N. Gronich,1 I. Lavi,1 O. Barnett,1 D. R. Abernethy,2 G. Rennert1; 1Carmel Medical Center, Haifa, Israel, 2US Food and Drug Administration, Silver Spring, MD

BACKGROUND: Tyrosine kinases targeting drugs, including small molecule tyrosine kinase inhibitors and monoclonal antibodies, have been shown to increase survival in hematological and solid malignancies. As many patients will have prolonged post-treatment survival late side effects become an important consideration, among them is induction of heart failure. We aimed to evaluate which tyrosine kinase targeting drugs are associated with congestive heart failure (CHF) risk, and to assess risk factors to develop CHF.
METHODS: Retrospective cohort study using a nested case-control analysis within Israeli Clalit Health Services database. Participants: A cohort of 30,902 patients newly treated with a tyrosine kinase targeting drug and/or chemotherapeutic drug for a newly diagnosed malignant disease between 1.1.2005 and 31.12.2012. All incident cases of CHF occurring during follow up were identified and matched to up to 30 controls from the cohort, on calendar year, age, gender, and duration of follow up.
RESULTS: 936 cases were newly diagnosed with CHF during 71,742 person years of follow up (incidence rate 1,305/100,000 person years). Trastuzumab (odds ratio 1.90, 95% confidence interval 1.46 to 2.49), cetuximab (odds ratio 1.72, 1.10 to 2.69), panitumumab (odds ratio 3.01, 1.02 to 8.85), and sunitinib (odds ratio 3.39, 1.78 to 6.47) were associated with new-onset CHF. No dose-toxicity or duration- toxicity effects were observed. Comorbidities associated with higher risk included: diabetes mellitus, hypertension, chronic renal failure, ischemic heart disease, valvular heart disease, arrhythmia, and smoking.
CONCLUSION: Treatment with trastuzumab, cetuximab, panitumumab and sunitinib is associated with increased risk of new-onset CHF in patients with malignant diseases.