Effect of anakinra on mortality in COVID-19: a patient level meta-analysis
Authors: Kyriazopoulou Evdoxia , Huet Thomas , Cavalli Giulio , Gori Andrea , Kyprianou Miltiades , Pickkers Peter , Eugen-Olsen Jesper , Clerici Mario , Veas Francisco , Chatellier Gilles , Kaplanski Gilles , Netea Mihai G. , Pontali Emanuele , Gattorno Marco , Cauchois Raphael , Kooistra Emma , Kox Matthijs , Bandera Alessandra , Beaussier Hélène , Mangioni Davide , Dagna Lorenzo , van der Meer Jos W. M. , Giamarellos-Bourboulis Evangelos J , Hayem Gilles ,   International collaborative group for Anakinra in COVID-19
Published: April 2021

Background

Anakinra may represent an important therapy to improve the prognosis of COVID-19 patients. This meta-analysis using individual patient data was designed to assess the efficacy and safety of anakinra treatment in patients with COVID-19.

Methods

Based on a pre-specified protocol (PROSPERO: CRD42020221491), a systematic literature search was performed in MEDLINE (PubMed), Cochrane, medRxiv.org, bioRxiv.org and clinicaltrials.gov databases for trials in COVID-19 comparing administration of anakinra with standard-of-care and/or placebo. Individual patient data from eligible trials were requested. The primary endpoint was the mortality rate and the secondary endpoint was safety.

Findings

Literature search yielded 209 articles, of which 178 articles fulfilled screening criteria and were full-text assessed. Aggregate data on 1185 patients from 9 studies were analyzed and individual patient data on 895 patients from 6 studies were collected. Most studies used historical controls. Mortality was significantly lower in anakinra-treated patients (38/342 [11·1%]) as compared with 137/553 (24·8%) observed in patients receiving standard-of-care and/or placebo on top of standard-of-care (137/553 [24·8%]); adjusted odds ratio (OR), 0·32; 95% CI, 0·20 to 0·51; p <0·001. The mortality benefit was similar across subgroups regardless of diabetes mellitus, ferritin concentrations, or baseline P/F ratio. The effect was more profound in patients exhibiting CRP levels >100 mg/L (OR 0·28,95%CI 0·27-1·47). Safety issues, such as increase of secondary infections, did not emerge.

Interpretation

Anakinra may be a safe anti-inflammatory treatment option in patients hospitalized with moderate-to-severe COVID-19 pneumonia to reduce mortality, especially in the presence of hyperinflammation signs such as CRP>100mg /L.

Funding

Sobi.

Research in context

Evidence before this study

Since the emergence of the COVID-19 pandemic, numerous drugs have been tried in an effort to prevent major detrimental consequences, such as respiratory and multiorgan failure and death. Early during the pandemic, it was realized that drugs aiming to regulate the immune host reaction may play an important role in the treatment of COVID-19. Evidence from a small number of patients with moderate or severe COVID-19 treated with anakinra, and interleukin-1 receptor antagonist, has suggested therapeutic efficacy. We systematically searched all available literature and aimed to present cumulative evidence of anakinra treatment in COVID-19 and the related effect on mortality.

Added value of this study

This is the first patient-level analysis on the effect of anakinra treatment in COVID-19 patients, which, on the one hand, suggests a significant benefit in the reduction of mortality and on the other hand, reassures safety of the treatment. Most importantly, the current study identifies a subgroup of patients with CRP>100mg/L, that may benefit most from treatment with anakinra. Confirmation of these effects in larger randomized clinical trials (RCTs) is urgently needed.

Implications of all the available evidence

Anakinra may be an effective and safe immunomodulatory treatment in moderate-to-severe cases of pneumonia due to COVID-19 to prevent unfavorable outcomes. Anakinra may be helpful to avoid adverse events, such as breakthrough infections observed often with dexamethasone use, and may be considered an alternative in specific subgroups of patients e.g. diabetics. Larger trials, summarized in the Table, are ongoing and their results are urgently needed to investigate anakinra’s best place in the treatment of COVID-19.