Baricitinib or Tocilizumab? Treatment of Patients Hospitalized With Severe COVID-19*

Pharmacologic treatment of COVID-19 has continued to evolve since the onset of the pandemic, and yet many questions remain about optimal treatment. Medicine strives to provide evidence-based guidance on treatments, but what if there is simply not enough evidence? Ambiguity persists within recommendations for COVID-19 optimal management identified by the simple use of the word “or.” The National Institutes of Health (NIH) treatment recommendations for treatment of patients with COVID-19 who are hospitalized and require supplemental oxygen, or high levels of airway support, include the use of baricitinib or tocilizumab but lack guidance on which to choose (1). An indirect comparison meta-analysis suggested noninferiority between these drugs (2). Data comparing these two treatment options are necessary to provide guidance on if one of these two medications should be the preferred choice.

The article in this issue of Critical Care Medicine by Peterson et al (3) aims to provide additional clarity on if there should be a preference toward baricitinib or tocilizumab, all other things being as equal as they can be in medicine. The study is a large retrospective, observational cohort of adult patients with severe COVID-19 who received at least one dose of baricitinib or tocilizumab between June and October of 2021 from 11 hospitals within a single health system in Georgia. The primary and secondary outcomes were in-hospital mortality and incidence of adverse events, respectively. Nine hundred fifty-six patients were included, with a median age of 57 years, 53% men, and 94% unvaccinated. Use of remdesivir and dexamethasone was similar between groups. 39.6% of baricitinib patients required ICU level care at the time treatment was initiated, as compared to 65.6% of tocilizumab patients. A propensity score matching was completed among a total of 582 patients, with no difference in mortality (baricitinib 30.9% vs tocilizumab 32%; odds ratio 0.95; 95% CI 0.7–1.4; p = 0.79) but a statistically significant higher rate of adverse events among those who received tocilizumab as compared with baricitinib. These tocilizumab side effects included secondary infections (32% vs 22%; p < 0.01), thrombotic events (24% vs 15%; p < 0.01), and acute liver injury (8% vs 3%; p < 0.01). Additionally, there was no significant difference in ICU length of stay or progression to mechanical ventilation or extracorporeal membrane oxygenation. Based on these results, the authors conclude that baricitinib may be the preferred choice for severe COVID-19 infections.

There are several strengths to the study by Peterson et al (3). First, this is a large, real-world study aiming to help answer a key clinical question regarding the use of two different treatments for severe COVID-19 among adults. Although this is a retrospective observational cohort, the use of propensity scoring adds confidence to these results. Although the adequate randomization process remains the best study methodology to reduce selection bias and confounding, observational studies remain useful to provide external validity and safety assessment of therapies already tested in randomized trials. However, observational studies require specific statistical techniques to minimize bias and confounding. Propensity scoring is among the methods employed to decrease the selection bias and confounding by indication present in observational studies in order to attempt to mimic a randomized controlled trial. However, these strengths are accompanied by several limitations. Missing data due to lack of data or documentation, a population skewed to unvaccinated and obese men, and data on race and some medical conditions such as underlying heart or lung disease were not reported. The high rate of unvaccinated persons at the time of the study, combined with the decreased overall level of severity of disease at current times, may limit the generalizability of the risk to benefit ratio with these medications. The authors propose that efficacy would not be different based on mechanism of action; however, with current status of higher levels of immunity, reassessment of the degree of inflammation dysregulation impacted by these medications would be helpful. That being said, a recent randomized controlled trial on baricitinib showed consistent baricitinib’s survival benefits in both vaccinated and nonvaccinated patients (4).

Baricitinib and tocilizumab act via different mechanisms of action. The use of both concurrently is notably not recommended (1). Baricitinib is a Janus Kinase inhibitor that modulates the immune and inflammatory responses, whereas tocilizumab is an interleukin-6 antagonist (3).

The placebo-controlled double-blind randomized trial remains the most reliable study design to discover efficacy inferences regarding treatment interventions but less dependable to detect safety inferences from the same interventions. The reason for that is because most randomized trials are not powered for safety outcomes and collect limited safety data. On the other side, the observational cohort study is less reliable for efficacy causal inferences because of confounding and selection bias, but it can be more dependable to detect safety outcomes if safety data collection is comprehensive. The understanding of these design differences has direct implications for clinical practice: tocilizumab has failed to show efficacy in all placebo-controlled double-blind randomized trials, but it had positive results only in open-label trials (5), whereas observational studies have shown significant safety issues with tocilizumab, mainly by increasing the risk of secondary infections, such as hospital-acquired infections (6,7) and COVID-19–associated pulmonary aspergillosis (8). Baricitinib has proven efficacy and safety in all placebo-controlled double-blind randomized trials plus open-label trials (4,9–11), whereas observational studies have not detected safety issues with baricitinib (12–15). Thus, the prior efficacy and safety data from these two drugs are very informative to understand the results of the new study by Peterson et al (3), a observational study that did not detect efficacy differences, but it detected higher safety risks—significantly more secondary infections, thrombotic events, and acute liver injury with tocilizumab, compared with baricitinib.

