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Anakinra or tocilizumab for prevention of COVID-19 death? A big dilemma

      Keywords

      We have read with great interest the meta-analysis of observational studies performed by Pasin and colleagues [
      • Pasin L
      • Cavalli G
      • Navalesi P
      • Sella N
      • Landoni G
      • Yavorovskiy AG
      • Likhvantsev VV
      • Zangrillo A
      • Dagna L
      • Monti G.
      Anakinra for patients with COVID-19: a meta-analysis of non-randomized cohort studies.
      ] published in the European Journal of Internal Medicine, assessing the efficacy of anakinra, a recombinant interleukin-1 (IL-1) receptor antagonist, in patients with COVID-19 infection. The authors pooled data from 4 studies in a total of 184 patients, demonstrating that anakinra is superior to standard of care in terms of preventing COVID-19 related death, by reducing the corresponding risk by 74% [
      • Pasin L
      • Cavalli G
      • Navalesi P
      • Sella N
      • Landoni G
      • Yavorovskiy AG
      • Likhvantsev VV
      • Zangrillo A
      • Dagna L
      • Monti G.
      Anakinra for patients with COVID-19: a meta-analysis of non-randomized cohort studies.
      ]. Another immunomodulatory agent, namely tocilizumab, an interleukin-6 (IL-6) inhibitor, has also been shown to decrease the risk for COVID-19 death among eligible patients [
      • Khan FA
      • Stewart I
      • Fabbri L
      • Moss S
      • Robinson K
      • Smyth AR
      • Jenkins G.
      Systematic review and meta-analysis of anakinra, sarilumab, siltuximab and tocilizumab for COVID-19.
      ]. In the absence of an effective treatment option against COVID-19, the steadily increased mortality among infected subjects and the delay in the widespread vaccination of the general population, it seems that immunomodulatory agents might be crucial for the management of the disease. However, it remains unclear which one should be preferred, although they could be administered sequentially in refractory cases [
      • de la Calle C
      • López-Medrano F
      • Pablos JL
      • Lora-Tamayo J
      • Maestro-de la Calle G
      • Sánchez-Fernández M
      • et al.
      Effectiveness of anakinra for tocilizumab-refractory severe COVID-19: a single-centre retrospective comparative study.
      ,
      • Aomar-Millán IF
      • Salvatierra J
      • Ú Torres-Parejo
      • Faro-Miguez N
      • Callejas-Rubio JL
      • Á Ceballos-Torres
      • Cruces-Moreno MT
      • Gómez-Jiménez FJ
      • Hernández-Quero J
      • Anguita-Santos F
      Anakinra after treatment with corticosteroids alone or with tocilizumab in patients with severe COVID-19 pneumonia and moderate hyperinflammation. A retrospective cohort study.
      ].
      Therefore, we sought to determine whether anakinra is superior to tocilizumab in terms of COVID-19 related death prevention. We searched PubMed database for relevant published studies up to 21st March 2021. We set as primary efficacy outcome the surrogate endpoint of COVID-19 death. After implementing the search terms “anakinra”, “tocilizumab”. “COVID-19” and “SARS-CoV-2” combined with the use of Boolean operators AND or OR, we retrieved 81 relevant results. After comprehensive screening at title and abstract level, 3 observational studies were eligible for inclusion in our quantitative synthesis [
      • Cavalli G
      • Larcher A
      • Tomelleri A
      • Campochiaro C
      • Della-Torre E
      • De Luca G
      • Farina N
      • Boffini N
      • Ruggeri A
      • Poli A
      • Scarpellini P
      • Rovere-Querini P
      • Tresoldi M
      • Salonia A
      • Montorsi F
      • Landoni G
      • Castagna A
      • Ciceri F
      • Zangrillo A
      • Dagna L.
      Interleukin-1 and interleukin-6 inhibition compared with standard management in patients with COVID-19 and hyperinflammation: a cohort study.
      ,
      • Iglesias-Julián E
      • López-Veloso M
      • de-la-Torre-Ferrera N
      • Barraza-Vengoechea JC
      • Delgado-López PD
      • Colazo-Burlato M
