Effect of Tocilizumab in Reducing the Mortality Rate in COVID-19 Patients: A Systematic Review with Meta-Analysis
Abstract
:1. Introduction
2. Materials and Methods
2.1. Search Strategy
2.2. Study Selection, Data Extraction and Quality Assessment
2.3. Statistical Analysis
3. Results
3.1. Search Results
3.2. Study Characteristics
3.3. Quality Assessment
3.4. Meta-Analysis of the TCZ Therapy on Mortality
3.5. Sensitivity and Subgroup Analyses in RCTs
3.6. Sensitivity and Subgroup Analyses in the Observational Studies
3.7. Meta-Regression Analyses
4. Discussion
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Condition | Definition |
---|---|
Population | COVID-19 patients admitted in hospital |
Intervention | Patients treated with Tocilizumab plus Standard Therapy |
Comparator | Patients treated with Standard Therapy alone |
Outcome | Mortality |
Source | Country | Primary Outcome | Total Pts (n) | Mean Age | Sex, (Male %) | Oxygen Support | TCZ Administer Route and Dosage | Time from Symptoms Onset to TCZ Start (days) | Time from Hospital Admission to TCZ Start (days) | Death (%) (p Value) |
---|---|---|---|---|---|---|---|---|---|---|
Albertini [26] | Europe | Efficacy of TCZ on respiratory clinical conditions | 44 TCZ: 22 ST: 22 | 65 | 70.45 | No-IMV/IMV | 8 mg/kg | 10 | NA | TCZ: 13.6 ST: 9 (p = NA) |
Ayerbe [27] | Europe | Mortality with Heparin therapy | 2019 TCZ: 421 ST: 1598 | 67.57 | 61.268 | No-IMV/IMV | NA | NA | NA | TCZ: 21.14 ST: 12.33 (p = NA) |
Balena [28] | Europe | Crude mortality and AdE | 164 TCZ:16 ST:148 | 77.5 | 48 | No-IMV/IMV | 8 mg/kg i.v. | NA | NA | TCZ: 31 ST:23 (p = 0.074) |
Biran [29] | America | Mortality in patients requiring ICU | 630 TCZ:210 ST:420 | 65 | 58.413 | No-IMV/IMV | 8 mg/kg i.v. | 7 | NA | TCZ: 49 ST: 61 (p = 0.0040) |
Campochiaro [30] | Europe | Clinical improvement and overall survival | 59 TCZ:32 ST:27 | 62 | 86.154 | No- IMV | 400 mg i.v., repeated after 24 h (n = 9) | 11 | NA | TCZ: 16 ST: 33 (p = 0.15) |
Canziani [31] | Europe | Mortality | 128 TCZ:64 ST:64 | 63.5 | 73 | No-IMV/IMV | 8 mg/kg i.v., repeated after 24 h (n = 61) | 13 | NA | TCZ: 27 ST: 38 (p = 0.185) |
Capra [32] | Europe | Mortality | 85 TCZ:62 ST:23 | 66.5 | 75 | No- IMV | 400 mg i.v. 324 mg s.c. | NA | 4 | TCZ: 3.22 ST: 47.8 (p = 0.004) |
Colaneri [33] | Europe | ICU admission and 7-day mortality rate | 112 TCZ:21 ST:91 | 63.03 | 73.215 | No- IMV | 8 mg/kg i.v. and repeated after 12 h | NA | NA | TCZ: 24 ST: 21 (p = 0.84) |
De Rossi [34] | Europe | Survival rate | 158 TCZ:90 ST:68 | 66.95 | 71.52 | No- IMV/IMV | 400 mg i.v. or 324 mg s.c. | NA | 9 | TCZ: 7.7 ST: 50 (p < 0.001) |
Eimer [35] | Europe | 30-day death after admission to ICU | 87 TCZ:29 ST:58 | 56.5 | 84 | IMV | 8 mg/kg i.v. | 11 | NA | TCZ: 17.2 ST: 32.8 (p = 0.20) |
