Mechanisms of Anti-VEGF Induced Hypertension
Mechanisms of Anti-VEGF Induced Hypertension
Background: High blood pressure is a common complication observed in cancer patients
 prescribed anti-VEGF drugs. Increased blood pressure increases the risk of heart attacks and
 strokes, thus adversely affecting survival and quality of life in this patient group.
 However, little is known about the mechanisms leading to high blood pressure with anti-VEGF
 drugs. As a result, the management of anti-VEGF drug-induced hypertension is largely
 empirical. A better knowledge of effects of specific blood pressure lowering drugs, i.e.
 antihypertensives, on anti-VEGF drug-induced hypertension would optimize therapeutic
 management and reduce the risk associated with hypertension and proteinuria in patients with
 cancer.

 Methods: Datasets of two completed GSK clinical trials using the anti-VEGF drug pazopanib,
 i.e. VEG108844 and VEG105192, will be accessed to 1) determine the way blood pressure changes
 over time after commencing anti-VEGF treatment; 2) identify whether there are any
 relationships between pre-study and baseline blood pressure values, treatment with specific
 antihypertensive drugs, and changes in blood pressure after commencing anti-VEGF treatment;
 and 3) identify whether specific antihypertensive drugs and drug combinations, prescribed
 either before or after commencing anti-VEGF treatment, lead to a better blood pressure
 control and prevent proteinuria during anti-VEGF treatment. Specific statistical analyses
 will be conducted to assess and identify associations and will account for other patient's
 characteristics and repeated observations over time. The investigators plan to conduct this
 study over 6 months.

 Studies VEG108844 and VEG105192 have been selected as they investigate the same anti-VEGF
 drug, pazopanib, in a homogeneous group, i.e. patients with renal cancer. At the same time,
 inclusion of a placebo arm as well as a treatment arm with a different anti-VEGF drug,
 sunitimib, will allow initial comparisons across different groups.

 The results deriving from this study will provide important knowledge on 1) patterns of blood
 pressure changes with anti-VEGF drugs and 2) whether specific antihypertensive drugs or drug
 classes might be better than others in preventing and managing anti-VEGF induced hypertension
 and proteinuria.
Background: High blood pressure is a common complication observed in cancer patients
 prescribed a class of medications known as anti-VEGF drugs. Increased blood pressure, also
 known as hypertension, increases the risk of heart attacks and strokes, thus adversely
 affecting survival and quality of life in this patient group. However, little is known about
 the mechanisms leading to high blood pressure with anti-VEGF drugs. As a result, the
 management of anti-VEGF drug-induced hypertension is largely empirical, hence sub-optimal. A
 better knowledge of effects of specific blood pressure lowering drugs, i.e.
 antihypertensives, on anti-VEGF drug-induced hypertension would optimize therapeutic
 management and reduce the risk associated with hypertension and proteinuria in patients with
 cancer.

 Methods: The investigators will access the datasets of two GSK clinical trials using the
 anti-VEGF drug pazopanib, i.e. VEG108844 and VEG105192, in order to 1) determine the way
 blood pressure changes over time after commencing anti-VEGF treatment; 2) identify whether
 there are any relationships between pre-study and baseline blood pressure values, treatment
 with specific antihypertensive drugs, and changes in blood pressure after commencing
 anti-VEGF treatment; and 3) identify whether specific antihypertensive drugs and drug
 combinations, prescribed either before or after commencing anti-VEGF treatment, lead to a
 better blood pressure control and prevent proteinuria during anti-VEGF treatment. Specific
 statistical analyses will be conducted to assess and identify associations and will account
 for other patient's characteristics and repeated observations over time. The investigators
 plan to conduct this study over 6 months.

 Studies VEG108844 and VEG105192 have been selected as they investigate the same anti-VEGF
 drug, pazopanib, in a homogeneous group, i.e. patients with renal cancer. At the same time,
 inclusion of a placebo arm as well as a treatment arm with a different anti-VEGF drug,
 sunitimib, will allow initial comparisons across different groups.

 The results deriving from this study will provide important knowledge on 1) patterns of blood
 pressure changes with anti-VEGF drugs and 2) whether specific antihypertensive drugs or drug
 classes might be better than others in preventing and managing anti-VEGF induced hypertension
 and proteinuria. This research will pave the way for further clinical studies aimed at
 testing the hypotheses generated. The evidence generated could contribute to the development
 of national and international guidelines for the management of anti-VEGF induced
 hypertension.

