Adverse Cardiovascular Events Associated With Cyclin-Dependent Kinase 4/6 Inhibitors in Patients With Metastatic
Michael G Fradley1, Nam H K Nguyen2, David Madnick3
1Cardio-Oncology Center of Excellence, Division of Cardiology, Department of Medicine Perelman School of Medicine at the University of Pennsylvania Philadelphia PA.
Abstract:
Background Cyclin-dependent kinase (CDK) 4 and 6 inhibitors have significantly improved survival in patients with hormone receptor-positive metastatic breast cancer. There are few data regarding the epidemiology of cardiovascular adverse events (CVAEs) with these therapies. Methods and Results Using the OneFlorida Data Trust, adult patients without prior cardiovascular disease who received at least 1 CDK4/6 inhibitor were included in the analysis. CVAEs identified from International Classification of Diseases, Ninth and Tenth Revisions (ICD-9/10) codes included hypertension, atrial fibrillation(AF)/atrial flutter (AFL), heart failure/cardiomyopathy, ischemic heart disease, and pericardial disease. Competing risk analysis (Fine-Gray model) was used to determine the association between CDK4/6 inhibitor therapy and incident CVAEs. The effect of CVAEs on all-cause death was studied using Cox proportional hazard models. Propensity-weight analyses were performed to compare these patients to a cohort of patients treated with anthracyclines. A total of 1376 patients treated with CDK4/6 inhibitors were included in the analysis. CVAEs occurred in 24% (35.9 per 100 person-years). CVAEs were slightly higher in patients who received CKD4/6 inhibitors compared with anthracyclines (P=0.063), with higher death rate associated with the development of AF/AFL or cardiomyopathy/heart failure in the CDK4/6 group. The development of cardiomyopathy/heart failure and AF/AFL was associated with increased all-cause death (adjusted hazard ratio [HR], 4.89 [95% CI, 2.98-8.05]; and 5.88 [95% CI, 3.56-9.73], respectively). Conclusions CVAEs may be more common with CDK4/6 inhibitors than previously recognized, with increased death rates in these patients who develop AF/AFL or heart failure. Further research is needed to definitively determine cardiovascular risk associated with these novel anticancer treatments.
Insights
Cardiovascular adverse events (CVAEs) may be more common with cyclin-dependent kinase (CDK) 4/6 inhibitors than expected. These events, particularly heart failure and atrial fibrillation, are linked to increased mortality in breast cancer patients.
Area of Science:
- Oncology
- Cardiology
- Pharmacology
Background:
- Cyclin-dependent kinase (CDK) 4 and 6 inhibitors improve survival in metastatic breast cancer.
- Limited data exist on the cardiovascular adverse events (CVAEs) associated with CDK4/6 inhibitors.
Purpose of the Study:
- To investigate the epidemiology of CVAEs in patients treated with CDK4/6 inhibitors.
- To assess the association between CDK4/6 inhibitor therapy and incident CVAEs.
- To determine the impact of CVAEs on all-cause mortality.
Main Methods:
- Retrospective analysis of adult patients without prior cardiovascular disease who received CDK4/6 inhibitors using the OneFlorida Data Trust.
- Identification of CVAEs using ICD-9/10 codes.
- Competing risk analysis (Fine-Gray model) and Cox proportional hazard models were employed.
- Propensity-weight analyses compared CDK4/6 inhibitor patients to anthracycline-treated patients.
Main Results:
- 1376 patients treated with CDK4/6 inhibitors were analyzed.
- CVAEs occurred in 24% of patients (35.9 per 100 person-years).
- CVAEs were slightly higher in the CDK4/6 inhibitor group compared to anthracyclines (P=0.063).
- Development of atrial fibrillation/flutter (AF/AFL) or cardiomyopathy/heart failure was associated with increased all-cause death (HRs 5.88 and 4.89, respectively).
Conclusions:
- CVAEs may be more frequent with CDK4/6 inhibitors than previously recognized.
- Increased mortality is associated with AF/AFL or heart failure in patients receiving CDK4/6 inhibitors.
- Further research is needed to fully understand the cardiovascular risks of these novel anticancer agents.
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