Major Adverse Cardiovascular Events in Patients With Renal Cell Carcinoma Treated With Targeted Therapies

Abstract

Background: The risk for major adverse cardiovascular events (MACE) with targeted therapies for patients with advanced renal cell carcinoma (RCC) in real-world practice remains unclear.

Objectives: The aim of this study was to compare the risk for MACE associated with targeted cancer therapies with that associated with cytokine treatment in patients with advanced RCC.

Methods: Using Taiwan's National Health Insurance Research Database, a retrospective nationwide cohort study was conducted involving patients with advanced RCC who had received targeted therapy (sunitinib, sorafenib, pazopanib, everolimus, or temsirolimus) or cytokine therapy (interleukin-2 or interferon gamma) from 2007 to 2018. Cox proportional hazards models were used to estimate the risk for MACE (a composite of myocardial infarction, ischemic stroke, heart failure, and cardiovascular death) in the cohort using the propensity score method of stabilized inverse probability of treatment weighting.

Results: In this cohort of 2,785 patients with advanced RCC, 2,257 (81%) and 528 (19%) had received targeted and cytokine therapy, respectively. After stabilized inverse probability of treatment weighting, the incidence rates of MACE were 6.65 and 3.36 per 100 person-years in the targeted and cytokine therapy groups, respectively (HR: 1.80; 95% CI: 1.19-2.74). Baseline history of heart failure (HR: 3.88; 95% CI: 2.25-6.71), atrial fibrillation (HR: 3.60; 95% CI: 2.16-5.99), venous thromboembolism (HR: 2.50; 95% CI: 1.27-4.92), ischemic stroke (HR: 1.88; 95% CI: 1.14-3.11), and age ≥ 65 years (HR: 1.81; 95% CI: 1.27-2.58) were independent risk factors for targeted therapy-associated MACE.

Conclusions: Among patients with advanced RCC, the risk for MACE associated with targeted cancer therapy is higher than that associated with cytokine therapy.

Keywords: CV, cardiovascular; GBM, generalized boosted model; MACE, major adverse cardiovascular event(s); NHIRD, National Health Insurance Research Database; RCC, renal cell carcinoma; TKI, tyrosine kinase inhibitor; VEGF, vascular endothelial growth factor; VEGFR, vascular endothelial growth factor receptor; cardiovascular toxicity; mTOR, mechanistic target of rapamycin; renal cell carcinoma; sIPTW, stabilized inverse probability of treatment weighting; targeted cancer therapy.

Graphical abstract

Figure 1

Enrollment and Follow-Up of Study Patients From 2007 to 2018, 16,366 patients with incident renal cell carcinoma (RCC) were identified. After relevant exclusion, 2,785 patients with advanced RCC were included in the study, of whom 2,257 (81.0%) and 528 (19.0%) received targeted therapy and cytokine therapy. Stabilized inverse probability of treatment weighting was used to balance baseline characteristics. Risks for major adverse cardiovascular events were compared between the 2 study groups.

Figure 2

Fine and Gray Cumulative Incidence Rates of MACE and CV Death After adjustment for competing risk events (noncardiovascular deaths), the risks for (A) major adverse cardiovascular events (MACE) and (B) cardiovascular (CV) death were consistently higher in the targeted therapy group than in the cytokine therapy group. sHR = subdistribution hazard ratio.

Figure 3

Risk for MACE by Subgroup Patients receiving targeted therapy had a higher risk for MACE than did those receiving cytokine therapy regardless of age or conventional CV risk factors (coronary artery disease, diabetes, hypertension, hyperlipidemia, and chronic kidney disease). When dividing the targeted cancer therapy group into the vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitor (TKI) and mechanistic target of rapamycin (mTOR) inhibitor subgroups, the VEGFR TKI and mTOR inhibitor subgroups had an individually higher risk for MACE than did the cytokine therapy group, and the interaction effect of higher CV risk was more apparent in the mTOR inhibitor subgroup (interaction P = 0.047). Inc = incidence rate (per 100 person-years); other abbreviations as in Figure 2.

Figure 4

Fine and Gray Cumulative Incidence Rates of MACE for Each Targeted Therapy Type There were significant differences in MACE risk among patients treated with different VEGFR TKIs and mTOR inhibitors. The incidence of MACE was higher among patients receiving temsirolimus or sorafenib than among those receiving sunitinib therapy. Abbreviations as in Figures 2 and 3.

Central Illustration

Increased Risk for Major Adverse Cardiovascular Events Associated With Targeted Therapies for Advanced Renal Cell Carcinoma The incidence of major adverse cardiovascular events (MACE) was higher in the targeted therapy group than in the cytokine therapy group. In patients with advanced renal cell carcinoma, prior heart failure, atrial fibrillation, venous thromboembolism, ischemic stroke, and age ≥65 years were risk factors for MACE. MACE served as a composite endpoint of myocardial infarction (MI), ischemic stroke, heart failure (HF), and cardiovascular death.