Hypertension
Quick Facts
- Patients receiving bevacizumab are at increased risk of developing HTN
- Bevacizumab-associated hypertension should be treated according to published guidelines for primary hypertension
- Nurses can have a significant impact on prevention of worsening complications resulting from untreated HTN by assessing patients regularly and reporting abnormal vital signs to physicians
Background
Hypertension (HTN) is one of the most common side effects of antiangiogenic therapy, including bevacizumab. The incidence of HTN (> 150/100 mm Hg) in patients receiving bevacizumab with a 5-FU–based regimen ranged from 60% to 67%, compared with 43% in the control arm not receiving bevacizumab. The incidence of severe HTN (National Cancer Institute Common Toxicity Criteria [NCI CTC] grade 3/4; = 200/110 mm Hg) was 7% to 10%, compared with 2% in patients not receiving bevacizumab.1 The incidence of severe HTN increased in patients receiving bevacizumab compared with controls. Across clinical studies, the incidence of NCI-CTC grade 3 or 4 HTN ranged from 8% to 18%.1 The presence of HTN during bevacizumab therapy is statistically associated with proteinuria, although a causative relationship has not yet been established. No temporal relationship between HTN and proteinuria was found in an observational study by Martel and colleagues, who noted that half the patients developed HTN first and the other half, proteinuria.2
Pathophysiology
The mechanism of primary HTN is poorly understood. Secondary HTN—when HTN is the side effect of a medication, procedure, or comorbid condition—may be explained by the mechanism of action of the implicated agent. Bevacizumab-associated HTN may be due to a cascade of events initiated by the inhibition of vascular endothelial growth factors (VEGF), which then fails to stimulate the production of nitrous oxide, a vasodilator.3 When less nitrous oxide is available, vasoconstriction may occur, causing a significant rise in blood pressure. Sane et al also hypothesized that VEGF may have effects on the renin-angiotensin system, resulting in HTN.3 It is possible that there is a common pathophysiologic mechanism involved in the development of hypertension and proteinuria associated with bevacizumab.2
In an observational report, Mir et al4 noted that patients who developed bevacizumab-associated HTN had increased eosinophils (> 500/mm3). HTN with concomitanteosinophilia is a known feature of cholesterol emboli syndrome (CES). These authors therefore hypothesized that VEGF inhibition could be responsible for CES and that in the subset of patients with atherosclerosis, CES may account for bevacizumab-induced acute complications, including HTN.
Assessment Tools
Table 1. JNC 7 Blood Pressure Classification
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Blood Pressure Classification
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Systolic Blood Pressure, mm Hg
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Diastolic Blood Pressure, mm Hg
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Normal
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< 120
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< 80
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Prehypertension
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120-139
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80-99
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Stage 1 hypertension
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140-159
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90-99
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Stage 2 hypertension
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= 160
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= 100
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JNC = Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure.
Based on information from Chobanian et al.5
Table 2. Common Terminology Criteria for Adverse Events v4.02 (CTCAE) Grading of Hypertension
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Grade
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Adverse Event
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1
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Prehypertension (systolic BP 120-139 mmHg or diastolic BP 80-89 mmHg)
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2
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Stage 1hypertension (systolic BP 140-159 mmHg or diastolic BP 90-99mmHg; medical intervention indicated; recurrent or persistent (>=24 hrs); symptomatic increase by >20 mmHg (diastolic) or to >140/90 mmHg if previously WNL; monontherapy indicated
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3
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Stage 2hypertension (systolic BP>=160mmHg or diastolic BP>=100 mgHg); medical intervention indicated; more than one drug or more intensive therapy than previously used indicated
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4
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Life-threatening consequences (e.g.malignant hypertension, transcient or permanent neurologic deficit, hypertensive crisis); urgent intervention indicated
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5
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Death |
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Data from 2010 NCI CTEP.6
Guidelines
National High Blood Pressure Education Program. JNC7 Express: The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Bethesda MD: US Department of Health and Human Services, National Heart, Lung, and Blood Institute; NIH Publication 03-5233; December 2003.7
Note: JNC 8 hypertension guidelines are scheduled for release in Summer 2010.
