Risk of arterial thromboembolic events with vascular endothelial growth factor receptor tyrosine kinase inhibitors: an up-to-date meta-analysis

Abstract

Purpose: Arterial thromboembolic events (ATEs) with vascular endothelial growth factor receptor tyrosine kinase inhibitors (VEGFR-TKIs) have emerged as a serious concern, we perform a meta-analysis of randomized controlled trials (RCTs) to determine the incidence and risk of ATEs in cancer patients treated with these agents.

Methods: The databases of PubMed and Web of Science were searched for relevant articles. Statistical analyses were conducted to calculate the summary incidence, odds ratio (OR), and 95% confidence intervals (CIs) by using either random effects or fixed effect models according to the heterogeneity of included studies.

Results: A total of 9711 patients from 19 RCTs were included. The overall incidence of ATEs was 1.5% (95%CI: 1.0-2.3%). The use of VEGFR-TKIs significantly increased the risk of developing ATEs when compared with controls (OR 2.26, 95%CI: 1.38-3.68, p=0.001). Sensitivity analysis indicated that the significance estimate of pooled ORs was not significantly influenced by omitting any single study. In subgroup analyses, the odds ratio of ATEs did not significantly vary with tumor types (p=0.70), VEGFR-TKIs (p=0.32), treatment regimens (p=0.76), phase of trials (p=0.37) and sample size (p=0.89). Additionally, the most common events for ATEs were cardiac ischemia/infarction (67.4%), CNS ischemia (7.9%) and cerebrovascular accident (6.7%).

Conclusion: In this largest meta-analysis to date, we find that treatment with VEGFR-TKIs significantly increase the risk of developing ATEs. Further studies are still needed to investigate this association. In the appropriate clinical scenario, the use of these drugs remains justified in their approved indications.

Keywords: Angiogenesis inhibitors; Arterial thromboembolic events; Meta-analysis; VEGFR–TKIs.