Cardiovascular Effects of Tyrosine Kinase Inhibitors in Patients With Advanced Renal Cell Carcinoma at the VA San Diego Healthcare System

Methods

Each year, the VASDHS oncology team diagnose 5 to 10 patients with RCC who begin TKI therapy. When sorafenib was approved by the FDA in 2005, VASDHS estimated that about 100 of its patients had an RCC diagnosis and would be treated with a TKI between December 2005 and July 2017.

The authors identified VASDHS patients with a diagnosis of advanced RCC who received axitinib, cabozantinib, pazopanib, sorafenib, or sunitinib between December 1, 2005 and July 31, 2017. Patients were included if they had been on therapy for at least 30 days. The VASDHS pharmacy informatics team assisted in extracting a list of patients with an ICD-9 or ICD-10 diagnosis of RCC and using prescription fills for any of the 5 TKIs previously noted. Medical records were reviewed for frequency of prescription fills, age, sex, Eastern Cooperative Oncology Group (ECOG) performance status, TKI treatment duration, previous history of CVD, ethnicity, and smoking status. If documented, the incidence of CV events was reviewed for each patient at 0, 1, 3, 6, and 12 months. Patients who received medications (Appendix) for their CVD were assessed for adherence based on history of prescription refills from their medical records. Adherence was evaluated for the duration that patients were concurrently taking an oral TKI. The institutional review board at VASDHS approved the study design.

All patients included in this study started TKI therapy since the December 2005 FDA approval of sorafenib, the first oral TKI for treatment of RCC. Each new start was recorded as a separate event, regardless of previous oral TKI therapy. Albiges and colleagues found that the approximate median time from starting TKI therapy to complete response was 12.6 months, and the median duration of TKI therapy after complete response was 10.3 months.¹¹ Based on these results, the follow-up period for patients in this study was 2 years after the start of each TKI therapy. For data analysis, patients were stratified by CVD history (yes or no). In addition, composite outcomes were evaluated to identify a potential cumulative increased risk for CV events for patients who had been on multiple TKI therapies.

For this study, CV toxicities were characterized using Common Terminology Criteria for Adverse Events (CTCAE) version 4.03; severity of adverse events (AEs) was graded 1 to 5. CTCAE commonly has been used to assess AEs in oncology clinical trials. The CV AEs selected for this study included QTc prolongation, hypertension, left ventricular dysfunction, stroke, myocardial infarction (MI), and pulmonary arterial hypertension. CTCAE was not used to assess left ventricular dysfunction, as the rating is based on symptomology. Instead, worsening left ventricular ejection fraction (LVEF) was based on comparisons of ECG results at baseline with results at 1, 3, 6, and 12 months. A normal ECG result was defined as no structural change in the left ventricle, or LVEF ≥ 55%, and an abnormal result was defined as structural changes in the left ventricle, or LVEF < 55%. Given updates in blood pressure (BP) guidelines and uncertainty regarding the clinical utility of prehypertension, grade 1 hypertension was excluded as an AE.