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What is the prevalence of CVD in patients with prostate cancer and how do we assess CV risk when deciding treatment strategy?

Alexander Lyon

Lyons senza slides-HD

Dr Lyon presents data showing that the risk of cardiovascular events and new onset diabetes is increased by treatment with GnRH agonists, but GnRH antagonists may provide an option with less cardiovascular toxicity. During treatment of prostate cancer, cardiovascular health should be optimized and cardiovascular risk should guide treatment strategies.

Transcript

What is the prevalence of CVD in patients with prostate cancer and how do we assess CV risk when deciding treatment strategy? - Dr Alexander Lyon

What is the prevalence of CVD in patients with prostate cancer and how do we assess CV risk when deciding treatment strategy? - Dr Alexander Lyon

Francesco Montorsi: I am very pleased to introduce to you Dr Alexander Lyon, who is going to talk about the prevalence of cardiovascular disease in patients with prostate cancer and how to assess the cardiovascular risks during treatment. Alexander, welcome, and the floor is yours.

Thank you Francesco. It is probably rather unusual for you to have a cardiologist stand up and speak in this audience, in this conference and, I must admit I probably a few years ago wouldn’t have counted it on the list of conferences I would be going to speak to, but I think our worlds are colliding. They are colliding because of the success of modern care, both in prostate cancer, where you are now seeing a wonderful survivorship and success story of men living for much longer than previously, but they are now arriving in my cardiology clinics and in the emergency rooms with cardiac problems. You should also know in treating myocardial infarction we have had a wonderful success story now – the mortality rate has gone down from 30% to 4% for in-hospital mortality for MI, which means all our MI patients are living longer to get prostate cancer and to come into your clinics, so I think we are going to be seeing a lot more of each other’s fruits of success.

Disclosures

Here are my disclosures.

Prostate cancer and cardiovascular disease

In England we have a term “Out of the frying pan into the fire” and I think for the world of oncology and cardiology we are having this now – we are curing or allowing people to live longer from one serious illness only to then develop another one.

Which of the following best reflects your practice?

I am going to start with some options just to get a feel, or a survey as to what your current practice is. Does this statement resonate to you “I have a busy clinical practice and I do not have time to review and discuss non-prostate cancer-related health matters with my patients”?

“I quickly ask if my patients have any other major health problems at the first consultation, record their answer and then focus on their prostate cancer for the rest of their care with me.”

“I directly ask my patients if they have had a prior cardiovascular disease at the time of diagnosing the prostate cancer, but this does not influence my decisions regarding prostate cancer treatment selection.”

The same “I directly ask my patients if they have had cardiovascular disease and highlight the importance that they should see their family physician to optimise their cardiovascular risk management, but this does not influence my decisions regarding prostate cancer treatment selection.”

Finally “I do directly ask my patients if they have had cardiovascular disease and highlight the importance of seeing their family physician to optimise their risk factors but this does influence my decisions regarding prostate cancer treatment selection.” You have your buttons and if you want to choose which of those reflects honestly your current practice.

[Vote]

Okay. The job is half done if that is the truth. Excellent. You are already monitoring and making sure they are on statin therapy and so forth, that is excellent news; I can sit down.

Case

I also had a case, but with a different feel. I am not going to specifically focus on the prostate cancer, but rather risk. A 61 year old solicitor, as it happens, which always focusses the mind, with a newly diagnosed locally invasive prostate cancer that was a Gleason grade 8.

There are two scenarios here: one is he was a hypertensive for five years on thiazide and it was that that maybe drove the urinary symptoms that led to his presenting. His total cholesterol is 5.3 and he currently has that diet controlled. He is a non-smoker, he is slightly overweight with a body mass index of 28. You might consider how you would approach his risk.

Would it be different if he told you he had had a myocardial infarction, had a coronary stent, he was type-2 diabetic, had aspirin, atorvastatin and Ramipril already in view of his previous MI; how would that influence your thoughts?

Prostate cancer and cardiovascular disease

In Western society the two main causes of mortality in men are cardiovascular disease and cancer and when I say cardiovascular disease, I am including myocardial infarction, heart failure, stroke and sudden cardiac death.