 The investigators plan to disseminate the findings at national and international oncology
 and/or hypertension conferences and by publishing the results in peer-reviewed scientific
 journals.

 Study Design

 The selected studies, VEG105192 and VEG108844, have been designed to investigate the efficacy
 of the anti-VEGF drug pazopanib vs. placebo (randomised, double-blind, placebo-controlled
 study, VEG105192) and vs. another anti-VEGF drug (sunitimib, randomised, open-label, parallel
 group study, VEG108844) in two renal cancer patient populations. Both studies provide data on
 repeated blood pressure measurements (systolic, diastolic and pulse pressure), medications
 (including anti-hypertensive medications) and dose changes as well as a number of clinical,
 demographic and biochemical characteristics. This information is essential to conduct
 analysis of associations between these variables.

 Studies Selected and Study Populations

 The studies VEG105192 and VEG108844 have been selected because they compare the chosen
 VEGF-inhibitor (pazopanib) vs. either a placebo or another VEGF-inhibitor (sunimitib) in
 similar study groups, i.e. patients with renal cancer. Moreover, both studies provide
 repeated measures of blood pressure and data on medications and dose changes. Considering
 both studies will allow: 1) characterising blood pressure temporal changes in patients
 receiving different anti-VEGF drugs vs. placebo; and 2) assessing whether the blood pressure
 lowering effects of antihypertensive drugs are similar in patients receiving pazopanib vs.
 sunitimib.

 Primary and Secondary Endpoints for the Study

 There will be four primary aims:

 1. To assess which anti-hypertensive drug class is most effective for the treatment of
 hypertension induced by anti-VEGF drugs (pazopanib and sunitinib).

 As the mechanism seems primarily nitric oxide (NO) mediated, with possible additional
 involvement of the renin-angiotensin system, the investigators hypothesise that drugs
 with salutary effects on endothelial function (angiotensin converting enzyme inhibitor
 [ACEI], angiotensin II receptor blocker [ARB] and calcium channel blocker [CCB] based
 treatment regimens) are more likely to be effective than traditional thiazide diuretics,
 beta-blockers or other vasodilators

 2. To assess whether use of specific anti-hypertensive drugs prior to starting an anti-VEGF
 drug may reduce the risk of anti-VEGF drug mediated hypertension.

 As the mechanism seems primarily NO-mediated, with possible additional involvement of
 the renin-angiotensin system, the investigators hypothesise that drugs with salutary
 effects on endothelial function (ACEI, ARB and CCB-based treatment regimens) may have a
 preventative effect on VEGF inhibitor mediated hypertension.

 3. To assess whether use of ACEI or ARB drugs prior to starting an anti-VEGF drug may
 reduce the risk of anti-VEGF drug mediated proteinuria.

 As ACEI and ARB drugs have been widely demonstrated to prevent or reduce proteinuria,
 the investigators hypothesise that these drugs are more likely to be prevent anti-VEGF
 drug mediated proteinuria than individuals using other anti-hypertensive drugs or no
 anti-hypertensive drugs.

 4. To assess whether use of ACEI or ARB drugs is prognostic for improved survival in renal
 cell carcinoma with anti-VEGF drug use.

 This is a confirmatory study based on findings from a recent pooled analysis of renal cancer
 trials which found that users of ACEI or ARB had improved overall and progression free
 survival [J Clin Oncol 32, 2014 (suppl 4; abstr 437)].

 The investigators further aim to undertake exploratory analyses to provide greater insight of
 anti-VEGF drug mediated hypertension and proteinuria and raise hypotheses for confirmation in
 subsequent studies, e.g. time frame, form and extent of BP changes, BP changes leading to
 initiation of anti-hypertensives, distribution of anti-hypertensive strategies utilized, and
 time-frame, form and extent of BP reductions. Baseline covariates influencing the risk of
 hypertension and proteinuria as well as predicting the extent of BP reduction with
 antihypertensive therapy.
Inclusion Criteria:

 -  Renal Cancer

 Exclusion Criteria:

 -  Other terminal illness