DO ALL CRITICALLY ILL COVID-19 PATIENTS BENEFIT from INTENSIFYING with TOCILIZUMAB?

ABSTRACT

Background: Treatment guidelines recommend the use of tocilizumab in patients with a current CRP >7.5 mg/dl. Recent data showed that survival benefit might be greater in those with higher CRP levels. We aimed to estimate the causal effect of intensification with tocilizumab on mortality overall and after stratification for PaO2/FiO2 ratio, CRP levels. Methods: Observational cohort study of patients with severe COVID-19 pneumonia. Primary endpoint was day-28 mortality. Survival analysis was conducted to estimate the conditional and average causal effect of tocilizumab intensification vs. glucocorticoids alone using Kaplan-Meier curves and Cox regression models with a time-varying variable for the intervention. Analysis was controlled for age, ethnicity, duration of symptoms, at hospital admission (baseline, BL) PaO2/FiO2 ratio, CRP (BL and current), Charlson comorbidity index and post-BL use of remdesivir and invasive mechanical ventilation. The hypothesis of the existence of effect measure modification by CRP and PaO2/FiO2 ratio was tested by including an interaction term in the model. Results: 992 patients median age 69 years, 72.9% males, 597 (60.2%) treated with monotherapy and 395 (31.8%), adding tocilizumab upon respiratory deterioration were included. At BL, median CRP was 6.0 mg/dl (IQR 3.0-15.0) and median PaO2/FiO2 ratio was 261 mmHg (200-303). The two groups differed for median values of CRP (6 vs 7 mg/dL;p<.001)), IL-6, (27.6 vs 175.0 mg/L;p<.001) LDH (525 vs 622 U/L;p<.001), lymphocytes (939 vs 835/mm3;p<.001) and PaO2/FiO2 ratio (276 vs 235 mmHg;p<.001) at BL. In the unadjusted analysis there was no statistically significant difference in mortality between the two groups, but there was strong evidence for an effect of the intensification after controlling for key BL and post-BL confounders, consistent with the estimate in trials (adjusted hazard ratio (aHR)=0.59, 95% CI0.38-0.90). Although the study was not powered to detect interactions (p>0.57) there was a signal for intensification to have a larger effect in subsets, especially participants with high levels of CRP at intensification (Figure). Conclusion: Our data suggest that intensification with tocilizumab confers reduced survival benefit in those intensifying with a CRP of 0-7.5 mg/dl. It also provides substantial benefit even in patients who are intensified with a CRP>15 mg/dl. Large randomised studies are needed to establish an exact cut-off for clinical use.