Incorporation of Tocilizumab into an Evidence Informed Guideline: An Evidence to Decision Approach

ABSTRACT

Aim and background: COVID-19 was a new disease-causing a pandemic and hence generated uncertainty, and a great deal of anxiety with regard to appropriate therapeutic interventions. Many treatment regimens were tried with no evidence supporting the same. Critical and fatal COVID-19 due to immune dysregulation results in severe inflammation or a cytokine storm with markedly elevated pro-inflammatory cytokines like interleukin-6 (IL-6). Tocilizumab, an IL-6 receptor antagonist, is reported to prevent disease progression. However, since this is an expensive intervention, it is important that evidence is reviewed systematically regarding its utility. The India COVID guidelines is a group of experts and methodologists who came together to use a process of evidence synthesis to inform treatment guidelines using an evidence to decision framework (www.indiacovidguidelines.org). We report the data regarding tocilizumab in severe to critical COVID-19 infection. Objectives: To assess the efficacy and safety of tocilizumab in patients with COVID-19. Materials and methods: Search methods: We performed a systematic search till 15.10.2021 of the following databases Pubmed, WHO ICTRP, L.OVE platform, Cochrane library, and COVID-NMA. Selection criteria We selected only randomised controlled trials (RCT) evaluating tocilizumab use in COVID-19. Data collection and analysis: Two review authors independently screened and identified studies using Rayyan, did a risk of bias assessment using the Cochrane ROB 2 tool and extracted numerical data from studies for outcomes like all-cause mortality, disease progression, clinical improvement, and adverse events. Meta-analysis was performed using Review Manager 5.4. I2 statistics were used to measure residual heterogeneity. Certainty of evidence was evaluated using GRADE methodology. A group of experts then used the WHO evidence to decision framework to judge values and preferences, and a recommendation for tocilizumab applicable to a lower-middle-income country was generated. Results: Our search retrieved 1408 s from various databases. Twenty-three RCTs were included in this systematic review with 10,583 participants. All participants were hospitalised adults with moderate to severe disease with an average age of 54-65 years. Median C-reactive protein was ≥ 100 mg/L indicating significant systemic inflammation. Prevalence of comorbidities varied and tocilizumab was initiated in rapidly worsening patients within 24-48 hours of admission to intensive care in most trials. More than 80% of participants were administered corticosteroids. Tocilizumabtreated patients showed a significant reduction in mortality with RR 0.88 (95% CI 0.81, 0.94) and reduced disease progression with RR 0.87 (95% CI 0.72, 1.06) with moderate certainty of the evidence, increased clinical improvement with RR 1.04 (95% CI 1.00, 1.09), and reduced time to clinical improvement with HR 1.22 (95% CI 1.14, 1.30) with low certainty of evidence. There was very low certainty in the evidence for adverse events and serious adverse events. Secondary infections were uncommon in most trials with follow-up till 14 or 28 days, which may have been too early to detect the same. Conclusion: A systematic review and meta-analysis which generated efficacy data of tocilizumab was then applied to an evidence to decision framework by subject experts resulting in a robust evidence-informed guideline applicable to any Indian secondary or tertiary healthcare setting.