34,35,42,48,54,55,58,59,105,110], or placebo [53, 108]; five trials compared lopinavir-ritonavir versus standard care [32,40,106,110] or a co-intervention alone [45]; two trials compared interferon beta-1a versus standard care [36, 110]; four trials compared convalescent plasma versus standard care [39,51,78,91]; three trials compared azithromycin versus standard care [83] or co-interventions with standard care [54] or without standard care [82]; three trials compared colchicine versus standard care [49], placebo plus standard care [92], or placebo plus a co-intervention [107]; two trials compared immunoglobulin versus standard care [57] or placebo [95]; six trials compared tocilizumab versus standard care [93,111–113], placebo with standard care [90] or favipiravir alone as co-intervention [114];two trials compared bromhexine versus standard care [94, 104]; and three trials compared favipiravir versus standard care [41, 67] or a co-intervention alone [114].…”

Section: Resultsmentioning

confidence: 99%

“…We identified 10 trials (11 comparisons) randomizing 7,918 participants to corticosteroids versus standard care [52,56,87,89,96–99] or placebo [68, 88]. One trial was assessed at low risk of bias [88].…”

Section: Resultsmentioning

confidence: 99%

“…The remaining trials were assessed at high risk of bias ( S3 Table ). Five trials assessed the effects of methylprednisolone [56,68,96–98], three trials assessed the effects of dexamethasone [52,87,99], and two trials (three comparisons) assessed the effects of hydrocortisone [88, 89]. One trial assessing the effects of methylprednisolone was not eligible for meta-analysis, as approximately half of the participants in the experimental group were non-randomized [56].…”

Section: Resultsmentioning

confidence: 99%

“…We contacted the trial authors and asked for separate data for all randomized participants, but did not receive any response. Another trial assessing the effects of methylprednisolone was not eligible for meta-analysis, as the trial did not report on any of our review outcomes [96]. We requested data for our review outcomes from the trial authors but did not receive a response.…”

Section: Resultsmentioning

confidence: 99%

“…Two trials did not report the results in a usable way; one trial reported results of the experimental group with a proportion of participants being non-randomized [56], and the second trial reported the results as per-protocol, and there was participant crossover [42]. Seven trials did not report on our review outcomes [44,62,63,67,71,96,101]. We have contacted all corresponding authors, but we have not been able to obtain outcomes for our analyses from the trialists yet.…”

Section: Resultsmentioning

confidence: 99%

See 3 more Smart Citations

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

¹

,

²

,

³

et al. 2020

Preprint

View full text Add to dashboard Cite

BackgroundCOVID-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 findingsWe 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 bromhexidine 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.ConclusionsNo 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 intraveneous 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 bromhexidine 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 CRD42020178787Author summaryWhy was this study done?Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has spread rapidly worldwide, causing an international outbreak of the corona virus disease 2019 (COVID-19).There is a need for a living systematic review evaluating the beneficial and harmful effects of all possible interventions for treatment of COVID-19.What did the researchers do and find?We conducted the second edition of our living systematic review with meta-analyses and Trial sequential analyses to compare the effects of all treatment interventions for COVID-19.Very low certainty evidence indicated 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 intraveneous 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 bromhexidine might reduce the risk of non-serious adverse events.Nine single trials showed statistically significant results on our predefined outcomes but were underpowered to confirm or reject realistic intervention effects.None of the remaining trials showed evidence of a difference of the experimental interventions on our predefined outcomes.What do these findings mean?No evidence-based treatment for COVID-19 currently existsMore high quality, low risk of bias randomized clinical trials are urgently needed.

Systemic corticosteroids for the treatment of COVID-19

¹

,

²

,

³

et al. 2021

Cochrane Database of Systematic Reviews

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No abstract

Systemic corticosteroids for the treatment of COVID-19: Equity-related analyses and update on evidence

¹

,

²

,

³

et al. 2022

Cochrane Database of Systematic Reviews

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No abstract

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