Welcome to this evening’s Treatment Options for Patients with Uncontrolled Hypertension webinar. My name is Dr Trish Kahawita and I will be your host for the evening. Before we get started, I would like to acknowledge the traditional owners of the land from which each of us is joining today. I wish to pay my respect to the elders, past, present and emerging. Just a few housekeeping notes. This webinar is being recorded and you will receive a copy in the upcoming weeks. If you cannot see the control panel on your screen, move your cursor over the bottom of your screen and the panel will appear. The control panel provides you with the audio tools for adjustment and is where you can ask questions via the Q&A module. We have put everyone on mute to ensure learning will not be disrupted by background noise. If you need assistance, please use the Q&A feature to raise your technical issues and to submit your questions throughout the presentation. We will be addressing questions throughout and after the presentation in the dedicated question and answer time. You can upvote questions by selecting the tick icon on the question. This will assist in reducing the amount of same or similar questions being submitted.
Tonight's webinar is proudly supported by Medtronic and our presenter this evening is Prof Markus Schlaich. Prof Schlaich is a renal physician and an ESH accredited hypertension specialist with a strong background in clinical research. Prof Schlaich has a specific interest in treatment modalities targeting the sympathetic nervous system and has contributed to the development of renal denervation as novel therapeutic approaches to hypertension. He is the president of the High Blood Pressure Research Council of Australia and serves on the Council of the International Society of Hypertension and is Co-Chair of the Regional Advisory Group for North Asia, South-East Asia & Oceania. We will now get started and I will hand over the presentation to Markus to commence his presentation. Thanks.
Trish, thank you very much for your kind introduction and welcome everybody. I am Prof Markus Schlaich and it's a great pleasure being here tonight and present on treatment options for patients with uncontrolled hypertension. We've got around an hour and we would certainly encourage people to ask questions via the chat function, so we hope you can get some learnings from this educational module today and hopefully, you will enjoy. So, without further ado, I will get into my presentation on Treatment Options for Patients with Uncontrolled Hypertension. These are my disclosures, and I will give you a minute to go through; actually a bit less than a minute. Here you go.
So, if we talk about elevated blood pressure or hypertension, I'm sure we are all familiar how common elevated blood pressure is. In fact, roughly a third of the adult population worldwide suffers from elevated blood pressure and we will come to the definition of hypertension in a moment. I just thought I'd start with giving you a bit of an idea of the size of the problem and that is perhaps best depicted by looking at it from a global perspective. This is data from the World Health Organisation and it compares the world in 2000 and a decade later, 2010 and you see that the world has become a darker place. So, the darker the red on the map, the higher the prevalence of hypertension and unfortunately, you can see that particularly in Africa, hypertension has significantly increased in prevalence but also in the eastern European countries, Russia and Australia unfortunately is no exception while the increase has not been as dramatic as in other countries, it's still going the wrong way and that means, we will have to work harder to curb the burden of hypertension and try to deal with it as good as we can. Now, this just summarises the true prevalence of hypertension across the globe and the World Health Organisation tends to divide the world into a number of regions, Africa, Americas, Europe, etc., and whether you look at males here in blue or females here in red, you see the prevalence doesn't differ much, even between lower, middle and high-income countries. It used to be that low-income countries have lower prevalence of hypertension, but unfortunately predominantly due to the availability of high-energy foods, fast foods, we have a bit of an epidemic of obesity which often lays the foundation for the development of hypertension, so you see the numbers are confirmed. Around 30% to 40% of the adult population across the globe suffers from hypertension and of course, we will have to deal with all the consequences of this down the track.
