A joint Congress by ERA-EDTA and ISN

BLOOD PRESSURE EFFECTS OF VEGF ANTAGONISM

Michel Azizi, Paris, France

Chair: Duk-Hee Kang, Seoul, Korea

Detlef Schöndorff, New York, USA

Dr Michel Azizi Clinical Investigation Center, Inserm George Pompidou European Hospita, APHP Paris, France

Slide 1

Thank you very much. I just want first to thank the organisers of the congress for having invited me to talk about the cardiovascular and blood pressure effects of anti-angiogenic treatments.

Slide 2

You have heard from the previous speakers that angiogenesis plays a major role in tumour progression and VEGF is one of the key mediators of this promotion of angiogenesis through interaction with its receptors, specifically the R2 receptor, which is going to activate and promote angiogenesis. Because of this key role and because of multiple tumour expression overexpressing VEGF, there have been multiple strategies to inhibit VEGF signalling.

Slide 3

Hypertension and diabetes are the most common comorbid conditions in cancer patients and may directly affect prognosis.

Slide 4

Long-term cancer survivors have a higher risk of cardiovascular disease than of recurrent cancer and hypertension has been associated with an excess rate of cancer mortality either in all-cause cancer, all types of cancer or specifically in renal cell carcinoma.
You have already heard about this meta-analysis about the effect of antiangiogenic agents on the incidence of new cases of hypertension. I just want to point out that hypertension is defined in these studies according to the common toxicity criteria for adverse events and that is an increase in diastolic blood pressure greater than 20 mm/Hg or a blood pressure greater than 150/100 mmHg. These thresholds are much higher than what we know about the hypertension level defined by a blood pressure level of over 140/90 mmHg.

Slide 5

So using this definition you see that the overall incidence of all grade hypertension is comprised somewhere between 16% and 30% with Bevacizumab or receptor tyrosine kinase inhibitor. This overall incidence is dose-dependent and using low doses of Bevacizumab is associated with a relative risk increase of 3. Whereas, a high dose of Bevacizumab gives you a larger relative risk increase. When we compare using the same definition patients with the renal cell carcinoma who have undergone nephrectomy to those patients having non-renal cell carcinoma, this overall incidence seems to be the same. So nephrectomy using this type of definition does not seem to affect the incidence of hypertension. However, we think that this incidence of hypertension is truly completely underestimated.

Slide 6

We have monitored normotensive patients with advanced renal cell carcinoma receiving two cycles of Sunitinib. These cycles are in the shaded area. Sunitinib is given for 4 weeks and then is interrupted for 2 weeks. We used tele-transmitted home blood pressure monitoring to follow the blood pressure of these patients. All patients at initiation were normotensive. You see as early as the first week of administration of Sunitinib blood pressure increased and the increase was of 14 mmHg systolic blood pressure, 10 mmHg of diastolic blood pressure. After 4 weeks of treatment the rise in blood pressure was 22 mmHg for systolic blood pressure and 17 mmHg for diastolic blood pressure and at that time all normotensive patients became hypertensive according to the ESH guidelines that is a home blood pressure level greater than 135/85 mmHg. When the drug was stopped the hypertension was reversed and patients became again normotensive. When the drug was again introduced you have a rise in blood pressure and probably a  slight amplification of this effect.
Interestingly, if you look here at the heart rate, you see that there is no rise in heart rate and the reverse you have a decrease in heart rate. This is the opposite pattern so this means that probably there’s no activation of the sympathetic pathway when given this type of drugs.

Slide 7

The second message is if you follow blood pressure using common office blood pressure monitoring, at the mean level you will see this effect but at the individual level you will miss the patient who will have this increase in blood pressure. So this is a strong argument for using home blood pressure monitoring to monitor a patient having this type of drugs.

Slide 8

There are more and more reports and this is one of these reports. This is a retrospective analysis of 75 patients with metastatic gastrointestinal stromal tumours receiving repeated cycles of Sunitinib and as you can see, 8% of the patients have congestive heart failure which was again reversible when Sunitinib was withdrawn. 2 patients died from myocardial infarction and cardiovascular death, so leading to 11% of cardiovascular events. About 20% of the patients had a left ventricular ejection fraction reduction and half of the patients were hypertensive according to the same criteria we saw before.

