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Bektaş et al. (2023), in a retrospective observational study, investigated the effect of high-dose intravenous anakinra on the clinical outcomes in patients with severe and critically ill coronavirus disease 2019 (COVID-19), compared to the standard of care. Expectedly, after propensity score matching of two groups of participants, the use of high-dose intravenous anakinra was associated with reduced admission into the intensive care unit (14.1% versus 30.8%) and reduced mortality (14.1% versus 32.1%), compared to standard of care. Furthermore, the reduced mortality with high-dose intravenous anakinra compared with standard of care was also apparent after adjustment of covariates in the multivariate analysis.
The findings of clinical benefits concur with those reported in the randomized controlled trial (Kyriazopoulou et al. 2021) of intravenous anakinra in patients with COVID-19. To illustrate, in the SAVE-MORE, double-blind, randomized controlled trial, intravenous anakinra treatment guided by soluble urokinase plasminogen receptor plasma levels resulted in more than 50% of the relative decrease in the 28-day mortality (hazard ratio = 0.45; 95% confidence interval 0.21–0.98; P = 0.045), compared to placebo (Nguyen et al. 2023).
In addition to the mortality benefits, we are particularly interested in the findings that high-dose intravenous anakinra was associated with reduced occurrence of pulmonary embolism (4.1% versus 9.0%), compared to standard of care (Bektaş et al. 2023). Although the difference did not achieve statistical significance, probably due to the low number of participants, we believe it is of clinical importance to explore further the potential for high-dose intravenous anakinra to reduce the risk of venous thromboembolism in patients hospitalized with COVID-19.
The ability of anakinra to reduce the occurrence of venous thromboembolism is not without its pharmacological plausibility. Growing understanding of the pathophysiology of COVID-19-related thrombosis has led to our findings that NETosis act as a scaffold for thrombus formation in patients with COVID-19 (Kow et al. 2020). As a recombinant interleukin-1-beta (IL-1β) receptor antagonist, anakinra prevents the binding of the proinflammatory cytokines IL-1β to the IL-1-receptor type 1, thus inhibiting the downstream IL-1β signaling. Previously, it has been shown in vitro that IL-1β–induced ceramide synthesis could trigger neutrophil extracellular trap formation (NETosis). Interestingly, IL-1β–induced NETosis can be attenuated in vitro by anakinra which interferes with IL-1β signaling (Meher et al. 2018).
Therefore, we believe the findings where high-dose intravenous anakinra resulted in reduced occurrence of pulmonary embolism, as reported by Bektaş et al. (2023), may not be entirely a coincidence. Although the reduced risk of venous thromboembolism was not apparent in the SAVE-MORE trial (Kyriazopoulou et al. 2021), the dose of anakinra treatment in the trial (100 mg daily) may be too low to elicit its clinical benefits on reduced venous thromboembolism. Indeed, the dose of anakinra administered in the retrospective observational study by Bektaş et al. (2023) was 400 mg daily with gradual up-titration to a maximum dose of 1,600 mg daily (10 mg/kg/day), if necessary. Future clinical trials investigating anakinra in patients with COVID-19 should administer a high-dose regimen to determine their efficacy on risk reduction of venous thromboembolism. Anakinra may be a safer alternative to anticoagulant therapy for preventing venous thromboembolism in patients with COVID-19 without associated bleeding risk.
Data Availability
Data sharing is not applicable to this article as no new data were created or analyzed in this study.
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Kow, C.S., Ramachandram, D.S. & Hasan, S.S. Anakinra for the prophylaxis of venous thromboembolism in patients with COVID-19. Inflammopharmacol 31, 2077–2078 (2023). https://doi.org/10.1007/s10787-023-01203-2
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DOI: https://doi.org/10.1007/s10787-023-01203-2