If we focus on men with prostate cancer and cardiovascular risk then we find that there is a lot of pre-existing cardiovascular risk, based not least on their age. The cardiovascular disease is the second most common cause of death in men with prostate cancer and in fact if you compare men with prostate cancer with men without prostate cancer, but the same cardiovascular risk, it seems that the men with prostate cancer have an increased risk of death from cardiovascular causes.

There are a number of factors, but one of the focuses is whether therapy is having an impact on this risk and particularly androgen deprivation therapy?

Androgen deprivation therapy (ADT) and cardiovascular risk

This has come about from data from a number of observational studies, a few of which I will highlight and a range of mechanistic studies, which reproducibly show that GnRH agonists introduce or worsen lipid profiles, including LDL cholesterol, inducing diabetes and the metabolic syndrome. If you scan the clinical data it is a level of evidence B which suggests there is a risk associated with these drugs and therapy, albeit that they are having a benefit impact on the prostate cancer. It is incorrect for cardiologists to just say “Stop the drugs”, rather “how do we support the best drug?” but we are missing randomised controlled trials.

ADT and elevated cardiovascular risk

If we look at androgen deprivation therapy why might they cause increased risk? This is GnRH agonists. I am sure many of your patients will report that they have skeletal muscle mass loss and increased abdominal adiposity in the months that they are on these drugs and that is a dangerous combination for inducing insulin resistance and diabetes, if they are not diabetic already. It also rises the LDL, interestingly a slight increase in protective HDL, but that is insufficient to counteract the other adverse burdens, and also changes in arterial wall thickness, which may in part reflect cholesterol deposition.

There may be some direct effects of these drugs, because of GnRH receptors. Maybe the most important is on T-cells and I don’t know if you remember the mechanisms of acute myocardial infarction, but essentially if you have a cholesterol plaque in your coronary artery the rupture of it is caused by thinning and destruction of the fibrous plaque and that is an inflammatory process, so inflammation drives coronary disease and myocardial infarction and there is evidence potentially that activation of T-cells by GnRH agonists can activate this process. Reduction in testosterone also has some adverse effects; testosterone causes coronary vasodilation, so if you have coronary disease and you suppress testosterone you can lead to constriction, which can induce angina or ischemia. There are also additional effects on abdominal adiposity.

ADT and elevated cardiovascular risk

As a cardiologist when I am thinking about patients being treated with GnRH agonists, essentially if they have already got coronary disease or vascular disease, there is an acute risk of starting these therapies, of destabilising the coronary disease that is there, causing acute cardiac events. Even in patients who don’t have coronary disease at the time of diagnosis, over the years that they may be being treated with these, and we have just heard the evidence that longer therapy is better at targeting the prostate malignancy, that we can get progression in de novo disease developing and we see that epidemiologically with late events.

FDA label for Zoladex

This has been highlighted on the FDA label for Zoladex. This label was updated at the end of 2010 and if you read regarding diabetes and hyperglycaemia there is an increased risk of developing diabetes in men who received GnRH agonists and this label recommends monitoring blood glucose levels and managing according to current clinical practice. Likewise, cardiovascular disease – an increased risk of myocardial infarction, sudden cardiac death and stroke has been reported in association with the use of GnRH agonists and again to monitor this, so it is an active process of monitoring this dynamic risk.

New incident diabetes and CV events in PCa patients with GnRH agonists

Where did this data come from? There are some large registry data from the US database. This is now published almost 10 years ago, just over 73,000 men being treated with GnRH agonists in a subgroup which was approximately a third, 36% of this cohort.

If you look at the prevalence of diabetes across the whole cohort it is 12%, but this increased in the men on the GnRH agonists to 38%. Of course this is a registry so it is not implying direct causation; it could be association, but it is strong evidence that there is a much higher risk of diabetes in these patients and likewise then coronary disease is common in this patient group – 18%, again increasing to a third in the men treated with the GnRH agonists but not in a smaller group, who had had surgical castration.

