Cardiotoxicity associated with tyrosine kinase inhibitor sunitinib.
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.


RESULTS
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.


CONCLUSIONS
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.
Chu
Tammy F
TF
Department of Cardiology, Children's Hospital Boston and Harvard Medical School, Boston, MA 02115, USA.
Rupnick
Maria A
MA
Kerkela
Risto
R
Dallabrida
Susan M
SM
Zurakowski
David
D
Nguyen
Lisa
L
Woulfe
Kathleen
K
Pravda
Elke
E
Cassiola
Flavia
F
Desai
Jayesh
J
George
Suzanne
S
Morgan
Jeffrey A
JA
Harris
David M
DM
Ismail
Nesreen S
NS
Chen
Jey-Hsin
JH
Schoen
Frederick J
FJ
Van den Abbeele
Annick D
AD
Demetri
George D
GD
Force
Thomas
T
Chen
Ming Hui
MH
D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects* / Q000627:therapeutic use; D001794:Blood Pressure / Q000187:drug effects; D005260:Female; D046152:Gastrointestinal Stromal Tumors / Q000188:drug therapy; D006333:Heart Failure / Q000139:chemically induced*; D006801:Humans; D007211:Indoles / Q000009:adverse effects* / Q000627:therapeutic use; D008297:Male; D051379:Mice; D008875:Middle Aged; D015337:Multicenter Studies as Topic; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D011758:Pyrroles / Q000009:adverse effects* / Q000627:therapeutic use; D051381:Rats; D012189:Retrospective Studies; D013318:Stroke Volume / Q000187:drug effects; D000077210:Sunitinib
D000970:Antineoplastic Agents; D007211:Indoles; D011758:Pyrroles; D011505:Protein-Tyrosine Kinases; D000077210:Sunitinib