Non-uniform cardiovascular risks of tyrosine kinase inhibitors associated with inhibition of C-terminal Src kinase

Background Tyrosine Kinase Inhibitors (TKI) were reportedly associated with cardiovascular (CV) events but such risks were not uniform. Off-target inhibition of C-terminal Src Kinase (CSKI) may provide a mechanistic basis but data on long-term clinical outcomes were absent. Purpose To investigate for the role of CSKI in the clinical burden of CV event risk associated use with TKI. Methods We performed a territory-wide retrospective cohort study of a metropolitan covering all public hospitals in the jurisdiction during the period 1 Jan 1993 to 30 Jun 2021, and identified patients who received TKI with or without CSKI. Multivariable Cox regression model was used to analyze the effect of CSK on incident composite CV endpoints, defined as acute myocardial infarction, ischemic heart disease, newly diagnosed cardiomyopathies, congestive heart failure, ischemic and hemorrhagic stroke and/ or peripheral vascular disease. Results Amongst 16886 patients who received TKI (54.8% female, mean age 63.9±13.0 years), 612 patients (3.6%) received a TKI with CSKI. Of 14925 TKI users who were free of prior composite CV events at baseline (88.4%), CSKI was associated with significantly higher incident rates of composite CV events (9.5% versus 6.6%, P=0.007). Multivariable logistic regression showed that, after adjustment for potential confounders, CSKI independently predicted increased risk of composite CV events (Odds ratio=1.84 [95%CI 1.36 to 2.50], P<0.001). The Number-Needed-To-Treat (NNT) to prevent CV outcomes by avoiding CSKI was 34. Conclusions CSKI is independently associated with increased risk of CV events in cancer patients who received TKI. Future studies should explore the potential clinical role of CSKI avoidance in TKI use where clinically appropriate.