      • Ubeira-Iglesias M
      • Montero-Baladía M
      • Lorenzo-Martín A
      • Minguito-de-la-Iglesia J
      • García-Muñoz JP
      • Sanllorente-Sebastián R
      • Vicente-González B
      • Alemán-Alemán A
      • Buzón-Martín L.
      High dose subcutaneous Anakinra to treat acute respiratory distress syndrome secondary to cytokine storm syndrome among severely ill COVID-19 patients.
      ,
      • Langer-Gould A
      • Smith JB
      • Gonzales EG
      • Castillo RD
      • Figueroa JG
      • Ramanathan A
      • Li BH
      • Gould MK.
      Early identification of COVID-19 cytokine storm and treatment with anakinra or tocilizumab.
      ]. We extracted the data from the eligible reports, by using a pilot tested, data extraction form.
      As we assessed only a dichotomous variable, difference was calculated with the use of risk ratio (RR), with 95% confidence interval (CI), after implementation of the Mantel-Haenszel (M-H) random effects formula. Statistical heterogeneity among studies was assessed by using I2 statistics. All analyses were performed at the 0.05 significance level, while they were undertaken with RevMan 5.3 software.
      We pooled data from the 3 aforementioned observational studies [
      • Cavalli G
      • Larcher A
      • Tomelleri A
      • Campochiaro C
      • Della-Torre E
      • De Luca G
      • Farina N
      • Boffini N
      • Ruggeri A
      • Poli A
      • Scarpellini P
      • Rovere-Querini P
      • Tresoldi M
      • Salonia A
      • Montorsi F
      • Landoni G
      • Castagna A
      • Ciceri F
      • Zangrillo A
      • Dagna L.
      Interleukin-1 and interleukin-6 inhibition compared with standard management in patients with COVID-19 and hyperinflammation: a cohort study.
      ,
      • Iglesias-Julián E
      • López-Veloso M
      • de-la-Torre-Ferrera N
      • Barraza-Vengoechea JC
      • Delgado-López PD
      • Colazo-Burlato M
      • Ubeira-Iglesias M
      • Montero-Baladía M
      • Lorenzo-Martín A
      • Minguito-de-la-Iglesia J
      • García-Muñoz JP
      • Sanllorente-Sebastián R
      • Vicente-González B
      • Alemán-Alemán A
      • Buzón-Martín L.
      High dose subcutaneous Anakinra to treat acute respiratory distress syndrome secondary to cytokine storm syndrome among severely ill COVID-19 patients.
      ,
      • Langer-Gould A
      • Smith JB
      • Gonzales EG
      • Castillo RD
      • Figueroa JG
      • Ramanathan A
      • Li BH
      • Gould MK.
      Early identification of COVID-19 cytokine storm and treatment with anakinra or tocilizumab.
      ] in at total of 237 subjects with documented COVID-19 infection. As shown in Fig. 1, anakinra is superior to tocilizumab in terms of COVID-19 death prevention, by decreasing the corresponding risk by 40% (RR = 0.60, 95% CI; 0.36 – 0.98, I2 = 0%). No heterogeneity was documented for this comparison.
      Fig. 1
      Fig. 1Effect of anakinra compared to tocilizumab on the risk for COVID-19 death.
      This brief analysis of non-randomized cohort studies is the first to investigate the effect of anakinra versus tocilizumab on the risk for COVID-19 death, showing a clear benefit of IL-1 versus IL-6 inhibition. Future studies, ideally randomized, will provide further insights into these interesting findings and establish the role of immunomodulatory agents as treatment options in COVID-19 patients.

      Funding

      None.

      Declaration of Competing Interest

      None declared.

      Acknowledgments

      None.

      References

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        Anakinra for patients with COVID-19: a meta-analysis of non-randomized cohort studies.
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        Systematic review and meta-analysis of anakinra, sarilumab, siltuximab and tocilizumab for COVID-19.
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        Effectiveness of anakinra for tocilizumab-refractory severe COVID-19: a single-centre retrospective comparative study.
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