A not inconsequential number of therapeutic agents or chemical substances can increase blood pressure (BP). The degree to which BP increases determines whether a specific definitional threshold has been crossed, at which time the patient is designated as having become hypertensive. Drugs that cause hypertension do so by either causing vasoconstriction, increasing extracellular fluid (ECF) volume, and/or by decreasing vascular compliance. In aggregate, these processes can override the effects of numerous antihypertensive therapies.^1–2
Vascular Endothelial Growth Factor and Blood Pressure

Vascular endothelial growth factor (VEGF) antagonists (or angiogenesis inhibitors) can now be added to this extensive list of compounds tied to a treatment-related increase in BP.^3–5 Several lines of reasoning would suggest the likelihood of BP ‘decreasing’ with angiogenic growth factor therapy and ‘increasing’ with angiogenesis inhibitor therapy. First, a number of studies in animals and humans have noted a drop in BP with angiogenic growth factor administration.^6–7 For example, in the VEGF in Ischemia for Vascular Angiogenesis Trial (VIVA), both intra-coronary and intravenous infusions of recombinant human VEGF were accompanied by falls in systolic BP of up to 22% at the highest doses.8 Second, VEGF both enhances endothelial nitric oxide synthase (eNOS) activity and upregulates the message and protein levels of VEGF in human endothelial cells; thus, nitric oxide generation would appear to be a necessary component of the response pattern to angiogenic growth factors.^9–10 Finally, angiogenic growth factors present a strong stimulus for the assembly of new capillaries and the recruitment of endothelial progenitor cells.¹¹ It has been recognized for some time that small arteries and precapillary arterioles are important determinants of vascular resistance and a reduction in their density—so-called capillary and arteriolar rarefaction—is observed in a number of animal models of hypertension.¹¹

Overview of Angiogenesis Inhibitors

Treatment for cancer has been traditionally rooted in cytotoxic chemotherapy, although specific targeted therapies are increasingly available. An important target for such therapies is the inhibition of angiogenesis. A variety of therapeutic strategies, designed to block VEGF or its receptor signaling system, have been developed for the treatment of various types of cancer. The most advanced approaches to angiogenesis inhibition include the blockade of the VEGF/VEGF-receptor by monoclonal antibodies and the inhibition of receptor signaling with tyrosine kinase inhibitors. Bevacizumab and BAY 43-9006 represent each of these two types of angiogenesis inhibitors.

Bevacizumab

Bevacizumab is a recombinant humanized monoclonal antibody that prevents the binding of VEGF to its receptors (rhuMAb-VEGF).12 Bevacizumab has been assessed in phase II and III trials in a wide range of tumor types, with promising results obtained in colorectal cancer, non-small cell lung cancer (NSCLC), renal cell carcinoma, and breast cancer.^13–15 Early studies with bevacizumab added to fluorouracil-based combination chemotherapy (irinotecan, bolus fluorouracil, and leucovorin) presented the first signal as to the prevalence of hypertension with angiogenesis inhibitors. In the study by Hurwitz et al., 402 patients were treated with bevacizumab (5mg per kilogram body weight every two weeks) and hypertension occurred in 22% of the cases (control population—8.3%). Grade 3 hypertension (or that requiring therapy) was noted in 11% and 2.3% of the bevacizumab and placebo-treated cohorts, respectively.¹⁴ There were no discontinuations of bevacizumab due to hypertension or hypertension-related deaths in this group. Yang et al. evaluated two doses of bevacizumab (3 and 10mg per kilogram body weight) in patients with metastatic renal cell carcinoma.³ Hypertension was more common in the high-dose bevacizumab group. Among all bevacizumab-treated patients who required therapy for newly diagnosed hypertension (for whom the dates of onset could be most accurately determined), the median interval from the first dose of bevacizumab to the onset of hypertension was 131 days (range 7–316). Hypertension (and BP) uniformly decreased at the completion of therapy; however, and not unexpectedly, complete resolution of these adverse effects could not be confirmed because of multiple confounding variables—such as death and the start of other therapies.³

In a phase III trial conducted by Miller et al. in metastatic breast cancer patients, grade 3 hypertension was observed in 17.9% of those receiving capecitabine and bevacizumab compared with capecitabine alone.¹⁵ Pre-infusion systolic and diastolic BP values dropped by a mean of 2.6 and 0.7mmHg, respectively, in the capecitabine-alone group, while increasing by 5.5 and 4.6mmHg in the capecitabine and bevacizumab combination group; no relationship was observed with the duration of bevacizumab therapy or pre-existing hypertension. In these studies, four patients had bevacizumab stopped as the result of hypertension. An apparent association between proteinuria and hypertension was noted in the combination arm of this study in that patients who developed proteinuria were more likely to become hypertensive (47.1% versus 16.9%; p<0.001) than patients who did not develop proteinuria.¹⁵

BAY 43-9006

BAY 43-9006 is a novel bi-aryl urea initially developed as a specific inhibitor of c-Raf and b-Raf. Subsequent studies have shown this compound also to inhibit several important tyrosine kinases involved in tumor progression, including VEGF.^16–19 Veronese et al. have shown with little question that BAY 43-0096- treated patients, more likely than not, will experience a rise in BP if exposed to this compound in sufficient amounts.20 These investigators have observed significant increases in BP in a large proportion of patients receiving BAY 43-9006. To this end, 12 of 20 patients (60%) studied experienced a systolic BP increase of 20mmHg or more after three weeks of BAY 43-9006 at a dose of 400mg twice daily. These investigators gathered strong supporting evidence suggesting that activation of hypertension-producing neurohumoral pathways and/or overt volume expansion are not major contributing factors to BAY 43- 9006-related hypertension. These studies did, however, observe a rise in vascular stiffness, although it could not be established whether this was a cause or an effect of the BP elevation.²⁰ The frequency with which BP elevations were observed in these studies is higher than that previously observed with both BAY 43-0096 and other angiogenesis inhibitors, in part because these investigators were specifically and carefully observing for BP changes. In other studies, no doubt the gravity of the illness, confounding hemodynamic and volume factors, and limited monitoring precluded an accurate assessment of BP changes.