Cardiotoxicity associated with tyrosine kinase inhibitor sunitinib
Tammy F Chu1, Maria A Rupnick, Risto Kerkela
1Department of Cardiology, Children's Hospital Boston and Harvard Medical School, Boston, MA 02115, USA.
Background:
Sunitinib, a multitargeted tyrosine-kinase inhibitor, which is approved by both US and European Commission regulatory agencies for clinical use, extends survival of patients with metastatic renal-cell carcinoma and gastrointestinal stromal tumours, but concerns have arisen about its cardiac safety. We therefore assessed the cardiovascular risk associated with sunitinib in patients with metastatic gastrointestinal stromal tumours.
Methods:
We retrospectively reviewed all cardiovascular events in 75 patients with imatinib-resistant, metastatic, gastrointestinal stromal tumours who had been enrolled in a phase I/II trial investigating the efficacy of sunitinib. The composite cardiovascular endpoint was cardiac death, myocardial infarction, and congestive heart failure. We also examined sunitinib's effects on left ventricular ejection fraction (LVEF) and blood pressure. We investigated potential mechanisms of sunitinib-associated cardiac effects by studies in isolated rat cardiomyocytes and in mice.
Findings:
Eight of 75 (11%) patients given repeating cycles of sunitinib in the phase I/II trial had a cardiovascular event, with congestive heart failure recorded in six of 75 (8%). Ten of 36 (28%) patients treated at the approved sunitinib dose had absolute LVEF reductions in ejection fraction (EF) of at least 10%, and seven of 36 (19%) had LVEF reductions of 15 EF% or more. Sunitinib induced increases in mean systolic and diastolic blood pressure, and 35 of 75 (47%) individuals developed hypertension (>150/100 mm Hg). Congestive heart failure and left ventricular dysfunction generally responded to sunitinib being withheld and institution of medical management. Sunitinib caused mitochondrial injury and cardiomyocyte apoptosis in mice and in cultured rat cardiomyocytes.
Interpretation:
Left ventricular dysfunction might be due, in part, to direct cardiomyocyte toxicity, exacerbated by hypertension. Patients treated with sunitinib should be closely monitored for hypertension and LVEF reduction, especially those with a history of coronary artery disease or cardiac risk factors.
Insights
Sunitinib treatment for gastrointestinal stromal tumours can cause cardiovascular events, including heart failure and reduced left ventricular ejection fraction (LVEF). Close monitoring for hypertension and LVEF changes is recommended for patients receiving sunitinib.
Area of Science:
- Cardiovascular research
- Oncology
- Pharmacology
Background:
- Sunitinib is an approved tyrosine-kinase inhibitor extending survival for metastatic cancers.
- Concerns exist regarding sunitinib's cardiac safety profile.
- This study assesses cardiovascular risk in metastatic gastrointestinal stromal tumour (GIST) patients treated with sunitinib.
Purpose of the Study:
- To evaluate the cardiovascular risk associated with sunitinib in patients with metastatic GIST.
- To investigate sunitinib's impact on left ventricular ejection fraction (LVEF) and blood pressure.
- To explore potential mechanisms of sunitinib-induced cardiac effects.
Main Methods:
- Retrospective review of cardiovascular events in 75 patients with imatinib-resistant metastatic GIST.
- Analysis of composite cardiovascular endpoints: cardiac death, myocardial infarction, congestive heart failure.
- In vitro and in vivo studies using rat cardiomyocytes and mice to investigate cardiac toxicity mechanisms.
Main Results:
- 11% of patients experienced cardiovascular events, with 8% developing congestive heart failure.
- 28% of patients at the approved dose showed LVEF reductions of at least 10%.
- 47% of patients developed hypertension; sunitinib induced cardiomyocyte apoptosis and mitochondrial injury.
Conclusions:
- Left ventricular dysfunction may result from direct cardiomyocyte toxicity and hypertension.
- Patients on sunitinib require close monitoring for hypertension and LVEF reduction.
- Individuals with pre-existing cardiac conditions should be particularly cautious.
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