Management
In the presence of HTN, careful monitoring of blood pressure (BP) prior to each chemotherapy treatment or more frequently is warranted.8,9 Patients who develop HTN during therapy should be advised to purchase a home BP monitoring system. BP should be checked at home at least once daily, and patients should be advised to contact the clinic if they note either intermittent elevated BP levels or a trend toward an increase.
Bevacizumab-related HTN should be treated with standard oral antihypertensive therapy, titrated to effect. Published HTN management guidelines should be followed. (Figure 1). If BP control is less than optimal, the patient should be referred to a cardiologist or to an internist specializing in HTN management. Standard oral antihypertensive agents used to manage bevacizumab-related HTN include1,10
- Angiotensin-converting enzyme (ACE) inhibitors
- Beta blockers
- Calcium channel blockers
- Diuretics
Treatment with bevacizumab should be temporarily suspended in patients with severe HTN that is not controlled with medical management and permanently discontinued in patients with hypertensive crisis. HTN can persist after discontinuation of bevacizumab.1
Figure 1. JNC 7 Hypertension Treatment Algorithm
Figure from National High Blood Pressure Education Program.7 JNC 8 hypertension guidelines are scheduled for release in Summer 2010.
Nursing Implications
Oncology nurses must be aware of side effects of agents commonly used in the treatment of patients with CRC. Unlike traditional cancer therapy side effects, hypertension may be overlooked or incorrectly attributed to other medical conditions. A basic understanding of HTN assessment and treatment guidelines will help nurses intervene early and seek appropriate treatment on the patient’s behalf. Nurses can have a significant impact on prevention of worsening complications resulting from untreated HTN by assessing patients and reporting occurrences to physicians and nurse practitioners.11
References
- Avastin (bevacizumab) full prescribing information. http://www.gene.com/gene/products/information/pdf/avastin-prescribing.pdf. Accessed February 18, 2010.
- Martel CL, Presant CA, Ebrahimi B, et al. Bevacizumab-related toxicities: association of hypertension and proteinuria. Community Oncol. 2006;3:90-93.
- Sane DC, Anton L, Brosnihan KB. Angiogenic growth factors and hypertension. Angiogenesis. 2004;7:193–201.
- Mir O, Mouthon L, Alexandre J, et al. Bevacizumab-induced cardiovascular events: A consequence of cholesterol emboli syndrome? [Correspondence]. J Natl Cancer Inst. 2007;88:85-86.
- Chobanian AV, Bakris GL, Black HR, et al. The seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. JAMA. 2003;289:2560-2572. [Pub Med]
- National Cancer Institute Cancer Therapy Evaluation Program. Common Terminology Criteria for Adverse Events v4.02 (CTCAE), page 77, Vascular Disorders.http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.02_2009-09-15_QuickReference_8.5x11.pdf . Accessed February 18, 2010.
- National High Blood Pressure Education Program. JNC 7 Express: The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Bethesda MD: US Department of Health and Human Services, National Heart, Lung, and Blood Institute; NIH Publication 03-5233; December 2003. http://www.nhlbi.nih.gov/guidelines/hypertension/jnc7full.htm Accessed February 18, 2010.
- Knoop T. Nursing management of patients receiving angiogenesis inhibitors [monograph]. In: Current Topics in Colorectal Cancer: Targeting VEGF. Miami, FL:Institute for Medical Education and Research; 2005.
- Wilkes GM. Therapeutic options in the management of colon cancer: 2005 update. Clin J Oncol Nurs. 2005;9:31-44.
- Miles JS. Hypertension therapy for the oncology patient. Community Oncol. 2006;3:94-99.
- Rosiak J, Sadowski L. Hypertension associated with bevacizumab. Clin J Oncol Nurs. 2005;9:407-411.
Key Definitions
cholesterol emboli syndrome—cluster of symptoms or abnormalities that include worsening renal function, hypertension, eosinophilia, or acute multisystem dysfunction
eosinophilia—increased eosinophils in the blood
eosinophils—white blood cells, which are one of the immune system components responsible for combating infection and parasites in vertebrates. Along with mast cells, they also control mechanisms associated with allergy and asthma
hypertensive crisis—a sudden, severe increase in blood pressure to a level exceeding 200/120 mm Hg
proteinuria—excess protein in the urine
renin-angiotensin system—hormone system that regulates blood pressure and fluid balance
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