Galvan-Romàn [36] | Europe | Need for IMV, mortality | 146 TCZ: 58 ST: 88 | 63 | 66 | No-IMV/IMV | 8 mg/kg (max 800 mg), repeated after 12 h | NA | NA | TCZ: 24 ST: 18 (p = NA) |
Garcia [37] | Europe | ICU admission and/or death | 171 TCZ: 77 ST: 94 | 61 | 65.498 | No- IMV | 400 mg/24 h iv (Pts ≤ 75 kg) 600 mg/24 h iv (Pts > 75 kg) with the possibility to repeat the dose every 12 h up to 3 doses. | NA | 6.5 | TCZ: 10.3 ST: 18 (p = 0.156) |
Gokhale [38] | Asia | Overall survival | 161 TCZ: 70 ST: 91 | 53.5 | 62.11 | No-IMV/IMV | 400 mg/die i.v. and repeated after 24 h (n = 9) | NA | 12 | TCZ: 47 ST: 67 (p = 0.011) |
Guaraldi [39] | Europe | IMV requirement and/or death | 544 TCZ: 179 ST: 365 | 67 | 66 | No- IMV | 8 mg/kg i.v., repeated after 12 h, or 324 mg s.c. | NA | 7 | TCZ: 7 ST: 20 (p < 0.001) |
Hill [40] | America | Clinical improvement | 88 TCZ: 43 ST: 45 | NA | 69 | No-IMV/IMV | 400 mg i.v. | NA | 2 | TCZ: 21 ST: 33 (p = 0.26) |
Holt [41] | America | Survival time and mortality | 62 TCZ: 32 ST: 30 | 68.5 | 70.97 | No-IMV/IMV | 400 mg i.v. | NA | 2 | TCZ: 31.25 ST: 30 (p = 0.36) |
Kewan [42] | North America | Median LOS, ICU LOS, duration of IMV, mortality. | 51 TCZ: 28 ST: 23 | 66 | 61 | No-IMV/IMV | 400 mg i.v. | NA | 2 | TCZ: 11 ST: 9 (p > 0.99) |
Kimmig [43] | North America | Infection and clinical outcomes (discharged, died) | 60 TCZ:28 ST: 32 | 63.15 | 55.856 | No-IMV/IMV | 400 mg i.v. with possible redosing | NA | NA | TCZ: 35.2 ST: 19.3 (p = 0.020) |
Klopfenstein [44] | Europe | IMV requirement and/or death | 206 TCZ: 30 ST;176 | 73.75 | 60.7 | No- IMV | 8 mg/kg i.v. (1 or 2 doses) | 12 | NA | TCZ: 26.7 ST: 37.5 (p = 0.253) |
Klopfenstein [45] | Europe | ICU admission and/or death | 44 TCZ: 19 ST: 25 | 74.95 | NA | No- IMV | NA | 13 | NA | TCZ: 25 ST: 48 (p = 0.066) |
Martinez-Sanz [46] | Europe | Time to death | 1229 TCZ: 260 ST: 969 | 65.5 | 72.246 | No-IMV/IMV | NA | NA | 4 | TCZ: 23 ST: 12 (p < 0.001) |
Matthew [47] | America | Overall mortality 30 days from the date of intubation | 115 TCZ: 45 ST: 70 | 58.4 | 69.566 | IMV | 400 mg i.v. | NA | 2.5 | TCZ: 29 ST: 40 (p = 0.23) |
Menzella [48] | Europe | In-hospital mortality rate | 79 TCZ: 41 ST: 38 | 66.5 | 70.89 | No-IMV/IMV | 8 mg/kg i.v (max 800 mg) or 162 mg s.c | NA | NA | TCZ: 24 ST: 53 (p = 0.01) |
Mikulska [49] | Europe | Failure-free survival and overall survival | 95 TCZ: 29 ST: 66 | 69 | 67.35 | No- IMV | 8 mg/kg i.v. 162 mg s.c. | NA | 7 | TCZ: 14.2 ST: 28.1 (p = NA) |
Moreno-Pérez [50] | Europe | Death, LOS | 236 TCZ: 77 ST: 159 | 59.5 | 59.746 | No-IMV/IMV | 600 mg i.v., with second or third dose (400 mg i.v.) | 10 | NA | TCZ: 12.9 ST: 1.9 (p = 0.002) |
