Table 4.
Meta analyses of trials of tocilizumab and sarilumab in COVID-19
| Study | Benefit | |||||||
|---|---|---|---|---|---|---|---|---|
| Ref. | Number of studies included | Total number of patients | Number of patients in Anti-IL6R group | Survival benefit | Progression to ICU admission | Progression to invasive mechanical ventilation | Place of corticosteroids | Serious adverse events |
| [153] | 23 | 6279 | 1897 |
Morality: - All types of severity:–0.062 (- 0.118,–0.005) - Severe patients:–0.119 (- 0.177,–0.06) |
- All types of severity: 0.003 (-0.135, 0.141) - Severe patients:0.096 (- 0.009, 0.200) |
- All types of severity:–0.041 (- 0.145, 0.063) - Severe patients:–0.108 (- 0.193,–0.024) |
Not evaluated | Not evaluated |
| [139] | 27 | 10 930 | 6449 |
Day 28: OR: 0.86, 95%CI: 0.79-0.95; P = 0.003 Absolute mortality risk: 22% for IL-6 antagonists and 25% for usual care/placebo - Tocilizumab: 0.83, 95%CI: 0.74-0.92; P < .001) - Sarilumab: 1.08 (95%CI: 0.86-1.36; P = .52) |
Not evaluated | Not evaluated |
Progression to IMV, ECMO or death (whole population): - without CS: 0.96, 95% CI: 0.79-1.17 - with CS: 0.71, 95% CI: 0.63-0.80 Progression to IMV, ECMO or death (Tocilizumab): - without CS: 0.95, 95% CI: 0.76-1.20 - with CS: 0.69, 95% CI: 0.61-0. 78 Progression to IMV, ECMO or death (Sarilumab): - without CS: 0.98, 95% CI: 0.67-1.44 - with CS: 1.08, 95% CI: 0.67-1.75 28-days mortality: - without CS: 1.09, 95% CI: 0.91-1.30 - with CS: 0.78, 95% CI: 0.69-0.88 |
Not evaluated |
| [142] | 10 | 6493 | 3358 |
- Mortality: 24.4% vs. 29.0%; OR 0.87, 95% CI: 0.74–1.01; p = 0.07; I2 = 10%. - Mortality in patients requiring ICU admission at enrollment: 34.7% vs. 39.6%; OR 0.84, 95% CI: 0.65–1.10; p = 0.20; I2 = 24% - Mortality in trials with low risk of bias: 12.3% vs. 10.7%; OR 1.09, 95% CI: 0.75–1.57; p = 0.65; I2 = 0%. - Sensitivity analysis using a fixed effect model: OR 0.85, 95% CI: 0.76–0.96; p = 0.006; I2 = 10%; TSA adjusted CI: 0.70–1.04. |
34.9% vs. 41.5%; OR 0.73, 95% CI: 0.38–1.39; p = 0.34; I2 = 60% - Progression to severe disease: 28.9% vs. 36.6% ; OR 0.72, 95% CI: 0.59–0.89; p = 0.002; I2 = 26% |
8.7% vs. 10.5%; OR 0.70, 95% CI: 0.54–0.89; p = 0.004; I2 = 0% |
Not evaluated | Not evaluated |
| [150]† |
36 RCT: 8, Cohorts: 28 |
6311 | 3267 | - short term mortality: RR: 0.91, 95%CI: 0.72, 1.07, I2 = 25%). | “Poor outcome”: RR: 0.82 (95% CI: 0.76, 0.90, I2 = 3%) | RR: 0.84, 95% CI: 0.76, 0.93, I2 = 0% |
Composite factor (mortality or mechanical ventilation): - Receiving CS: 1.02, 95%CI: 0.79, 1.31 - Not receiving CS: 0.98, 95%CI: 0.89, 1.07 |
