Early tocilizumab treatment in ICU tied to lower COVID-19 mortality

Critically ill patients who received tocilizumab within 2 days of admission to the intensive care unit (ICU) for COVID-19 had a lower risk of mortality than those not treated with tocilizumab, according to a recent study.

The study population comprised 3,924 critically ill adults (median age 62 years, 62.8 percent male) admitted to ICUs in the US for COVID-19 between March 4 and May 10, 2020, who were enrolled in the multicentre STOP-COVID* study. The researchers compared mortality outcomes in patients who had and had not received intravenous or subcutaneous tocilizumab within 2 days of ICU admission.

Eleven percent of patients (n=433) received tocilizumab within 2 days of ICU admission. Prior to inverse probability weighting (IPW), tocilizumab recipients were younger than non-recipients (median age 58 vs 63 years) and had fewer comorbidities such as hypertension (54.0 percent vs 62.6 percent) or coronary artery disease (9.0 percent vs 14.4 percent). They were more likely to have hypoxemia (47.3 percent vs 37.9 percent), elevated inflammation markers (85.7 percent vs 65.6 percent), and have received corticosteroids (18.7 percent vs 12.6 percent) at ICU admission. However, baseline and illness severity were well-balanced between groups after IPW.

Patients were followed up for a median 27 days. Of the 1,544 patients who died (39.3 percent), 28.9 and 40.6 percent did and did not receive tocilizumab, respectively.

The risk of mortality was lower among patients who received tocilizumab compared with non-recipients (hazard ratio, 0.71, 95 percent confidence interval, 0.56–0.92). [JAMA Intern Med 2021;181:41-51]

Mortality at 30 days was estimated at 27.5 and 37.1 percent in recipients and non-recipients of tocilizumab, respectively (risk difference, 9.6 percent).

The results were consistent across multiple subgroups including age, sex, and PaO₂:FiO₂ ratio**, receipt of vasopressors, and receipt of corticosteroids at ICU admission.

The reduction in mortality risk with tocilizumab was notably greater among patients with ICU admission within 3 days compared with after 3 days of symptom onset (HRs, 0.41 and 0.85, respectively; p_interaction=0.03).

“The greater benefit estimated in this group of patients may reflect greater efficacy of tocilizumab in those with a more rapid disease trajectory,” suggested the authors. “Alternatively, tocilizumab may be more effective when administered earlier in the course of disease, before irreversible organ injury has occurred,” they said.

Secondary infections occurred at a comparable rate between tocilizumab recipients and non-recipients (32.3 percent vs 31.1 percent). Other adverse events (AEs) reported included AST or ALT level elevations of >250 U/L (16.6 percent vs 12.9 percent) or >500 U/L (8.5 percent vs 5.6 percent), arrhythmia (14.5 percent vs 17.2 percent), and thrombotic complications (10.6 percent vs 9.8 percent).

The AEs highlight the importance of monitoring for infections and hepatotoxicity in tocilizumab-treated patients, cautioned the authors.

Is there a role for tocilizumab?

The authors noted that the differences in baseline characteristics between groups before vs after IPW “raise the possibility of residual confounding.” There is also no information on number of tocilizumab doses received or duration of concomitant medication. “[T]he study [also] did not shed light on whether the response to tocilizumab may have varied according to pretreatment levels of inflammatory parameters,” they said.

According to Assistant Professor Jonathan Parr from the University of North Carolina at Chapel Hill, North Carolina, US, the findings from STOP-COVID and other observational studies contrast with that of randomized trials (RTs) which have so far found no COVID-19 mortality benefit from tocilizumab. [JAMA Intern Med 2021;181:24-31; JAMA Intern Med 2021;181:32-40]

“[RTs] will ultimately determine tocilizumab’s role in COVID-19,” he said in an editorial. [JAMA Intern Med 2021;181:12-15] “Newly released RTs suggest a potential role for tocilizumab in COVID-19 but do not show clear evidence of efficacy … their findings do not support the routine use of tocilizumab for COVID-19 in most settings.”