Pan-Li [51] | Asia | Improvement and death | 58 TCZ: 39 ST: 19 | 73.9 | 63.8 | No- IMV/IMV | 4–8 mg/kg (max dose of 800 mg) | NA | NA | TCZ: 30.8 ST: 47.3 (p = NA) |
Patel [52] | America | Clinical outcomes and survival | 83 TCZ: 42 ST: 41 | 67.5 | 50.603 | No-IMV/IMV | NA | NA | 4 | TCZ: 21.4 ST: 26.8 in severe Pts TCZ: 14.2 ST: 28.6 (p = NA) |
Potere [53] | Europe | Overall survival and survival-free of IMV | 80 TCZ: 40 ST: 40 | 55.25 | 65 | No- IMV | 324 mg s.c. (bid) | NA | 5 | TCZ: 5 ST: 27.5 (p = 0.006) |
Quartuccio [54] | Europe | Optimal patient selection to be treated with TCZ | 111 TCZ: 42 ST: 69 | 58.3 | 69.4 | No-IMV/IMV | 8 mg/kg i.v. | 8.4 | NA | TCZ: 9.5 ST: 0 (p = NA) |
Ramaswamy [55] | North America | Mortality | 86 TCZ: 21 ST: 65 | 63.7 | 57 | No- IMV | 400 mg i.v. 8 mg/kg i.v. | NA | NA | TCZ: 14 ST: 12 (p = 0.81) |
Rodríguez-Bano [56] | Europe | Intubation or death | 432 TCZ: 88 ST: 343 | 67.5 | 77.702 | No- IMV | 400–600 mg i.v. with second or third dose | 10 | NA | TCZ: 2.3 ST: 11.9 (p = 0.004) |
Rojas-Marte [57] | North America | Mortality | 193 TCZ = 96 ST = 97 | 60.4 | 71 | No-IMV/IMV | NA | NA | NA | TCZ: 52 ST: 62 (p = 0.09) excluding intubated TCZ: 6 ST: 27 (p = 0.024) |
Roomi [58] | America | Clinical effectiveness of HCQ and TCZ | 170 TCZ: 134 ST: 36 | 61.8 | 48.83 | No- IMV | NA | NA | NA | TCZ: 4.5 ST: 36 (p = 0.44) |
Rossotti [59] | Europe | Overall survival and hospital discharge | 222 TCZ: 74 ST: 148 | 59 | 81.532 | No-IMV/IMV | 8 mg/kg i.v. (max dose of 800 mg) with possible second dose | NA | NA | TCZ: 25.7 ST: 60.1 (p = 0.035) |
Roumier [60] | Europe | IMV requirement and death | 59 TCZ: 30 ST: 29 | 65 | 80 | No- IMV | 8 mg/kg i.v. (renewable once) | 14 | NA | TCZ: 17.2 ST: 18.7 (p = 0.837) unadjusted TCZ: 10 ST: 31 (p = 0.41) |
Ruiz-Antora’n [61] | Europe | Mortality | 506 TCZ: 268 ST: 238 | 68 | 64.03 | No- IMV | 600 mg (3 doses n = 22, 2 doses n = 92, 1 dose n = 154) | 11 | NA | TCZ: 16,8 ST: 31,5 (28days/ death) (p = 0.001) |
Somers [62] | North America | Survival probability after intubation | 154 TCZ = 78 ST = 76 | 58 | 66 | IMV | 8 mg/kg i.v. (max 800 mg) | NA | 3.9 | 18% in TCZ 36% in ST (28days/ death) (p = 0.01) |
Tsai [63] | America | Mortality | 274 TCZ: 84 ST: 190 | 63 | 61.4 | No- IMV | 400 mg i.v. (n = 53) 600 mg i.v. (n = 3) 800 mg i.v (n = 10) (second dose n = 4) | NA | NA | TCZ: 21.4 ST: 9.4 (p = NA) |
Van den Eynde [64] | Europe | Mortality | 139 TCZ = 21 ST = 118 | 73.2 | 66.91 | No- IMV | 400 mg or 600 mg (once or twice daily) | NA | NA | TCZ: 33,3 ST: 58,4 (p < 0.001) |
Wadud [65] | North America | LOS, days on ventilator, in-hospital and ICU, mortality. | 94 TCZ: 44 ST: 50 | 55.5 | NA | IMV | NA | NA | NA | 3TCZ: 8.64 ST: 52 (p < 0.001) |
