Tocilizumab, sarilumab may improve COVID-19 outcomes

Two interleukin-6 receptor antagonists – tocilizumab and sarilumab – fared better than standard of care in improving survival and speeding up recovery in critically ill patients with COVID-19, according to findings of the REMAP-CAP* trial.

Participants in this international, open-label trial were 865 adults (mean age 61.4 years, 73 percent male, 72 percent White and 17 percent Asian) critically ill with COVID-19 admitted to the intensive care unit (ICU). Within 24 hours of initiating organ support in the ICU, they were randomized to receive one of two interleukin-6 receptor antagonists – intravenous sarilumab (single dose of 400 mg; n=48) or tocilizumab (single dose of 8 mg/kg to a maximum 800 mg with a potential second dose 12–24 hours later if insufficient improvement; n=353) – or standard of care (control group; n=402).

Median body mass index was 30.5 kg/m² and median APACHE** II score was 12. SARS-CoV-2 infection was confirmed in 84 percent of patients. Prior to enrolment, patients had been in the ICU for a median 13.6 hours and in hospital for a median 1.2 days. All but three patients were on respiratory support at randomization, with 29 percent each receiving invasive mechanical ventilation and high-flow nasal cannulae and 42 percent on non-invasive ventilation.  

The median number of respiratory and cardiovascular organ support-free days*** up to day 21 was comparable between the tocilizumab and sarilumab arms (10 and 11 days, respectively) compared with 0 days with control. [N Engl J Med 2021;384:1491-1502]

There was an increased likelihood of survival and more organ support-free days (shorter time to clinical improvement) with tocilizumab (median adjusted odds ratio [adjOR], 1.64, 95 percent credible interval [CrI], 1.25–2.14) or sarilumab (median adjOR, 1.76, 95 percent CrI, 1.17–2.91) compared with control. The posterior probabilities of superiority to control exceeded 99.9 and 99.5 percent, respectively.

In-hospital mortality occurred in 27 percent of the pooled interleukin-6 receptor antagonist population compared with 36 percent in the control group. In-hospital survival was increased with tocilizumab (median adjOR, 1.64, 95 percent CrI, 1.14–2.35) and sarilumab (median adjOR, 2.01, 95 percent CrI, 1.18–4.71) compared with control, with a posterior probability of superiority of 99.6 and 99.5 percent, respectively.

Survival at 90 days was also improved with both interleukin-6 receptor antagonists (pooled group) compared with control (hazard ratio [HR], 1.61, 95 percent CrI, 1.25–2.08), with a posterior probability of superiority of >99.9 percent vs control. Tocilizumab also improved time to ICU discharge (HR, 1.42) and hospital discharge (HR, 1.41), as did sarilumab (HRs, 1.64 and 1.51, respectively) compared with control.

No serious adverse events (AEs) were reported in the sarilumab group. There were nine serious AEs in the tocilizumab group (one incident each of vision deterioration and secondary bacterial infection, two cardiac events, and five bleeding events) and eleven in the control group (seven thrombosis events and four bleeding events).

More benefits in critically ill?

“We found that in critically ill patients with COVID-19, the interleukin-6 receptor antagonists tocilizumab and sarilumab were both effective as compared with the current standard of care, which included glucocorticoids in [>80 percent] of patients,” the investigators said.

The design of the present study contrasted with many previous trials which excluded patients already on respiratory support and included a less critically ill population, they continued. The results of those studies did not show a benefit of tocilizumab on survival and had varying results with regard to tocilizumab effect on disease progression.

According to the investigators, this suggests that interleukin-6 receptor antagonists may confer greater benefits in a more severely ill population with COVID-19. The enrolment within 24 hours of organ support in the ICU points to the potential importance of early treatment in this population at a time when “developing organ dysfunction may be more reversible,” they said. However, the short follow-up period means that long-term outcomes of the treatments remain to be seen.