Slide 9

What were the predictors of these cardiovascular events? These were not age or sex, you see here the odds ratio associated with the composite cardiovascular endpoint neither the anthracycline use but the history of coronary artery disease, you see this odds ratio with a very wide confidence interval and the presence of hypertension before or induced during treatment.

Slide 10

Another very exceptional complication has also been reported. This is reversible posterior leukoencephalopathy syndrome with antiangiogenic agents, this is not specific for antiangiogenic treatment, it has been reported with other immunosuppressive agents, such as cyclosporine. The brain capillary leak syndrome related to acute hypertension and fluid retention, it is associated to headaches, seizures, impaired vision with acute hypertension. It’s again reversible when the drug is stopped and at MRI it gives signal changes in the posterior cerebral white matter.

Slide 11

What is the pathophysiology of anti-VEGF treatment-induced hypertension?

Slide 12

Well we know from experimental data in animal models but also in patients that when VEGF is injected, you obtain a hypotensive effect. This is shown here some in a weird manner, this is the vasodilatation, this is the VEGF-dependent hypotensive response here. You see that this is reversible when you give a receptor tyrosine kinase inhibitor and dose dependently can completely blunt this hypotensive effect.

Slide 13

So VGEF is a vasodilator. This vasodilating effect is due to induction of NO from endothelial cells because VEGF upregulates endothelial nitric oxide synthase expression. You see here that there is a clear dose-dependent increase in NO production by endothelial cells and when you look to isolated vessels in a concentration-dependent manner, you achieve a relaxation with VEGF which is completely abolished when you remove the endothelium and partly blunted when you give a NO inhibitor.

Slide 14

So, this is why some others have looked at the endothelial function in patients receiving receptor tyrosine kinase inhibitors and in some small series of patients they have observed that there is a reduction in some patients of the flow-mediated vasodilation but also of the endothelium independent vasodilation.

Slide 15

In contrast, no humoral factors have been modified when a receptor tyrosine kinase inhibitor is given and you see here that after 3 weeks of administration of these drugs there is no change in the plasma catecholamine levels, plasma renin levels, aldosterone levels or endothelin-1 levels.

Slide 16

One of our colleagues in Paris, Jean Jacques Mourad has studied with Bernard Levy skin capillary rarefaction induced by Bevacizumab in patients with colonic cancer. They observed a mild decrease here in the capillary density which is inversely correlated to the cumulative dose of Bevacizumab.

Slide 17

So to summarise the putative mechanisms underlying the development of hypertension associated with VGEF inhibition, there is reduced NO production or function, reduced capacity of the endothelium to react to vasodilating stimuli. Increased activity of vasoconstrictor stimuli, reduction of the number of arterioles and capillaries. Structural alterations of the microvascular beds, I didn’t show you but also it seems that there’s a reduction in vascular wall compliance and distensibility.

Slide 18

So to conclude the antiangiogenic-induced hypertension has the following characteristics.

Slide 19

It has an early onset, it is dose-dependent, it is reversible when the drug is interrupted. It can be severe and complicated and it’s generally associated, but I have not shown it here, with proteinuria. At the present time antiangiogenic drugs are indicated in patients with advanced carcinomas and short life time expectancy. So the anti-tumoral benefit of their use should not be outweighed by the cardiovascular and cerebrovascular risk conferred by the occurrence of drug related hypertension. However, this balance, this benefit risk ratio may not be as favourable at earlier stages of cancer in patients who will be exposed for a much longer period of time to cumulative doses of these drugs.

Slide 20

The French society of Nephrology and the Hypertension Society have edited some recommendations about the use of these drugs and to treat them and deal with hypertension in these patients. The first thing is that all cardiologists, nephrologists and hypertension specialists should interact with oncologists to optimise patient treatment. Blood pressure should be monitored with home blood pressure monitoring to identify those patients who will need intervention.

