Cardiovascular toxicity of angiogenesis inhibitors in treatment of malignancy: A systematic review and meta-analysis

Abstract

Background: The cardiovascular risk of angiogenesis inhibitors is not well-quantified. We hypothesized that, compared to direct vascular endothelial growth factor (VEGF) inhibitors (anti-VEGF antibodies or decoy receptors), small molecule agents have higher risk due to their less specific mechanism.

Methods: We searched the MEDLINE, EMBASE, and Cochrane Central Register of Controlled Trials for phase III randomised controlled trials comparing angiogenesis inhibitor-based therapy to other systemic therapy. Outcomes evaluated were hypertension, severe hypertension, cardiac dysfunction, congestive heart failure, cardiac ischemia, arterial thromboembolism, venous thromboembolism, and fatal cardiovascular events. Data were pooled using Mantel-Haenszel random effects method to generate odds ratios (OR).

Results: We identified 77 studies meeting inclusion criteria. Compared to routine care, angiogenesis inhibitors were associated with a higher risk of hypertension (OR 5.28 [4.53-6.15], number needed to harm [NNH] 6), severe hypertension (OR 5.59 [4.67-6.69], NNH 17), cardiac ischemia (OR 2.83 [1.72-4.65], NNH 85) and cardiac dysfunction (OR 1.35 [1.06-1.70], NNH 139). VEGF inhibitors were associated with an increased risk of arterial thromboembolism (OR 1.52 [1.17-1.98], NNH 141). No significant interaction was observed between the two drug subgroups for any outcomes. We identified no significant increase in the risk of the other outcomes evaluated.

Conclusion: Angiogenesis inhibitors increase the risk of hypertension, arterial thromboembolism, cardiac ischemia and cardiac dysfunction. There was no significant difference in cardiovascular risk between direct VEGF inhibitors and small molecule agents.

Keywords: Aflibercept; Angiogenesis inhibitors; Antineoplastic agents/adverse effects; Bevacizumab; Cardiotoxins; Sorafenib; Sunitinib; Vandetanib; Vascular endothelial growth factor.