Baricitinib versus dexamethasone for adults hospitalised with COVID-19 (ACTT-4): a randomised, double-blind, double placebo-controlled trial

The AI-Assisted Identification and Clinical Efficacy of Baricitinib in the Treatment of COVID-19

“…In addition, it appears that the JAK inhibitor baricitinib is the most effective treatment, even conferring added benefit in the presence of antivirals and other immune modulators. The ACTT-4 trial, which showed no difference between baricitinib and dexamethasone in the presence of remdesivir, is consistent with one advantage of baricitinib, namely, its anti-viral properties [77].…”

“…It is also noticeable that even in the presence of dexamethasone, baricitinib, tofacitinib, and tocilizumab have all been shown to confer enhanced protection in randomised SoC-controlled clinical trials. There have not been many direct comparisons of the immune modulators in COVID-19 trials, except in the recently published ACTT-4 trial where the effect of baricitinib with remdesivir plus SoC was compared with dexamethasone plus remdesivir and SoC [77]. In this study there was no difference in survival of patients requiring supplemental oxygen, but there were significantly more grade 3 or 4 adverse events in the dexamethasone group.…”

“…In the large RECOVERY trial there were no significant increases in thrombosis, secondary infections, or other safety outcomes in those treated with baricitinib and a significant reduction in mortality was observed [73]. Similarly, baricitinib was shown to cause significantly fewer adverse events in the ACTT-4 trial when compared with dexamethasone, both in the presence of remdesivir [77]. These small improvements in safety were also seen in a meta-analysis covering 3564 patients in a mixture of RCT and observational trials where serious adverse events and secondary infections were approximately 20% fewer in those treated with baricitinib [76].…”

Key Advances in Intensive Care and the Coronavirus Disease-19 Research and Practice Boost

“…Relevant published evidence has already been partly systematically reviewed and/or meta-analyzed. Pertinent, prominent examples include (1) noninvasive techniques of respiratory support (e.g., high-flow nasal canula, continuous positive airway pressure), prone positioning (for ≥16 consecutive hours per day with lung-protective ventilation) and veno-venous extracorporeal membrane oxygenation (ECMO) in acute respiratory distress syndrome (ARDS) of varying severity [ 5 , 6 , 7 , 8 , 9 , 10 ]; (2) use of RCT evidence-supported physiological targets such as ventilator driving pressure of <15 cmH 2 O during low-tidal volume ventilation in ARDS [ 11 ]; (3) adjunctive hydrocortisone with or without fludrocortisone in septic shock, and dexamethasone in ARDS (of COVID-19 or non-COVID-19 etiology) [ 12 , 13 , 14 , 15 , 16 ]; (4) targeted temperature management (e.g., hypothermia or normothermia with target temperature of 33 or ≤37.5 °C, respectively) after cardiac arrest [ 17 , 18 , 19 ]; (5) vasopressin, stress-dose steroids, and epinephrine in in-hospital cardiac arrest [ 20 , 21 , 22 , 23 , 24 ]; (6) early inhibition of fibrinolysis by tranexamic acid in acute severe bleeding due to trauma and in postpartum hemorrhage [ 25 , 26 , 27 ]; (7) nucleotide inhibition of severe acute respiratory syndrome coronavirus 2 RNA-dependent RNA polymerase [ 28 , 29 ]; and (8) immunomodulating interventions such as interleukin (IL)-6 receptor blockade, Janus kinase inhibition, or IL-1 alpha and IL-1 beta antagonism guided by soluble urokinase plasminogen receptor plasma levels in COVID-19 [ 30 , 31 , 32 , 33 , 34 ].…”

“…During the COVID-19 pandemic, intensive care practice was guided by the prompt issuance of guidelines including recommendations based on both direct and indirect (i.e., extrapolated from other viral pneumonias) evidence [ 4 ] and by an abundance of concurrently emerging RCT data [ 8 , 28 , 29 , 30 , 31 , 32 , 33 , 34 ]. Furthermore, two simplified models of COVID-19-related ARDS (CARDS) were proposed as opposite extremes of a pathophysiological spectrum that includes “intermediate stages” with overlapping characteristics.…”