- SAE: 0.85, 95% CI: 0.63, 1.16 - Risk of infection: RR: 0.67, 95% CI: 0.45, 0.99 |
| [154] | 9 | 6489 | 3358 |
- Fixed-effect model: OR: 0.87; 95% CI: 0.75, 0.94; I2: 24% - Random-effect model: OR: 0.87; 95% CI: 0.71–1.07 - Mortality for moderate disease: * Global: OR: 1.30; 95% CI: 0.64–2.64; I2: 0% *Fixed-effect model: OR: 0.84; 95% CI: 0.75–0.94; I2: 53% *Random-effect model: OR: 0.89; 95% CI: 0.71–1.18 |
Not evaluated | Not evaluated | Not evaluated | Not evaluated |
| [155] | 8 | 6481 | 3264 |
- Global population: RR: 0.89, 95% CI: 0.82-0.96 - after exclusion of RECOVERY: RR: 0.89, 95% CI: 0.75-1.06 - ICU patients: RR: 0.94, 95%CI 0.74-1.19 (I2=60%) - Early mortality (14-15 days): RR: 2.18, 95% CI: 1.01-4.69, I2=31%). |
RR: 0.68, 95% CI 0.50-0.92, I2=6% | RR: 0.79, 95% CI: 0.68-0.91, I2=0% | Not evaluated |
- AE: RR: 0.97, 95% CI: 0.88-1.07, I2=28% - SAE: RR: 0.87, 95% CI: 0.72-1.06, I2=0% - Superinfection: RR: 0.64, 95% CI: 0.64-0.97, I2=44% - Severe superinfection: RR: 0.57, 95% CI: 0.35-0.93, I2=42% - Neutropenia: RR: 8.70, 95% CI: 2.34-32.39 |
| [156] | 52 (9 RCT, 43 observational) | 27004 among which RCT patients: 6604 | 8048 among which RCT patients: 3358 |
- Considering RCT: RR: 0.89, 95% CI: 0.82–0.96, 95%, PI: 0.80–0.97; I2 = 0.3% - Considering observational studies: RR: 0.69, 95% CI: 0.58–0.83, 95%, PI: 0.28 to 1.73 ; I2 = 84.0% |
- Considering RCT: RR: 0.81, 95% CI: 0.71 to 0.93, 95%, PI: 0.60 to 1.09; I2=0.0% - Considering observational studies: RR: 0.81, 95%, CI: 0.57 to 1.14, 95%, PI: 0.28 to 2.29 ; I2 = 70.2% |
Composite endpoint of ICU admission or IMV: - Considering RCT: RR: 0.80, 95% CI: 0.70 to 0.92, 95%, PI: 0.67 to 0.97; I2=0.0% - Considering observational studies: RR: 1.08, 95% CI: 0.85 to 1.38, 95% PI: 0.67 to 1.73; I2 = 18.4% |
- Considering RCT: RR: 0.99, 95% CI: 0.79, 1.24; I2 = 64.6% - Considering observational studies: RR: 0.67, 95% CI: 0.54, 0.81; I2 = 59.9% |
Not evaluated |
| [140] |
10 (Sarilumab and Tocilizumab) 20 (Tocilizumab) 11 (Sarilumab) 6 (Klazakisumab) 2 (Olokizumab) 1 (Siltuximab) 1(Levilimab) |
6428 | - |
Tocilizumab: - D28: RR: 0.89, 95% CI: 0.82 to 0.97; I2 = 0.0% - D≥60: RR: 0.86, 95% CI: 0.53 to 1.40; I2 = 0.0% Sarilumab: - D28: RR: 0.77, 95% CI: 0.43 to 1.36 - D≥60: RR: 1.00, 95% CI: 0.50 to 2.0 |
Progression Score of level of 7 or above: RR: 0.99, 95% CI: 0.56 to 1.74; I2 = 64.4% Tocilizumab and clinical improvement : RR: 1.06, 95% CI: 1.00 to 1.13; I2 = 40.9% |
- | Not evaluated |
