“…After exclusion of three non-randomized trials [ 28 – 30 ], three study protocols [ 31 – 33 ], and one study comparing tocilizumab against dexamethasone [ 34 ], a total of 15 studies randomizing 9320 patients were included in the analysis (Fig. 1 ) [ 35 – 49 ]. Fig.…”
Section: Resultsmentioning
confidence: 99%
“…Concomitant use of steroids was highly variable across studies, ranging from 10.6 to 91.1% of enrolled patients (Table 2 ). Seven studies specifically enrolled patients with documented hyperinflammation [ 35 , 36 , 39 , 42 – 44 , 49 ], including two studies enrolling patients with documented elevated IL-6 [ 39 , 42 ], and one study enrolling patients with elevated C-reactive protein (CRP) [ 43 ] (Table 1 ).…”
Section: Resultsmentioning
confidence: 99%
“…Five studies compared IL-6 inhibitors with placebo [ 36 , 38 , 40 , 45 , 47 ], nine studies with standard treatment, [ 35 , 37 , 41 – 44 , 46 , 48 , 49 ] and one study against favipiravir [ 42 ].…”
Purpose
COVID-19 is characterized by dysregulated immune response, respiratory failure and a relevant mortality rate among hospitalized patients. Interleukin-6 (IL-6) is involved in COVID-19-associated cytokine storm, and several trials investigated whether its inhibition could improve patients’ outcome. We performed a meta-analysis of randomized trials (RCT) to test this hypothesis.
Materials and methods
Two independent investigators searched PubMed, Scopus, ClnicalTrials.gov and medRxiv up to September 1st, 2021. Inclusion criteria were: administration of tocilizumab or sarilumab; COVID-19 adult patients with pneumonia; and being a RCT. Primary outcome was mortality at the longest follow-up. Secondary outcomes included intubation rate and incidence of adverse events. Two independent investigators extracted data from eligible trials.
Results
Of the 763 studies assessed, 15 RCTs were included (9,320 patients), all were multicentre, and the majority open-label vs standard treatment. IL-6 inhibitors were associated with reduced all-cause mortality at the longest follow-up (1315/5,380 [24.4%] in the IL-6 inhibitors group versus 1080/3,814 [28.3%] in the control group, RR = 0.90; 95% CI 0.84 to 0.96; p for effect = 0.003, I2 = 0%, with 13 studies included), with reduction in 28/30-day mortality and intubation rates, and with no increase in adverse events and secondary infections.
Conclusion
IL-6 inhibitors reduced longest follow-up mortality and intubation in COVID-19 patients. Findings need to be confirmed in high-quality RCTs.
“…After exclusion of three non-randomized trials [ 28 – 30 ], three study protocols [ 31 – 33 ], and one study comparing tocilizumab against dexamethasone [ 34 ], a total of 15 studies randomizing 9320 patients were included in the analysis (Fig. 1 ) [ 35 – 49 ]. Fig.…”
Section: Resultsmentioning
confidence: 99%
“…Concomitant use of steroids was highly variable across studies, ranging from 10.6 to 91.1% of enrolled patients (Table 2 ). Seven studies specifically enrolled patients with documented hyperinflammation [ 35 , 36 , 39 , 42 – 44 , 49 ], including two studies enrolling patients with documented elevated IL-6 [ 39 , 42 ], and one study enrolling patients with elevated C-reactive protein (CRP) [ 43 ] (Table 1 ).…”
Section: Resultsmentioning
confidence: 99%
“…Five studies compared IL-6 inhibitors with placebo [ 36 , 38 , 40 , 45 , 47 ], nine studies with standard treatment, [ 35 , 37 , 41 – 44 , 46 , 48 , 49 ] and one study against favipiravir [ 42 ].…”
Purpose
COVID-19 is characterized by dysregulated immune response, respiratory failure and a relevant mortality rate among hospitalized patients. Interleukin-6 (IL-6) is involved in COVID-19-associated cytokine storm, and several trials investigated whether its inhibition could improve patients’ outcome. We performed a meta-analysis of randomized trials (RCT) to test this hypothesis.
