Tyrosine kinase-targeting drugs-associated heart failure

Abstract

Background: The impact of cancer therapies on cardiac disease in the general adult cancer survivor population is largely unknown. Our objective was to evaluate which tyrosine kinase-targeting drugs are associated with greater risk for new-onset heart failure (HF).

Methods: A nested case-control analysis was conducted within a cohort of 27 992 patients of Clalit Health Services, newly treated with a tyrosine kinase-targeting, and/or chemotherapeutic drug, for a malignant disease, between 1 January 2005 and 31 December 2012. Each new case of HF was matched to up to 30 controls from the cohort on calendar year of cohort entry, age, gender, and duration of follow-up. Main outcome measure was odds ratio (OR) with 95% confidence interval (CI) of new-onset HF.

Results: There were 936 incident cases of HF during 71 742 person-years of follow-up. Trastuzumab (OR 1.90, 95% CI 1.46-2.49), cetuximab (OR 1.72, 1.10-2.69), panitumumab (OR 3.01, 1.02-8.85), and sunitinib (OR 3.39, 1.78-6.47) were associated with increased HF risk. Comorbidity independently associated with higher risk in a multivariable conditional regression model was diabetes mellitus, hypertension, chronic renal failure, ischaemic heart disease, valvular heart disease, arrhythmia, and smoking.

Conclusions: Trastuzumab, cetuximab, panitumumab, and sunitinib are associated with increased risk for new-onset HF.

Figure 1

Forest plot showing the risk of developing new-onset heart failure associated with tyrosine kinase-targeting and anti-CD20 drugs.Nested case–control study (N=26 312) matched by age, gender, duration of follow-up, and calendar year of cohort entry, within a cohort of patients newly diagnosed with malignant diseases and treated systemically. Multivariable model adjusted for diabetes mellitus, hypertension, hyperlipidaemia, ischaemic heart disease, peripheral vascular disease, carotid artery disease, atrial fibrillation, other arrhythmias, valvular heart disease, chronic renal failure, cirrhosis, obesity, smoking, alcohol abuse, drug abuse, class I and III antiarrhythmics, thiazolidinediones, systemic corticosteroids, non-steroidal anti-inflammatory drugs, systemic antimycotics imidazole and triazole derivatives, tumour necrosis factor alpha inhibitors, everolimus, temsirolimus, clozapine, colony-stimulating factors, gonadotropin-releasing hormone analogues, radiotherapy, the chemotherapy groups including: nitrogen mustard analogues, other alkylating agents, folic acid analogues, purine analogues, pyrimidine analogues, vinca alkaloids and analogues, etoposide, taxanes, anthracyclines and related substances, bleomycin, mitomycin, platinum compounds, procarbazine, other chemotherapeutics (estramustine, tretinoin, mitotane, pegaspargase, arsenic trioxide, anagrelide, and visemodegib), hydroxycarbamide, bortezomib, topotecan, and irinotecan, and hospital admission duration.