WHO NEW ** strong recommendation to use IL-6 receptor blockers (tociluzimab or sarilumab) in patients with severe or critical COVID-19 (published 6 July 2021); Dienstag, 06. Juli 2021 - 22:05
IL-6 receptor blockers reduce mortality and need for mechanical ventilation based on high certainty evidence. Low certainty evidence suggests they may also reduce duration of mechanical ventilation and hospitalization [8][9].
The evidence regarding the risk of SAEs is uncertain. Low certainty evidence suggested that the risk of bacterial infections in the context of immunosuppression treatment with IL-6 receptor blockers may be similar to usual care [7]. However the GDG had some concerns that, given the short-term follow-up of most trials and the challenges associated with accurately capturing adverse events such as bacterial or fungal infection, the evidence summary may under-represent the risks of treatment with IL-6 receptor blockers. Furthermore, the trials of IL-6 receptor blockers that inform this recommendation were mostly performed in high-income countries where the risk of certain infectious complications may be less than in some other parts of the world, and so the generalizability of the data on adverse events is unclear. We did not have any data examining differential risk of harm based on whether patients received one or two doses of IL-6 receptor blocker.
Subgroup analyses indicated no effect modification based on IL-6 receptor blocker drug (sarilumab or tocilizumab) or disease severity (critical vs severe) and therefore this recommendation applies to all adult patients with either severe or critical COVID-19 [23]. We were unable to examine subgroups based on elevation of inflammatory markers or age due to insufficient trial data (see Section 5). Subgroup analyses evaluating baseline steroid use found greater benefit of IL-6 receptor blockers in patients receiving steroids compared with those who were not (p=0.026), demonstrating that steroid use does not abolish and might enhance the beneficial effect of IL-6 receptor blockers. Since steroids are already strongly recommended in patients with severe and critical COVID-19, we did not formally evaluate the credibility of this subgroup analysis as there would be no rationale for a subgroup recommendation for patients not receiving corticosteroids.
Certainty of evidence was rated as high for mortality and need for mechanical ventilation. Certainty in duration of mechanical ventilation was rated as low due to serious risk of bias due to concerns regarding lack of blinding in included trials, and for imprecision as the lower limit of the confidence interval suggested no effect. Certainty in duration of hospitalization was rated as low due to serious risk of bias from lack of blinding in included trials, and for inconsistency related to differences in point estimates and lack of overlap in confidence intervals.
Certainty in SAEs was rated as very low due to risk of bias related to lack of blinding and ascertainment bias, and very serious imprecision due to very wide confidence intervals which did not rule out important benefit or harm; certainty in risk of bacterial or fungal infections was rated as low due to similar concerns regarding serious risk of bias and serious imprecision.
Certainty in evidence was rated as moderate when comparing the effect on mortality between tocilizumab and sarilumab due to issues with imprecision.
Applying the agreed values and preferences (see Section 5), the majority of the GDG inferred that almost all well-informed patients would want to receive IL-6 receptor blockers. The benefit of IL-6 receptor blockers on mortality was deemed of critical importance to patients, despite the very low certainty around SAEs. The GDG anticipated little variation in values and preferences between patients for this intervention.
Resource implications, equity and human rights
The GDG noted that, compared with some other candidate treatments for COVID-19, IL-6 receptor blockers are more expensive and the recommendation does not take account of cost-effectiveness. Currently, access to these drugs is challenging in many parts of the world, and without concerted effort is likely to remain so, especially in resource-poor areas. It is therefore possible that this strong recommendation for IL-6 receptor blockers could exacerbate health inequity. On the other hand, given the demonstrated benefits for patients, it should also provide a stimulus to engage all possible mechanisms to improve global access to these treatments. Individual countries may formulate their guidelines considering available resources and prioritize treatment options accordingly.
At a time of drug shortage, it may be necessary to prioritize use of IL-6 receptor blockade through clinical triage [21]. Many jurisdictions have suggested mechanisms for triaging use of these treatments. These include prioritizing patients with the highest baseline risk for mortality (e.g. those with critical disease over those with severe disease), in whom the absolute benefit of treatment is therefore greatest. For example, despite consistent relative effects (OR 0.86 for mortality) with IL-6 receptor blockers, the absolute risk reduction for mortality in the critically ill would be 31 fewer deaths per 1000 (95% CI 11 to 47 fewer deaths) and in the severely ill would be 13 fewer deaths per 1000 (95% CI 5 to 19 fewer deaths).
Other suggestions for prioritization, which lack direct evidence, include focusing on patients with an actively deteriorating clinical course and avoiding IL-6 receptor blocker therapy in those with established multi-organ failure (in whom the benefit is likely to be smaller).
Acceptability and feasibility
As IL-6 receptor blockers require intravenous administration, this treatment would be primarily indicated for patients with severe and critical COVID-19 who require hospitalization. IL-6 receptor blockers are relatively easy to administer, and only require one, or at most, two doses.