Based on all available evidence to date, there in fact may be greater rationale—higher benefit and lower risk—for use of baricitinib over tocilizumab when available and no other contraindications exist. Further evaluation of both, and also of all COVID-19 treatments, in the current pandemic status with higher levels of vaccine and disease-induced immunity is warranted for confirmation of continued benefit and safety but also to aid clinicians in making the best treatment decisions according to robust evidence from high-quality randomized and observational studies.

1. National Institutes of Health: COVID-19 Treatment Guidelines. Available at https://www.covid19treatmentguidelines.nih.gov/. Accessed September 30, 2022 2. Albuquerque AM, Eckert I, Tramujas L, et al.: Effect of tocilizumab, sarilumab, and baricitinib on mortality among patients hospitalized for COVID-19 treated with corticosteroids: A systematic review and meta-analysis. Clin Microbiol Infect. 2022 Jul 19; S1198-743X(22)00372-X 3. Peterson JH, Paranjape NS, Grundlingh N, et al.: Outcomes and adverse effects of baricitinib versus tocilizumab in the management of severe COVID-19. Crit Care Med. 2023; 51:337–346 4. Abani O, Abbas A, Abbas F, et al.: Baricitinib in patients admitted to hospital with COVID-19 (RECOVERY): A randomised, controlled, open-label, platform trial and updated meta-analysis. Lancet. 2022; 400:359–368 5. Shankar-Hari M, Vale C, Godolphin P, et al.: WHO rapid evidence appraisal for COVID-19 Therapies (REACT) Working Group: Association between administration of IL-6 antagonists and mortality among patients hospitalized for COVID-19: A meta-analysis. JAMA. 2021; 326:499–518 6. Kumar G, Adams A, Hererra M, et al.: Predictors and outcomes of healthcare-associated infections in COVID-19 patients. Int J Infect Dis. 2021; 104:287–292 7. Martínez-Martínez M, Plata-Menchaca EP, Nuvials FX, et al.: Risk factors and outcomes of ventilator-associated pneumonia in COVID-19 patients: A propensity score matched analysis. Crit Care. 2021; 25:235 8. Prattes J, Wauters J, Giacobbe DR, et al.: Risk factors and outcome of pulmonary aspergillosis in critically ill coronavirus disease 2019 patients—A multinational observational study by the European Confederation of Medical Mycology. Clin Microbiol Infect. 2022; 28:580–587 9. Kalil AC, Patterson TF, Mehta AK, et al.: Baricitinib plus remdesivir for hospitalized adults with COVID-19. N Engl J Med. 2021; 384:795–807 10. Marconi VC, Ramanan AV, de Bono S, et al.: COV-BARRIER study group: Efficacy and safety of baricitinib for the treatment of hospitalised adults with COVID-19 (COV-BARRIER): A randomised, double-blind, parallel-group, placebo-controlled phase 3 trial. Lancet Respir Med. 2021; 9:1407–1418 11. Ely EW, Ramanan AV, Kartman CE, et al.: COV-BARRIER study group: Efficacy and safety of baricitinib plus standard of care for the treatment of critically ill hospitalised adults with COVID-19 on invasive mechanical ventilation or extracorporeal membrane oxygenation: An exploratory, randomised, placebo-controlled trial. Lancet Respir Med. 2022; 10:327–336 12. Wolfe CR, Tomashek KM, Patterson TF, et al.: Baricitinib versus dexamethasone for adults hospitalised with COVID-19 (ACTT-4): A randomised, double-blind, double placebo-controlled trial. Lancet Respir Med. 2022; 10:888–899 13. Cantini F, Niccoli L, Matarrese D, et al.: Baricitinib therapy in COVID-19: A pilot study on safety and clinical impact. J Infection. 2020; 81:318–356 14. Bronte V, Ugel S, Tinazzi E, et al.: Baricitinib restrains the immune dysregulation in patients with severe COVID-19. J Clin Invest. 2020; 130:6409–6416 15. Rodriguez-Garcia JL, Sanchez-Nievas G, Arevalo-Serrano J, et al.: Baricitinib improves respiratory function in patients treated with corticosteroids for SARS-CoV-2 pneumonia: An observational cohort study. Rheumatology. 2021; 60:399–407 16. Stebbing J, Sánchez Nievas G, Falcone M, et al.: JAK inhibition reduces SARS-CoV-2 liver infectivity and modulates inflammatory responses to reduce morbidity and mortality. Sci Adv. 2021; 7:eabe4724

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