Comparative Venous and Arterial Thromboembolism Profiles Associated with Different Cyclin-Dependent Kinase 4/6 Inhibitors: A Real-World Study

Introduction: Cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors are used in conjunction with endocrine therapy in hormone receptor-positive breast cancer. Recent data from clinical trials and real-world observational studies have reported an increased venous and arterial thromboembolism rates associated with CDK4/6 inhibitors. However, there has been limited data on the comparative thromboembolism rates among different types of CDK4/6 inhibitors. To address this knowledge gap, we leveraged a large global database to compare the thromboembolism profiles among different CDK4/6 inhibitors. Methods: We performed a retrospective, propensity score-matched cohort study using the TriNetX Analytics Network database, which includes de-identified electronic health records from over 70 healthcare organizations and 101 million individuals. We included adult female breast cancer patients who received an aromatase inhibitor (AI) and a CDK4/6 inhibitor from February 2015 to June 2023. We excluded patients with a prior history of venous thromboembolism (VTE), arterial thromboembolism (ATE), atrial fibrillation, and those who received oral anticoagulation. The index date was determined as the start date of AI and CDK4/6 inhibitor therapy. The primary outcomes were VTE, which was defined as a composite of pulmonary embolism (PE) and deep venous thrombosis (DVT), and ATE, which was defined as a composite of myocardial infarction and ischemic stroke. The secondary outcomes were individual components of VTE and ATE. All outcomes were captured within 1 year of the index date. Cohorts were matched using a propensity score that incorporated variables such as age, sex, race, underlying comorbidities, components of the Khorana score, and breast cancer-directed therapy. Results: We identified a total of 8912 patients eligible for inclusion, among which 6632 received palbociclib, 790 received ribociclib, and 1490 received abemaciclib. After propensity score matching, cohorts were well-balanced across variables including age, sex, race, underlying comorbidities, Khorana score, and breast cancer-directed therapy. When compared with patients who received palbociclib, patients who received ribociclib had a lower incidence of composite VTE (2.6 vs. 4.1 events per 100 patient-years) and PE (0.6 vs. 2.8 events per 100 patient-years). Patients who received ribociclib had a trend towards a lower risk of VTE (Hazard ratio (HR), 0.63 [95% CI: 0.36-1.10]) than those who received palbociclib. Similarly, when compared with patients who received abemaciclib, patients who received ribociclib had a lower incidence of VTE (2.4 vs. 5.5 events per 100 patient-years) and PE (0.6 vs. 3.6 events per 100 patient-years). Patients who received ribociclib had an approximately 60% lower risk of VTE (Hazard ratio (HR), 0.42 [95% CI: 0.23-0.76]) than those who received abemaciclib. The risk of DVT was similar among patients receiving palbociclib, ribociclib, or abemaciclib. There were no differences in the rates of composite ATE, myocardial infarction, or ischemic stroke among the different types of CDK4/6 inhibitor. Conclusions: Conclusion: Ribociclib is associated with a lower risk of VTE, particularly PE, compared with palbociclib or abemaciclib in breast cancer patients undergoing endocrine therapy.