Cancer drugs that inhibit vascular endothelial growth factor (VEGF) cause hypertension in as many as 90% of patients and may put them at risk for serious cardiovascular events, according to an article published in the Canadian Journal of Cardiology.
Increased blood pressure has been observed in every trial of VEGF inhibitors, the investigators pointed out, making it the most common cardiovascular toxicity associated with use of these agents. However, a rise in blood pressure is not an adverse effect of VEGFs, but rather a mechanism-dependent toxicity that might be a marker of the drugs’ effectiveness.1
“Exactly how VEGF inhibitors cause hypertension is unknown,” said senior investigator Rhian M. Touyz, MD, PhD, of the Institute of Cardiovascular and Medical Sciences at the University of Glasgow. “However, what is clear is that inhibition of VEGF in the vasculature directly increases blood pressure because hypertension develops acutely in response to VEGF inhibitors and blood pressure returns to normal once the treatment is stopped.”
Virtually all patients given VEGF inhibitors experience an increase in blood pressure, and a subset develop hypertension. In clinical trials, the incidence of VEGF inhibitor-induced hypertension has ranged from 19% to 67% with currently approved agents and up to 90% with experimental, higher-potency VEGF inhibitors such as cediranib and axitinib, the investigators say.1
Risk factors for developing hypertension during VEGF therapy include a previous history of hypertension, combination therapy with more than one VEGF inhibitor, age older than 65 years, smoking, and possibly hypercholesterolemia.
Clinical trials have generally underestimated the incidence of hypertension associated with VEGF therapy because they used blood pressure threshold values that were higher than those defined in clinical guidelines, according to the investigators. In addition, patients with a history of hypertension or cardiovascular disease were usually excluded from the trials.
Although the mechanism by which VEGF inhibitors cause hypertension is not known, the connection is not in doubt because blood pressure increases are typically observed within hours to days after the start of VEGF therapy and are relieved upon withdrawal of the agents. VEGF-inhibitor-induced hypertension may be severe and resistant to treatment.
VEGF is critical to angiogenesis, the process whereby tumors secure a blood supply that enables their growth. VEGF also promotes tumor growth and metastasis, and increased VEGF expression is associated with tumor invasiveness and density.
By blocking VEGF signaling, VEGF inhibitors limit the blood supply available to tumors and thus restrict their growth. Eight VEGF inhibitors have been approved by the US Food and Drug Administration, and many more are in clinical development.
The investigators advocate aggressive blood pressure control for patients with cancer being treated with VEGF inhibitors who develop hypertension because they are at increased risk for cardiovascular events. Angiotensin-converting-enzyme inhibitors and dihydropyridine calcium channel blockers are recommended agents. Nondihydropyridine calcium blockers interfere with the metabolism of VEGF inhibitors and should be avoided.
“As VEGF inhibitors become more widely used and the number of older patients with cardiovascular risk factors and preexisting hypertension are treated with these drugs, the need to better understand the molecular mechanisms underlying VEGF inhibitor-induced hypertension and the risk factors predisposing to this condition are imperative, so that clear guidelines and improved management can be instituted,” Dr. Touyz concluded.
- Small HY, Montezano AC, Rios FJ, Svoia C, Touyz RM. Hypertension due to antiangiogenic cancer therapy with vascular endothelial growth factor inhibitors: understanding and managing a new syndrome. Canadian J Cardiol. 2014;30(5):534-543.