New incident diabetes and CV events in PCa patients with GnRH agonists

If we then look at the hazard ratios for risks from this dataset, you see the risk of having diabetes if you are on GnRH agonists is increased by 44% and for coronary heart disease increased by 16%, myocardial infarction by 11% and sudden cardiac death by 16%. If you put these together this is a high burden of serious, including life-threatening cardiovascular disease.

The impact of androgen-deprivation therapy (ADT) on the risk of cardiovascular (CV) events in patients with non-metastatic prostate cancer: a population-based study

Another study, published by Gandaglia and colleagues, described 140,000 men, again with non-metastatic prostate cancer over a 14 year window, from the SEER database. Approximately 57% were ADT naïve, whereas 42% or 60,000 of the patients were treated with androgen deprivation therapy and of that 60,000, approximately half had a parallel matched group of the no ADT to allow some propensity scoring studies.

Impact of ADT on CV events in non-metastatic PCa

If we look at this group of men, and this is a huge cohort, what happened to them? At 10 years they had a 4.4% mortality from prostate cancer and they had a 20% mortality from other causes, of which cardiovascular was the main cause. If you are diagnosing men in this type of disease stage, then we know they have a good prognosis on the best therapy you can offer, but we should also be thinking about how to target the main killer for them, providing they survive their prostate cancer. We can see here that 10 year risk, comparing the ADT-naïve with those treated with GnRH agonists, the main comment as a cardiologist is just how common and high the risk is in the whole group and then this impact of increasing their risk with the GnRH agonist therapy. Are there alternatives?

Lower CV risk with GnRH antagonists?

There are some signals coming out that maybe GnRH antagonists do not have the same cardiovascular risk that the GnRH agonists do. There is this study from Albertsen, which pooled six small prospective randomised controlled trials comparing their GnRH agonists and antagonists and did a meta-analysis to look at the impact on cardiovascular risk. This is a retrospective meta-analysis of these trials.

Lower CV risk with GnRH antagonists?

In total there were just over 2,300 men and this analysis reported a 40% relative risk reduction for a cardiovascular event or death in the men treated with degarelix compared with one of the GnRH agonists.

In addition there is pre-clinical data to suggest that degarelix does not induce the weight-gain, adiposity, increased LDL cholesterol and diabetes that GnRH agonists do. There is some mechanistic data to support this thought.

Lower CV risk with GnRH antagonists?

What was interesting in the meta-analysis of the patients is that the baseline cardiovascular risk was relevant, so that if patients did not have any history of cardiac disease, so low-risk patients, then there was no statistical difference in the CV risk profile between having been treated with a GnRH agonist or degarelix, but in the high-risk patients with pre-existing coronary or vascular disease, there was a significant reduction in the risk of a future CV event or death with degarelix. 56%, so when we are hearing about personalised medicine, it is about targeting those with the highest risk and the number needed to treat was 12 to prevent one CV event. I tell you if I had a new drug that was treating cardiac disease with that impact it would fly through licensing.

Prospective RCT planned

I mentioned there hasn’t been the prospective trails evidence yet, but I am pleased to see that there is a new trial called the PRONOUNCE study which is going to directly compare degarelix and GnRH agonists in a randomised controlled trial and the primary endpoint is going to be cardiovascular safety. Eventually we will get the answer to this question and this hypothesis, but what can we do now?

What can we do to improve CV outcomes in prostate cancer patients?

One of the messages is baseline cardiovascular risk assessment is important in patients diagnosed with prostate cancer, not least if it is the first time they have contacted modern medical care and this is an opportunity to get a lot of basic things right. The risk assessment, we need to know have they had a prior event, because they are immediately in the highest risk, if they have had an MI, angina, coronary stenting or bypass surgery for a previous stroke, and then there is a graduation of risk. Of course there is a scale based on age, diabetes, hypertension, smoking status, their cholesterol profile and family history.

This, for primary care physicians, is bread and butter medicine and we have a number of different risk tools that we can use to plug in this data and quantify an individual’s cardiovascular risk. Framingham from the US, a QRisk score that has been very popular, and I will show you a recent, new one called the JBS3 risk score from the UK.