Source | Country | Primary Outcome | Total Pts (n) | Mean Age | Sex, (Male %) | Oxygen Support | TCZ Administration Route and Dosage | Time from Symptoms Onset to TCZ Initiation (days) | Time from Hospital Admission to TCZ Initiation (days) | Death (%) (p Value) |
---|---|---|---|---|---|---|---|---|---|---|
BACC Stone [66] | America | Intubation or death | 242 TCZ:161 ST:81 | 59.8 | 58.05 | No-IMV | 8 mg/kg i.v. | NA | 9 | TCZ: 5.6 ST: 4.9 (p = 0.81) |
CORIMUNO-19 Hermine [67] | Europe | Death or respiratory support or IMV. | 130 TCZ:63 ST:66 | 63.5 | NA | No-IMV | 8 mg/kg i.v. | NA | 10 | TCZ: 11.1 ST: 9 (day 14) (p = NA) |
COVACTA Rosas [68] | America, Europe | Clinical Status | 438 TCZ: 294 ST: 144 | 60.75 | 69.863 | No-IMV/IMV | 8 mg/kg i.v. | 12 | NA | TCZ: 19.7 ST: 19.4 (p = 0.941) |
EMPACTA Salama [69] | America, Africa | IMV or death by day 28 | 377 TCZ:249 ST:128 | 55.9 | NA | No-IMV | 8 mg/kg i.v. | NA | 8 | TCZ: 10.4 ST: 8.6 (day 28) (p = NA) |
RCT-TCZ-COVID-19 Salvarani [70] | Europe | Clinical worsening within 14 days since randomization | 123 TCZ:60 ST:63 | 60 | 61.1 | No-IMV | 8 mg/kg i.v., repeated after 12h | NA | 7 | TCZ 1.7 ST 1,6 (day 14) (p = NA) |
RECOVERY Recovery Group [71] | Europe | All-cause mortality within 28 days after randomization | 4116 TCZ:2022 ST:2094 | 63.6 | 67.4 | No-IMV/ IMV | 400 mg i.v. 600 mg i.v. 800 mg i.v | 9 | NA | TCZ: 29 ST: 33 (p= 0.007) |
TOCIBRAS Veiga [72] | America | Clinical status at 15 days | 129 TCZ:65 ST:64 | 57.4 | NA | No-IMV/ IMV | 8 mg/kg i.v. | 10 | NA | TCZ: 17 ST: 3 (p = NA) |
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Conti, V.; Corbi, G.; Sellitto, C.; Sabbatino, F.; Maci, C.; Bertini, N.; De Bellis, E.; Iuliano, A.; Davinelli, S.; Pagliano, P.; et al. Effect of Tocilizumab in Reducing the Mortality Rate in COVID-19 Patients: A Systematic Review with Meta-Analysis. J. Pers. Med. 2021, 11, 628. https://doi.org/10.3390/jpm11070628
Conti V, Corbi G, Sellitto C, Sabbatino F, Maci C, Bertini N, De Bellis E, Iuliano A, Davinelli S, Pagliano P, et al. Effect of Tocilizumab in Reducing the Mortality Rate in COVID-19 Patients: A Systematic Review with Meta-Analysis. Journal of Personalized Medicine. 2021; 11(7):628. https://doi.org/10.3390/jpm11070628
Chicago/Turabian StyleConti, Valeria, Graziamaria Corbi, Carmine Sellitto, Francesco Sabbatino, Chiara Maci, Nicola Bertini, Emanuela De Bellis, Antonio Iuliano, Sergio Davinelli, Pasquale Pagliano, and et al. 2021. "Effect of Tocilizumab in Reducing the Mortality Rate in COVID-19 Patients: A Systematic Review with Meta-Analysis" Journal of Personalized Medicine 11, no. 7: 628. https://doi.org/10.3390/jpm11070628