Tocilizumab: - AE: RR: 1.23, 95% CI: 0.87 to 1.72; I2 = 86.4% - SAE: RR: 0.89, 95% CI: 0.75 to 1.06; I2 = 0.0% Sarilumab: - AE: RR: 1.05, 95% CI: 0.88 to 1.25 - SAE: RR: 1.17, 95% CI: 0.77 to 1.77 |
| [114] | 45 comparatives studies and 28 single-arm studies | 13189 and 1770 |
3992 and “not appropriate" |
Risk of mortality: RR: 0.76, 95%CI: 0.65 to 0.89, P < 0.01 |
Clinical improvement (comparative studies): RR: 1.19 (95% CI: 1.00 to 1.42; P = 0.05, I2 = 81.2%) ICU admission (comparative studies): RR: 0.98 (95% CI: 0.36 to 2.66; P = 0.99; I2 = 89.4%) |
RR:0.48, 95% CI: 0.24 to 0.97, p = 0.04 | Not evaluated | Secondary infections (comparative studies): RR: 1.24 (95% CI: 0.98 to 1.56; P = 0.07; I2 = 66.5%) |
| [163] | 13 | 2120 | 674 | OR: 0.42, 95% CI: 0.26 to 0.69, P = 0.0005, I2 = 55% | Not evaluated |
OR = 0.95, 95% CI: 0.53 to 1.72, P= 0.88, I2 = 61% |
Not evaluated | Not evaluated |
| [143] | 38: 3 double-blinded RCT, 4 open-label RCT, 23 prospective cohorts, 5 case-control studies | 13 412 | 4090 |
Whole population: OR: 0.54, 95 % CI: 0.42– 0.71, p < 0.00001, I2 = 79 % Subgroup analysis excluding observational studies: OR: 0.90, 95 % CI: 0.64–1.26, p = 0.54, I2 = 0 % |
Alteration of severity: OR: 1.05, 95 % CI: 0.92–1.20, p = 0.47, I2 = 84 % | Not evaluated |
- SAE: OR: 0.91, 95 % CI: 0.71–1.15, p = 0.42, I2 = 46 % |
|
| [144] | 6 | 2057 | 1177 | HR: 0.83; 95% CI 0.66–1.05 | Not evaluated |
Composite endpoint of requirement of mechanical ventilation and all-cause mortality: OR: 0.62; 95% CI: 0.42-0.91 |
Not evaluated | Not evaluated |
| [146] |
71 (including 6 RCT): - Tocilizumab: 58 - Anakinra: 6 - Tocilizumab and Anakinra: 1 - Sarilumab and Tocilizumab: 1 - Sarilumab: 4 - Siltuximab: 1 |
22058 |
7328 (therapy under review) 6563 (Tocilizumab) |
Tocilizumab: - Global: RR: 0.83, 95% CI: 0.72 to 0.96, I2=0.0% -Prospective studies: HR: 0.70, 95% CI: 0.44 to 1.10, I2=0% -Retrospective studies: HR: 0.52, 95% CI: 0.41 to 0.66, I2=76.6% -RCT alone: RR: 0.85, 95% CI: 0.71 to 1.01 I2=0.0%) Sarilumab: aOR: 2.01, 95% CI: 1.18 to 4.71 |
Outcomes on the Ordinal scale: * Tocilizumab: - Prospective studies: GenOR: 1.09, 95% CI: 0.99 to 1.19, I2=84.3% - Retrospective studies: GenOR: 1.34, 95% CI: 1.10 to 1.64, I2=98%. * Sarilumab: GenOR: 1.07, 95% CI: 0.90 to 1.27 |
Not evaluated | “similar” | |
| [145] | 6 | 1038 | - |
RR: 1.03; 95% CI: 0.72 to 1.46; p = 0.89, I2 = 0.0% |
- Random-effect: RR: 0.71; 95% CI: 0.37 to 1.38; p = 0.32, I2 = 36% |
- Random-effect: RR: 0.70; 95% CI: 0.51 to 0.96; p = 0.02, I2 =0% |
Not evaluated |
