Hypertension Related to VEGF Inhibitors

Mechanisms of VEGF inhibitor-induced hypertension need to be better understood and guidelines developed to improve management

New cancer therapies, particularly agents that block vascular endothelial growth factor (VEGF) signaling, have improved the outlook for patients with some cancers and are now used as a first line therapy for some tumours. However, almost 100% of patients who take VEGF inhibitors (VEGFIs) develop high blood pressure, and a subset develops severe hypertension. The mechanisms underlying VEGF inhibitor-induced hypertension need to be better understood and there is a need for clear guidelines and improved management, say investigators in a review article published in the Canadian Journal of Cardiology.

A side effect of treatment or mechanism-dependent on-target toxicity

"Exactly how VEGFIs cause hypertension is unknown. However, what is clear is that inhibition of VEGF in the vasculature directly increases blood pressure because hypertension develops acutely in response to VEGFIs and blood pressure returns to normal once the treatment is stopped," says senior investigator Dr Rhian Touyz of the Institute of Cardiovascular and Medical Sciences, University of Glasgow, Scotland.

When VEGF and other endothelial growth factors bind to their receptors on endothelial cells, signals within these cells are initiated that promote the growth and survival of new blood vessels, which are necessary for tumour growth. Angiogenesis inhibitors interfere with various steps in this process.

Increased blood pressure has been observed in every trial involving VEGFIs and is the most common cardiovascular complication. It has an associated increased risk of fatal adverse cardiovascular events. VEGFI-induced hypertension is a dose-dependent phenomenon.

According to some studies, VEGFI-induced hypertension is not a side effect of treatment, but rather a mechanism-dependent on-target toxicity. This has led to the concept that hypertension might be indicative of effective VEGF inhibition and a positive antiangiogenic response, and as such could be a biomarker of a favourable outcome from VEGFI treatment. "This further adds to the challenges, because improved cancer responsiveness might thus be associated with potentially greater cardiovascular risk," notes Dr Touyz.

Molecular mechanisms and risk factors for VEGFI-induced hypertension

Molecular mechanisms underlying VEGFI-induced hypertension are unclear, but endothelial dysfunction and increased vascular resistance, due to impaired nitric oxide signalling, reduced prostacyclin production, endothelin-1 (ET-1) upregulation, oxidative stress, and rarefaction have been implicated.

The exact factors that predispose to VEGFI-induced hypertension still remain to be established, according to authors of the article. However, risk factors that have been associated with VEGFI-induced hypertension include a previous history of hypertension, combination therapy with more than one anti-VEGFI, over 65 years of age, smoking, and possibly high cholesterol.

Body mass index, renal function, race, a family history of hypertension, or cardiovascular disease do not seem to predict development of hypertension with VEGFI treatment.

Treatment of VEGFI-induced hypertension

Treatment of hypertension should be aimed at reducing the risk of short-term morbidity associated with hypertension while maintaining effective dosing of antiangiogenic therapy for optimal cancer treatment.

Although specific guidelines are not yet available for the management of VEGFI-induced hypertension, angiotensin-converting enzyme inhibitors and dihydropyridine calcium channel blockers are commonly used.

Severe hypertension might require reduction of VEGFI dosing, or in some cases, interruption of treatment.

As more potent VEGFIs are developed and as more cancer patients are treated with VEGFIs, the burden of hypertension toxicity will increase. This will be further compounded as the use of antiangiogenic drugs broadens to include older patients and those with pre-existing cardiovascular disease.

Reference

Small HY, Montezano AC, Rios FJ, et al. Hypertension Due to Antiangiogenic Cancer Therapy With Vascular Endothelial Growth Factor Inhibitors: Understanding and Managing a New Syndrome. Can J Cardiol 2014; 30(5):534-543. doi: 10.1016/j.cjca.2014.02.011.