Materials and methods
Two independent investigators searched PubMed, Scopus, ClnicalTrials.gov and medRxiv up to September 1st, 2021. Inclusion criteria were: administration of tocilizumab or sarilumab; COVID-19 adult patients with pneumonia; and being a RCT. Primary outcome was mortality at the longest follow-up. Secondary outcomes included intubation rate and incidence of adverse events. Two independent investigators extracted data from eligible trials.
Results
Of the 763 studies assessed, 15 RCTs were included (9,320 patients), all were multicentre, and the majority open-label vs standard treatment. IL-6 inhibitors were associated with reduced all-cause mortality at the longest follow-up (1315/5,380 [24.4%] in the IL-6 inhibitors group versus 1080/3,814 [28.3%] in the control group, RR = 0.90; 95% CI 0.84 to 0.96; p for effect = 0.003, I2 = 0%, with 13 studies included), with reduction in 28/30-day mortality and intubation rates, and with no increase in adverse events and secondary infections.
Conclusion
IL-6 inhibitors reduced longest follow-up mortality and intubation in COVID-19 patients. Findings need to be confirmed in high-quality RCTs.
“…There were ten potential RCTs to be incorporated for evidence-based prior distributions, [16][17][18][19][20][21][22][23][24][25] but one had highrisk of bias and five failed to report the required subgroup analyses and thus are not included in this analysis. [18,19,[21][22][23]25] RECOVERY mortality results were extracted from the peer reviewed publication, [1] and are presented in Table 1 as a function of baseline disease severity as determined by respiratory status and as a function of adjunctive corticosteroids therapy. Results from our search for prior tocilizumab mortality evidence is also presented in Table 1.…”
Section: All-cause Mortalitymentioning
confidence: 99%
“…[19,22,23,25] Although we could not also include six studies with allcause mortality data, these trials only contributed to less than 7% of weight in the meta-analysis (Supplementary Material). [18,19,[21][22][23]25]…”
Background:
Randomised Evaluation of COVID-19 Therapy (RECOVERY) demonstrated that tocilizumab reduces mortality in hospitalized COVID-19 patients. However, substantial uncertainty remains whether tocilizumab's effect is similar across clinically relevant subgroups. Whether this uncertainty can be resolved with Bayesian methods is unknown.
Design, Setting, Participants, and Interventions:
RECOVERY was a controlled, open-label, platform UK trial that randomized (1:1) 4116 adults with oxygen saturation <92% on room air or receiving oxygen therapy with C-reactive protein ≥75 mg/L to either usual care or tocilizumab plus usual care.
Main outcome measures:
Mortality and hospital discharge within 28 days.
Methods:
Using Bayesian methods, we combined RECOVERY with evidence-based priors incorporating previous COVID-19 tocilizumab RCTs. The probability of tocilizumab's benefit for respiratory support and corticosteroid subgroups and sensitivity analyses were performed with different prior distributions and baseline risks.
Results:
For all-cause mortality, the posterior probabilities of decreased deaths with tocilizumab were >99% and 19% in patients using and not using corticosteroids, respectively. In patients on simple oxygen only, non-invasive ventilation and invasive mechanical ventilation, the probabilities of decreased mortality were 96%, >99% and 77%, respectively. The probabilities for a clinically significant mortality reduction, as assessed by an absolute risk difference > 3% (number needed to treat ≤ 33), were 77%, 96%, 56%, respectively. Sensitivity analyses highlighted the uncertainty and lack of conclusive evidence for tocilizumab's effect in patients on invasive mechanical ventilation and those without concurrent corticosteroids. Posterior probabilities of benefit for hospital discharge outcome were high and consistent across most subgroups.
Conclusions:
In this Bayesian reanalysis, COVID-19 hospitalized patients exposed to corticosteroids or on non-invasive ventilation have a high probability of a clinically meaningful mortality benefit from tocilizumab. Tocilizumab also likely improves discharge from hospital in most subgroups. Future research should further address if patients on invasive mechanical ventilation can also benefit from tocilizumab.
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