Discussion
death, bleeding, COVID-19 disease, abnormal bleeding, garadacimab, deaths
THROMBOEMBOLIC EVENT, BLEEDING, DISEASE, MAY, ABNORMAL BLEEDING, EVENTS
In this phase 2 study of garadacimab in patients hospitalised with severe COVID-19, the primary efficacy endpoint, incidence of TI or death before intubation from randomisation to Day 28, was not met. Although there were no differences between the two groups in rate of TI or death before intubation, there were small numerical differences in favour of garadacimab. The heterogeneity of the study population and small sample size may account for the lack of a clear differentiation between the groups. Subgroup analyses did not reveal any impact of age group, sex or baseline comorbidities on the primary efficacy endpoint.The safety profile for garadacimab in this severely ill patient population was benign, with no garadacimab-related deaths, thromboembolic events or bleeding events—an important observation as many participants study were receiving anticoagulation therapy.The high incidence of thromboembolic events in patients with severe disease was expected given that COVID-19 activates the coagulation system thereby propagating a prothrombotic state [In our study, anticoagulant therapy was initiated in approximately half of patients during the 28-day study period. Even with coadministration of heparin in approximately one-third of patients receiving garadacimab, there were no differences in abnormal bleeding events between the two groups. In a single-centre study conducted in the USA from March to May 2020, only 4% of patients hospitalised with COVID-19 disease of any severity did not receive anticoagulants in either therapeutic, prophylactic or subclinical doses [The benign safety findings in this study are consistent with those reported for garadacimab in healthy volunteers [Limitations to this study include the challenges associated with conducting a study during an active pandemic, which necessitated the use of a flexible protocol allowing the use of any treatment that may have proved therapeutically useful. Patients often received numerous concomitant therapies alongside garadacimab, thus limiting the ability to separate the use of therapeutic and prophylactic anticoagulant doses, resulting in the lack of efficacy regarding primary endpoints. Further, the heterogeneity of the study population and small sample size may account for the lack of clear differentiation between the groups.