Cardiovascular toxicity of CDK4/6 inhibitors combined with endocrine therapy versus endocrine therapy alone in HR+/HER2- breast cancer: a real-world study based on the FAERS database

Figures

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  FIGURE 1. Process of selecting cases of CDK4/6 inhibitors-associated CV from the FAERS database. Abbreviations: DEMO, demographic and administrative information; REAC, reactions; n: the number of reports; PS, primary suspect.

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  FIGURE 2. Scanning for CDK4/6 inhibitor-related CVAEs based on the FAERS database. (A) world map illustrating the distribution of cardiovascular adverse events associated with the use of CDK4/6 inhibitors across different countries, as recorded in the FAERS database. (B) the upper bar chart illustrates the annual number of CDK4/6 inhibitor reports, both with and without CVAEs, over a period of 11 years. The stacked bar chart below shows the annual proportions of CDK4/6 inhibitor reports with and without CVAEs. (C) the upper bar chart displays the number of reports with and without CVAEs for various CDK4/6 inhibitors. The proportional bar chart below illustrates the proportions of reports with and without CVAEs for these inhibitors.

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  FIGURE 3. Disproportionality analyses calculated using ROR and IC. Disproportionality calculations using ROR and IC indicated elevated reporting signals of cardiovascular adverse events linked to CDK4/6 inhibitor monotherapy and combined regimens. Disproportionality analyses were performed using the reporting odds ratio (ROR) and information component (IC). These analyses identified disproportional reporting signals for cardiovascular adverse events associated with CDK4/6 inhibitors and their combination regimens. Abbreviations: CA, cardiac arrhythmias CARD, cardiomyopathy; CF, cardiac failure; ET, embolic and thrombotic events; HY, hypertension; IHD, ischemic heart disease; NM, noninfectious myocarditis; PH, pulmonary hypertension; QT, QT prolongation; ROR, reporting odds ratio; IC, information component.

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  FIGURE 4. Disproportional analysis of SMQs in the cardiovascular system and other systems. Abbreviations: CVAEs, cardiovascular adverse events; SMQ, Standardized MedDRA Queries; n, the number of reports; ROR, reporting odds ratio; 95%CI, the 95% confidence interval.

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  FIGURE 5. The lollipop plot to display the co-occurrence of CVAEs and non-CVAE SMQ.

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  FIGURE 6. Heatmap of ROR values for the top 30 cardiovascular adverse events with ≥3 reported cases. Data are stratified by CDK4/6 inhibitor treatment groups (overall cohort, palbociclib, abemaciclib and ribociclib). All, CDK4/6 inhibitors.

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  FIGURE 7. Multivariate logistic regression analysis of the ratios of cardiotoxic events associated with CDK4/6 inhibitors. This forest plot illustrates the adjusted odds ratios and 95% CI for factors influencing the reporting of cardiotoxicity associated with CDK4/6 inhibitors, derived from a multivariate logistic regression model. The analysis was adjusted for age (reference: 65 ≤ AGE <85), sex (reference: male), type of CDK4/6 inhibitor (reference: ribociclib), and specific comorbidities (reference: use of letrozole, anastrozole, exemestane or fulvestrant). Statistical significance is denoted by asterisks: *** (p < 0.001), ** (p < 0.01), and * (p < 0.05). Abbreviations: OR, odds ratios; X, represents the independent variables; Y, represents the dependent variables; 95%CI, the 95% confidence interval.

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  FIGURE 8. Regression analysis of hospitalization and death related to serious adverse events of CDK4/6 inhibitors. Abbreviations: OR, odds ratios; X, represents the independent variables; Y, represents the dependent variables. HO, hospitalization; DE, death.

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  FIGURE 9. Cloud and rain plots illustrating the onset timing of cardiovascular adverse reactions across distinct combination regimens. (A,E) show cardiac arrhythmias; (B,F) represent embolic and thrombotic events; (C,G) indicate QT prolongation; (D,H) correspond to shock. The bar graphs below present outcome indicators for cardiovascular adverse events related to these combination therapies.