Now, very recently, actually just a few weeks ago, there was a very important meta-analysis published by the Blood Pressure Lowering Treatment Trialists’ Collaboration. So, this is a unique group of researchers who have usually access to large studies, global studies, usually randomised controlled trials, and you have probably seen a number of these meta-analysis, but this one is specific because it is on an individual participant level. So, in other words, rather than just having the summary data of individual studies, these researchers have access to individual participant data and therefore, their analysis can be more accurate than what we have seen and the major message from this study is something we have already known but very nicely confirmed that with every 5mmHg reduction in office systolic blood pressure you can achieve roughly a 10% risk reduction in major cardiovascular events. So, just as pneumonic if you keep in mind 5mmHg relates to 10% risk reduction from cardiovascular events and the interesting aspect there is, they looked at patients and participants who had previous cardiovascular disease but also those ones who had no previous history of cardiovascular disease. So, perhaps people with a slightly lower overall risk, yet the effect of blood pressure lowering was essentially superimposable. In other words, blood pressure lowering works under all circumstances in terms of reducing overall cardiovascular risks. So, I think a very important study and it also demonstrated this graphic which again illustrates the almost linear relationship between the blood pressure reduction and the reduction of the hazard threshold for major cardiovascular events.
Here, you see a number of large trials and I'm sure you've heard of some of them sprint, in particular a few years ago but very influential study hided the big study in the elderly and if you look at all these studies, you receive the more the blood pressure reduction between the treatment and the control group there can be active treatment or placebo treatment, the more pronounced usually the risk reduction. So, it is very clear, it's undoubted, blood pressure lowering per se will reduce cardiovascular events, no matter where you start from. So, even if you only reduce your blood pressure from 160 to 155, certainly you haven't reached target but that in itself will already prove beneficial for your patients and I think this is important to keep in mind for all the other things we will discuss during this presentation.
So, that really might preamble to highlight again the problem of hypertension and its magnitude and the substantial impact on cardiovascular risk reduction with blood pressure lowering, so what we want to talk about today is more specifically difficult to control hypertension or resistant hypertension as we sometimes refer to, and I would like to cover briefly the definition of resistant hypertension, what usually characterises these patients, what are contributing factors to the problem, what are relevant mechanisms that play a role. I am a strong believer in physiology. If you understand the underlying physiology or pathophysiology, it's usually much easier to find the right treatment for a problem, so understanding underlying mechanisms is important. I will spend a few minutes on accurate blood pressure measurement. Remember, we base our treatment decisions essentially on the two numbers we get, the systolic and the diastolic, and we have to try to get this right. Otherwise, we start on the wrong foot. We are going to talk about the elephant in the room which is medication adherence and it's shocking to see some of the numbers we are aware of that people although we prescribed medication may not always take the medication as prescribed. We will touch on pharmacological management, what are the best drug combinations to use and we will touch on more recent novel, very exciting developments highlighting that there's alternatives and additional approaches we can use, particularly interventional approaches and renal denervation and then, I will wrap up at the end with a bit of take-home messages.
So, I think that's okay. I hope you enjoy and here we go.
So, how is resistant hypertension defined? The most commonly used definition is depicted here and I highlighted few relevant aspects. It is defined when a therapeutic plan that has included attention to lifestyle measures and we will have to reiterate the importance of lifestyle modification as a cornerstone of management of hypertension and the prescription of at least three antihypertensive drugs including a diuretic and I am going to talk about why a diuretic is important in adequate, ideally maximum doses has failed to lower systolic and diastolic blood pressure to goal. So, not too difficult to remember, three or more drugs including a diuretic, maximum or best tolerated doses blood pressure not at target, that's the definition of resistant hypertension, reasonably straightforward. Now, this is a bit of semantics, but sometimes we may get confused with a number of definitions that are out there and I thought I use this slide which I think helps to kind of put things into context. What you see here is controlled blood pressure, so if we use the Australian guidelines, any blood pressure below 140/90 and we are talking about office blood pressure in this context and uncontrolled, so if the blood pressure remains above target and here, you have the number of blood pressure lowering medications that are being used. So, if your blood pressure is above 140/90 and you are on one or two drugs, you obviously have uncontrolled hypertension. If you have a blood pressure below 140, so you have managed to get them to target, you still have hypertension. That's what it you are treated for, but you have done a great job and you achieved target blood pressure levels, so it's controlled hypertension. Now, resistant hypertension is defined as three or more drugs and blood pressure not controlled as you see here and then, we have kind of an extreme form which we have referred to as refractory hypertension and that is usually defined by patients who are prescribed more than five antihypertensive drugs and blood pressure remains uncontrolled. It's a bit of an academic kind of differentiation but just to get the nomenclature right and understand.
