Major adverse cardiovascular events associated with VEGF-targeted anticancer tyrosine kinase inhibitors: a real-life study and proposed algorithm for proactive management

Abstract

Background Vascular endothelial growth factor receptor (VEGFR)-targeted tyrosine kinase inhibitors (TKIs) are widely used in cancer treatment and burdened by cardiovascular toxicity. The majority of data come from clinical trials, thus in selected populations. The aim of our study is to evaluate the cardiotoxicity profile of VEGFR-targeted TKIs and the impact of cardiovascular risk factors in a real-life population. Patients and methods In this cohort, population-based study, patients treated with VEGFR-targeted TKIs, bevacizumab and trastuzumab between 2009 and 2014 were analyzed. A multi-source strategy for data retrieval through hospital, pharmaceutical and administrative databases of the Lombardy region, Italy, has been adopted. The primary endpoint was to determine the incidence and type of major adverse cardiovascular events (MACEs) along with their temporal trend. The secondary endpoint was to define the impact of cardiovascular risk factors in the occurrence of MACEs. Results A total of 829 patients were treated with VEGFR-targeted TKIs. Eighty-one MACEs occurred in the first year of follow-up [crude cumulative incidence (CCI): 9.79%] mainly consisting of arterial thrombotic events (ATEs, 31 events, CCI: 3.99%), followed by rhythm disorders (22 events, CCI: 2.66%), pulmonary embolisms and heart failures (13 events each, CCI: 1.57%). While the incidence of most MACEs showed a plateau after 6 months, ATEs kept increasing along the year of follow-up. Hypertension and dyslipidemia were associated with an increase in risk of ATEs [relative risk difference (RRD) +209.8% and +156.2%, respectively], while the presence of previous MACEs correlated with a higher risk of all MACEs in multivariate analysis (RRD 151.1%, 95% confidence interval 53.6% to 310.3%, P < 0.001). Conclusions MACEs occur in a clinically significant proportion of patients treated with VEGFR-targeted TKIs, with ATEs being predominant, mainly associated with hypertension and dyslipidemia. A clinical algorithm for effective proactive management of these patients is warranted.

Cardiotoxicity of Selected Vascular Endothelial Growth Factor Receptor Tyrosine Kinase Inhibitors in Patients with Renal Cell Carcinoma

“…The occurrence of cardiotoxicity could be underestimated in some studies since many clinical trials exclude patients with cardiovascular diseases [141]. A real-life setting study of major adverse cardiovascular events (MACE) incidence in patients treated with TKI revealed that arterial thrombotic events occurred in 3.99% of study participants, rhythm disorders (atrial fibrillation, atrioventricular block) in 2.66%, and pulmonary embolism and heart failure in 1.57% at 1 year of follow-up [141]. According to the authors, a high incidence of atrial fibrillation in the early period of therapy was associated with an anti-VEGFR treatment-related increase in blood pressure and diastolic dysfunction of the left ventricle.…”

Cardiovascular toxicity associated with angiogenesis inhibitors: A comprehensive pharmacovigilance analysis based on the FDA Adverse Event Reporting System database from 2014 to 2021

“…Although the application of angiogenesis inhibitors has revolutionized the therapy and substantially improved the outcomes for patients with a variety of malignancies, their side effects, especially cardiovascular toxicity, have been increasingly recognized along with their curative effects (1,2,(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20). Nevertheless, the real profiles of cardiovascular toxicity associated with angiogenesis inhibitors are still unclear due to scarce evidence in the real-world setting (20).…”

“…Although the application of angiogenesis inhibitors has revolutionized the therapy and substantially improved the outcomes for patients with a variety of malignancies, their side effects, especially cardiovascular toxicity, have been increasingly recognized along with their curative effects (1,2,(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20). Nevertheless, the real profiles of cardiovascular toxicity associated with angiogenesis inhibitors are still unclear due to scarce evidence in the real-world setting (20). To the best of our knowledge, this is the first comprehensive pharmacovigilance study on cardiovascular toxicity associated with angiogenesis inhibitors by leveraging the FAERS database, involving the frequency, spectrum, timing, and outcomes of cardiovascular toxicity, as well as the extensive comparison of such patterns between mAbs and TKIs with anti-VEGF(R) activity.…”

“…As for the time to onset of cardiovascular AEs, in Österlund's study ( 31 ), the median time to the onset of hypertension was 1 month (range of 1–15 months and within 6 months in 95%), as calculated from the start of bevacizumab treatment. In addition, a real-life study on the TKI cohort showed that the cumulative incidence of thrombotic events kept increasing all along the first year of treatment ( 20 ). Nevertheless, no study to date has investigated the disparity of timing according to different types of cardiovascular AEs associated with angiogenesis inhibitors.…”

“…Despite the remarkable anti-tumor effects of angiogenesis inhibitors in a variety of cancer cases, emerging evidence has shown cardiovascular toxicity associated with angiogenesis inhibitors (6)(7)(8). Although hypertension has received the most attention, a wider range of cardiovascular toxicity, including left ventricular systolic dysfunction, heart failure, myocardial ischemia, thromboembolic events, QT interval prolongation, and arrhythmia, has also been increasingly recognized (1,2,(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20). However, the majority of these data were from clinical trials, conducted in selected populations, which may underestimate the real burden of cardiovascular toxicity.…”