SAE: - Random-effect: RR: 0.63; 95% CI: 0.35 to 1.14; p = 0.12, I2 = 57.9% - Fixed-effect: RR: 0.68; 95% CI: 0.57 to 0.81; p = 0.00, I2 = 77.4% |
| [152] | 9 | 6778 | 3647 |
- Meta analysis: * Studies mortality rate: 0.19; 95% CI: 0.18 – 0.2, I2: 98.8% |
Not evaluated | Not evaluated | Not evaluated | Not evaluated |
| [157] | 26: 23 retrospectives, 1 prospective, 2 randomized controlled | 8272 | 2112 | RR: 1.65, 95% CI: 1.37 – 2.00, I2: 70% | Not evaluated | Not evaluated | Not evaluated | Not evaluated |
| [147] | 8 | 6314 | 3267 | D28: OR, 0.92; 95% CI, 0.66–1.28; I2 = 62% | D28: OR: 0.51; 95% CI: 0.28–0.92; I2 = 30% | Incidence of mechanical ventilation à D28: OR: 0.75; 95% CI: 0.62–0.90; I2 = 11% | Steroids at admission: OR: 0.89; 95% CI: 0.56–1.43; I2 = 81% |
- AE: OR: 1.03; 95% CI: 0.71–1.49; I2 = 43% - SAE: OR: 0.86; 95% CI: 0.67–1.12; I2 = 0% - Infection: OR: 0.87; 95% CI: 0.63–1.20; I2 = 0 |
| [148] | 29 | 11 487 | 2651 | RR: 0.74; 95% CI: 0.59–0.93; P = 0.008; I2 = 80% | RR: 1.40, 95% CI : 0.64–3.06 ; P = 0.4; I2 = 88% |
RR: 0.83 95% CI: 0.57–1.22; P = 0.34; I2 = 65% |
Secondary infection: RR: 1.30, 95% CI: 0.97–1.74; P = 0.08; I2 = 65% | |
| [158] | 25 | 10 201 | 4056 | OR: 0.70, 95% CI: 0.54–0.90, P = 0.007; I2: 74% | Not evaluated |
OR: 0.59, 95% CI: 0.37–0.93, P = 0.02; I2: 56% |
Not evaluated | Not evaluated |
| [151] | 9 | 6490 | 3358 |
RR: 0.89, 95% CI: 0.80–0.98, p = 0.02; I2: 6% |
Not evaluated | RR: 0.80, 95% CI: 0.71–0.89, p < 0.0001; I2: 0% | RR: 0.87, 95% CI 0.80–0.95, p = 0.0009; I2: 0% | Not evaluated |
| [141] |
18 - Tocilizumab: 16 - Sarilumab: 1 - Siltuximab: 1 RCT: 1, Cohort: 14, case control : 3 |
3303 | - | Tocilizumab or Sarilumab: RR: 0.61, 95% CI: 0.49–0.76; I2: 58% | Not evaluated | RR: 0.68, 95% CI: 0.32–1.45; I2: 75% | Not evaluated | Not evaluated |
| [159] | 17‡ | 14 054 | Not evaluated | “Treatment failure”: RR: 0.62, 95% CI: 0.42 – 0.91; I2: 60% |
Mortality in SOC vs Tocilizumab and corticosteroid therapy: RR: 0.62, 95% CI: 0.42 – 0.91; I2: 60% |
RR: 1.11, 95% CI: 0.81 – 1.53, I2 was 0%, ( p = 0.84) |
||
| [164] | 39 | 15 531 | 3657 |
OR 0.74, 95% CI: 0.55–1.01, p = 0.057, I2: 79.5% Studies with adjusted, estimated, Tocilizumab: HR: 0.50, 95% CI: 0.38–0.64, p < 0.001 |
OR: 3.79, 95% CI: 0.38–37.34, p = 0.254 Studies with adjusted, estimated, Tocilizumab: OR: 0.16, 95% CI: 0.06–0.43, p < 0.001 |
OR: 2.21 95% CI: 0.53–9.23, p = 0.277, I2: 86.57% | OR: 0.49, 95% CI: 0.36–0.65, p < 0.05 |
OR: 2.36, 95% CI: 1.01–5.54, p = 0.050, I2: 87.96% |
| [165] | 64: controlled observational studies: 54, RCT: 10 | 20 616 | 7668 |