JBS3 cardiovascular risk calculator Case (Scenario A) baseline CV risk

If you have a 10 year CV risk over 20% then you should have your risk factors medically managed; you are in high risk. If it is less than 10% then you are in a low risk and we will always advocate exercise and stopping smoking, but maybe not adding medical therapy. Then of course there is a grey zone of the intermediate risk.

JBS3 cardiovascular risk calculator Case (Scenario A) baseline CV risk

If we go back to our solicitor, at the time of his diagnosis if you opened the JBS3 risk calculator and plugged in his date of birth, gender, his height, weight and body mass index, he is a non-smoker, this was his cholesterol profile and he was on blood pressure treatment, this calculator will then give you a 10 year risk. It also tells you on average what the age he is likely to live to before he has a first major event.

JBS3 cardiovascular risk calculator Case (Scenario A) – Zoladex (6mo)

Initially, when he was treatment naïve for prostate cancer, his 10 year risk was 13%, but after being treated with Zoladex for six months he put on weight, 5kg, his cholesterol rose by 1 mmol and he now had diabetes, which he didn’t before.

JBS3 cardiovascular risk calculator Case (Scenario A) – Zoladex (6mo)

When you change these parameters in this risk calculator, his cardiovascular risk has now gone up to 24%, so transitioned immediately into a high risk where we would advocate treatment.

What can we do to improve CV outcomes in PCa patients?

What is the key and what can we do to improve cardiovascular outcomes in prostate cancer patients?

It is a multidisciplinary team effort and this is why we are combining urology, oncology, cardiology, primary care, nurses, where I think they have a role in helping support and educate these patients and, of course, having these patients at the centre of it to drive their risk factor management.

What can we do to improve CV outcomes in PCa patients? Low and moderate CV risk

If you are seeing patients who have low or moderate cardiovascular risk, the priority would be to highlight them to primary care as you are maybe starting them on androgen deprivation therapies and primary care can then help with smoking cessation, statin therapy for LDL cholesterol if it is elevated. He was on thiazide; they have no cardiovascular benefit, ACE inhibitors do and are very good blood pressure drugs – if you think about the best treatment for the blood pressure, metformin has some survival benefit for managing diabetes and again, exercise to counter these effects. This risk is dynamic; you are starting him on a new therapy and you are hoping that he will, continue on it for many years, so we have to educate primary care that they will need to serially review this risk factor profile; it is not static.

What can we do to improve CV outcomes in PCa patients? High CV risk

If they are high risk, particularly if they have had previous bypass surgery, stenting, myocardial infarction, they have known disease that could become destabilised by your treatments, then referral to cardio-oncology, which are these new dedicated cardiology services for patients having cancer treatments, or your local cardiologist. They can then perform a detailed cardiovascular assessment, really have an aggressive approach to risk factor management, prescribe exercise programmes and I think if an androgen deprivation therapy is indicated, considering a GnRH antagonist on the basis that it potentially has a cardiovascular risk and, again, monitoring that patient serially.

Patient information

In the UK we have partnered with our cancer charity, Macmillan to generate this patient information leaflet; this covers all malignancies, because there are lots of different cardio therapies, so this is available for patients to download.

Primary care education

We have also educated GPs and got the simple toolkit for GPs which you can download and share.

Summary

In summary patients we are seeing now are having high risks of cardiovascular events if they have prostate cancer, partly driven by their baseline risk and also your improved outcomes.

GnRH agonists may be attributing to the increased risk of cardiovascular events and new onset of diabetes – this can be a rapid, early effect in patients with pre-existing disease, but also over time leads to the progression of de novo disease, whereas GnRH antagonists appear to have less cardiovascular toxicity, at least in retrospective analyses and a prospective trial is underway to test this hypothesis of whether they are safer.

We need to all increase awareness among urology, oncology, also amongst cardiology, where this is not clearly recognised, primary care, nurses and the patients, and by optimising cardiovascular health, in guiding the appropriate treatment strategies, hopefully we can all improve outcomes for these patients. Thank you.

[Applause]

Francesco Montorsi: Thank you, Alexander. You gave a brilliant talk. It was very clear, straight to the point and we are taking home a number of excellent messages.