Slide 21

We should favour antihypertensive drugs with vasodilating activities such as ACE inhibitors or ARBs specifically if patients develop proteinuria, calcium channel blockers and specifically dihydropyridine. We should avoid diltiazem and verapamil because they are CYP 3A4 inhibitors and some molecules such as Sunitinib is metabolised by CYP 3A4. There may be a role for nitrates you have seen how the NO can be implicated in the blood pressure effect of anti-VEGF treatment. We should use with caution diuretics, specifically thiazide diuretics in patients prone to develop hypercalcemia. The same thing also, the same caution should be used with the use of beta blockers which increase PR and QT interval because some of these drugs, such as Sunitinib increase also QT interval. We should consider antiangiogenic drug holidays during the off antiangiogenic treatment period specifically with the drugs with receptor tyrosine kinase inhibitor. We should consider also antiangiogenic holidays or dosage reduction when hypertension is refractory to 3 or more antihypertensive treatments or in presence of end organ damage.
Finally, these drugs should permanently be discontinued in any patient who experiences a hypertensive crisis. I thank you for your attention.

Slide 22

Chairman: Thank you for a concise and organised presentation. This talk is now open for discussion.

Question: Could, I ask you a question about your recommendation about the hypertension treatment? These patients are already on multiple drugs. If somebody has a blood pressure of 160/90 mmHg for several months of treatment, that’s not going to do him any harm. Hypertension does harm over years and decades. So I don’t think we have to blimp that you have to discover by doing 24-hour measurements in order to label the patient as hypertensive doesn’t necessarily call for the reflex to treat and cause more trouble for the patient.

Dr. Azizi: I don’t call for a reflex to treat I just say to monitor blood pressure using home blood pressure and not ambulatory blood pressure monitoring.

Question: Are you recommending to treat them all if their blood pressure is over that?

Dr. Azizi: No according to the ESH guidelines and the ESC guidelines and if once again, even saying what you’re saying there are more and more patients developing cardiotoxicity due to these drugs which is triggered by hypertension.

Question: What is you evidence that the cardiotoxicity is triggered by hypertension?

Dr. Azizi: Well, these patients have two mechanisms we have first you have a --- effect in the heart of these drugs and secondly in all the studies the relative risk induced by the presence of hypertension is higher than in the absence of hypertension. So these are the data concerning hypertension. What I said is today these drugs are given in patients with very severe cancer disease and also with a short life time expectancy. So we have to take into account this effect. As Doctor Kurgan said 300 different clinical trials are ongoing with patients with milder and milder and milder forms of cancer. So these patients will be treated for a long period of time with this type of drug. You may remember that with --, which was given to patients, an increase of a few mmHg, 3-4 mmHg was associated with an increased risk of stroke and heart failure. There we have an increase of 20 mmHg so we have to take into account when patients will be under this treatment for a long period of time that there will be a cardiovascular and cerebrovascular risk added to their cancer risk.

Question: Along those lines the question of somebody with cardiac disease to start since you showed endothelial function does mean these drugs should not be used in somebody who’s had bypass surgery?

Dr. Azizi: No, it’s just you have to be aware that they can develop it more frequently and now it’s said that you need at least one echocardiography before starting these drugs in this type of patients.

Question: Do you think that cardiotoxicity there’s any that is all hypertension or is there a separate cardiotoxicity and particularly the mitochondrial?

Dr. Azizi: Yes you’re right but I didn’t have time to discuss about this yes absolutely. There is diuretic toxicity also in the heart and specifically in the mitochondria yes absolutely.

Question: I wondered what your thoughts were on hypertension or some rise in blood pressure as a surrogate marker for efficacy of anti-tumourgenic activity?

Dr. Azizi: This is also a very good question. Indeed it has been reported in various clinical trials that patients who had this side effect this increase in blood pressure have a better prognosis than those patients who do not increase blood pressure but I think that once again in these particular trials blood pressure was measured. I don’t know how it was measured so you may have completely underestimated it and put a cut off point somewhere very arbitrarily and so you see this occurs but I’m not really sure. I think that 100 % of the patients will have a rise in blood pressure when you give this type of drug. The problem is that they did not measure correctly blood pressure that’s all.

Chairman: I have one last question for all the speakers. What is your explanation that there are no retinal problems in these patients? The retina is highly dependent on VEGF and is a highly vasculature structure. Susan yes?

Dr. Quaggin: I don’t thin it’s been looked at systematically in the clinical trials. We are looking at the retinas in our mice of the whole body knockouts so I think we don’t know the answer to that and also with the anti-VEGF therapy that is being treated, two weekly injections which improves acutely AMD and over a course of a couple of years but we don’t know how long term and chronic suppression may have very different effects on the retina vasculatures so great question but I don’t think we know.

Chairman: Alright thank you very much.