Cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors have revolutionized the treatment of hormone receptor-positive metastatic breast cancer by significantly improving patient survival. However, while these therapies have proven effective against cancer, there is a notable gap in our understanding of their cardiovascular safety profile. In particular, the epidemiology of cardiovascular adverse events (CVAEs) associated with CDK4/6 inhibitors remains poorly characterized.

In this study, we leveraged the OneFlorida Data Trust to identify adult patients without prior cardiovascular disease who had received at least one CDK4/6 inhibitor. Using ICD-9/10 codes, we tracked a range of CVAEs, including hypertension, atrial fibrillation/atrial flutter (AF/AFL), heart failure or cardiomyopathy, ischemic heart disease, and pericardial disease. To assess the relationship between CDK4/6 inhibitor therapy and the onset of CVAEs, we applied a competing risk analysis using the Fine-Gray model. The impact of these adverse events on overall survival was further evaluated using Cox proportional hazards models, and we employed propensity-weighted analyses to compare our findings with a cohort of patients treated with anthracyclines.

Our analysis included 1,376 patients treated with CDK4/6 inhibitors. We found that 24% of these patients experienced CVAEs, equating to an incidence rate of 35.9 events per 100 person-years. There was a trend toward a higher incidence of CVAEs in the CDK4/6 inhibitor group compared with patients receiving anthracyclines (P = 0.063). More importantly, the development of AF/AFL or cardiomyopathy/heart failure in patients receiving CDK4/6 inhibitors was strongly associated with increased all-cause mortality. Specifically, the adjusted hazard ratio for death was 4.89 (95% CI, 2.98–8.05) for cardiomyopathy/heart failure and 5.88 (95% CI, 3.56–9.73) for AF/AFL.

In summary, our findings indicate that cardiovascular adverse events may be more common with CDK4/6 inhibitors than previously appreciated, and that these events, particularly AF/AFL and heart failure, significantly elevate the risk of death in this patient population. These results underscore the need for further research to more definitively determine the cardiovascular risks associated with these novel anticancer treatments and to guide strategies for mitigating these risks while maximizing therapeutic benefits. K03861