- Broad mortality: OR: 0.73, 95% CI: 0.56–0.93, I2 = 82%, (p < 0.001) - Patients receiving CS: OR: 0.67, 95% CI: 0.54–0.84 - In wards: OR: 1.25, 95% CI: 0.74–2.18, I2: 82.9% - In ICU: OR: 0.66, 95% CI: 0.59–0.76, I2: 0.00% - Tocilizumab before D10: OR: 0.71, 95% CI: 0.35–1.42 - Tocilizumab after D10: OR: 0.83, 95% CI: 0.48–1.45 |
Not evaluated | Not evaluated | Not evaluated | Secondary infection: OR: 1.04, 95% CI: 0.72–1.52, I2: 87.8% |
| [149] | 6 | 5426 | 2849 | RR: 0.90, 95% CI: 0.76 to 1.07, I2=0% | Not evaluated | Not evaluated separately | Not evaluated | SAE : RR: 0.82, 95% CI: 0.62 to 1.10, I2=0 |
| [160]# |
All experimental treatments: 222 Tocilizumab: 12 |
All experimental treatments: 102 950 Tocilizumab: 13606 |
- |
- Fixed-effect model: OR: 0.85, 95% CrI: 0.77–0.95 - Random-effect model: OR of 0.91, 95% CrI: 0.74 -1.16 |
Not evaluated |
OR: 0.75, 95% CrI: 0.65–0.86 |
Not evaluated | Not evaluated |
| [161]* | 15 (including 7 unpublished) | 5339 | 1661 |
- Oxygen only: median OR: 0.70 (95% CrI, 0.50-0.91). PPBA: 98.9%. PPMCA: 95.5% - NIV: median OR: 0.81 (95%CrI, 0.63-1.03). PPBA: 95.5% PPMCA: 82.2% - IMV: median OR: 0.89 (95%CrI, 0.61-1.22) PPBA: 75.4% PPMCA: 52.9% |
Not evaluated | Not evaluated | All included patients have received corticosteroids | Not evaluated |
| [162] | 9 | 6490 | 3358 |
OR: 0.87; 95% CI: 0.73-1.04; I2: 15% Non severe disease: OR: 0.1.3; 95% CI: 0.77-2.20; I2: 0% Severe disease: OR: 0.84; 95% CI: 0.63-1.12; I2: 57% |
OR: 0.66; 95% CI : 0.40-1.08; I2: 29% | OR : 0.74; 95% CI: 0.64-0.86; I2: 0% |
Initial use of steroids in more than 50% of participants: OR: 0.87; 95% CI: 0.66-1.13; I2: 46% Initial use of steroids in more than 50% of participants: OR: 1.07 ; 95% CI : 0.0.70-1.64; I2: 0% |
- One AE: OR: 1.38; 95% CI: 0.87-2.19; I2: 70% - Serious AE: OR: 0.90; 95% CI: 0.70-1.14; I2: 0% - Infection: OR: 0.89; 95% CI: 0.65-1.23; I2: 0% - Serious infection: OR: 0.57; 95% CI: 0.36-0.89 ; I2: 21% |
AE Adverse event, CS corticosteroids, ECMO extra-corporeal membrane oxygenation, IL-6R Receptor of interleukin-6, IMV invasive mechanical ventilation, NIV Noninvasive ventilation, NS not significant, PI prediction interval, PPBA Posterior probability of benefit association, PPMCA Posterior probability of meaningful clinical association, RCT Randomized and controlled trial, AE adverse events, SAE Severe adverse events, SOC standard of care
†Presented results include only the analysis of RCT.
‡ Corticosteroids: Methylprednisolone
# Bayesian meta-analysis
* Bayesian reanalysis of previous meta-analysis (33)
Positive results are indicated in bold