Cardiovascular toxicity risk assessment of tyrosine kinase inhibitors: a pharmacovigilance study using the VigiBase database

FIGURE 1. This flowchart illustrates the selection process of adverse event reports included in the analysis from VigiBase as of December 2022. Initially, 32, 520, 983 cases were reported. Of these, reports with missing data on age or sex totaling 9,339,444 cases were excluded from the analysis. The final dataset included 23, 181, 539 cases.

FIGURE 2. Risk assessment of adverse events induced by tyrosine kinase inhibitors across different subgroups. The heat map illustrates the risk of cardiotoxic adverse events associated with various tyrosine kinase inhibitors (TKIs). The drugs are categorized by receptor type (EGFR, HER2, VEGFR, FGFR, BCR-ABL, ALK, JAK, and BTK) along the horizontal axis, and the patient subgroups (sex and age categories) are categorized along the vertical axis. Color intensity indicates the level of risk based on the reported odds ratio (ROR) and P-value. The two darkest shades of red denote a significant risk signal (ROR > 1, P < 0.01), suggesting a higher incidence of adverse events in the database. Green shades indicate a ROR < 1, and the two darkest shades of green indicate a ROR < 1 and P < 0.01, representing a sufficient number of cases but no detected signal. Lighter shades of green denote subgroups with insufficient numbers of cases for validation. White cells indicate reports with relatively few cases to confirm significance. Cells with a dashed line (‘-‘) indicate no reports of that subgroup in the database (n = 0). This figure provides a visual representation of the comparative safety profiles…

FIGURE 3. Comparative risk of adverse cardiovascular events induced by tyrosine kinase inhibitors. This heatmap provides a comparative analysis of the risk levels for various adverse cardiovascular events induced by different tyrosine kinase inhibitors (TKIs) along the horizontal axis against a range of cardiovascular adverse events listed on the vertical axis. The top row, labeled “Cardiotoxicity,” aggregates the overall cardiovascular risk associated with each drug. Two shades of dark red indicate a statistically significant signal (high risk), with the darkest shade representing the highest risk level. Green shades indicate an ROR < 1 or a P ≥ 0.5, with darker green representing P < 0.01, representing a substantial number of cases without a detected signal. Lighter shades of green represent subgroups with insufficient cases to validate the results. White cells denote reports with relatively few cases to assess significance. A dash (‘-‘) signifies no reports for the subgroup in the database (n = 0). This visual representation aids in understanding the relative safety profiles of TKIs in the context of cardiovascular events.

FIGURE 4. Sex-based subgroup analysis of adverse cardiovascular events induced by tyrosine kinase inhibitors. (A) represents the risk levels of various cardiovascular adverse events induced by tyrosine kinase inhibitors (TKIs) in female patients. (B) Illustrates the same for male patients. The color intensity in the heatmap indicates the level of risk based on the reported odds ratio (ROR) and P-value: Two shades of dark red indicate a statistically significant signal (high risk), with the darkest shade representing the highest risk level. Green shades indicate an ROR < 1 or a P ≥ 0.5, with darker green representing P < 0.01, representing a substantial number of cases without a detected signal. Lighter shades of green represent subgroups with insufficient cases to validate the results. White cells denote reports with relatively few cases to assess significance. A dash (‘-‘) signifies no reports for the subgroup in the database (n = 0). These visual representations help in understanding the relative safety profiles of TKIs in the context of cardiovascular events among different sexes.

FIGURE 5. Age-based subgroup analysis of adverse cardiovascular events induced by tyrosine kinase inhibitors. (A) depicts the risk levels of various cardiovascular adverse events induced by tyrosine kinase inhibitors (TKIs) in younger patients. (B) Illustrates the same for older patients. The color intensity in the heatmap indicates the level of risk based on the reported odds ratio (ROR) and P-value: Two shades of dark red indicate a statistically significant signal (high risk), with the darkest shade representing the highest risk level. Green shades show an ROR < 1 or a P ≥ 0.5, with darker green representing P < 0.01, indicating a substantial number of cases without a detected signal. Lighter shades of green represent subgroups with insufficient cases to validate the results. White cells denote reports with relatively few cases to assess significance. A dash (‘-‘) signifies no reports for the subgroup in the database (n = 0). These visual representations help in understanding the relative safety profiles of TKIs in the context of cardiovascular events among different age groups.