Some propose also that if you need more than three drugs to control blood pressure, it is referred to as controlled resistant hypertension, but that's really semantics. But, I think it helps to put things into prospect. Now, does it make a difference, whether you're on three, four or five antihypertensive drugs. It certainly does. This is data from the large reach registry published a number of years ago, but more recent data has supported the same idea. What is highlighted here is the incidence of cardiovascular events like cardiovascular death, myocardial infarction, strokes and the number of antihypertensive medications these patients are on over a certain period of time and what you see here in black are those who are on less than three medications, red three medications, blue five medications, and green four medications. And, if you look at it, the higher the number of medications these patients are on, the more likely they have cardiovascular events. Now, you could argue while perhaps these patients don't take the medication and you've got a potential good point, but the point here is really that the more drugs you need to even try to get blood pressure controlled, the higher the risk for these patients, so we really have to take this seriously and understand that somebody needs more than three drugs, they are definitely at increased risk for cardiovascular events.
Now, how are these patients usually characterised. What are the contributing factors? And I'll summarise this here with a recent publication in the European Heart Journal. Very commonly and of course there's always exceptions to the rule, it is elderly patients who present with resistant hypertension often above the age of 75 and arterial stiffness tends to play an important role. Obesity is a very important contributing factor. In all the studies we have done the average body mass index is around 32kg/m² are Class 1 obesity. In African-Americans or in black people, in generally, it tends to be more common. We know there are certain differences they don’t tend to respond as well to ACE inhibitors and ARBs, for example and there may be other problems there. High salt intake, or dietary sodium intake rather, another important contributor. Here, at the Royal Perth Hospital in my hypertension clinic, we routinely screen for dietary sodium intake by assessing 24-hour urinary sodium excretion and it is significantly elevated in those patients, _____ around 90-100mmol/day what we see now a patient is often 250-270mmol, so 2 to 3 times higher salt intake than what is recommended. And, of course the longer they had the blood pressure for and the higher the blood pressure is the more likely they present with resistant hypertension. They often have concomitant conditions, particular HMOD, the modern word for target organ damage. This stands for hypertension-mediated organ damage such as left ventricular hypertrophy, chronic kidney disease, microalbuminuria, proteinuria, atherosclerotic vascular disease where the high blood pressure has already caused damage or if the damage is due to another cause, it contributes to raising blood pressure. So, I think this is something you see and can probably confirm from your own experience in your practice.
Now, what are the causes? So, whenever we have to deal with a patient with resistant hypertension, we should definitely think about potential secondary causes. As you may recall, 85% to 90% we estimate of all hypertension is primary or essential hypertension, so we are not able to identify secondary or specific causes, but 10% to 15%, we do. So, it's worthwhile to look for them and the most common ones are primary aldosteronism, elevation of aldosterone secretion usually from the adrenal glands and we have to look for those specifically, atherosclerotic renal vascular disease, renal artery stenosis. So, we should usually do an imaging study of the kidney arteries, a Doppler, a CT or an MRI. Sleep apnoea extremely common. In our experience, around 70% of people who present with resistant hypertension has some form of sleep apnoea and screening for that is important. Chronic kidney disease, mild, moderate or severe also a very common feature of these patients and again, something that can be targeted specifically. You are all aware of other causes, secondary causes, which are not all that common but still worthwhile of course to exclude, but today we don't have the time to go into too much detail, but there are listed here for completeness.
Now, another very important aspect I would like to highlight is whenever you see a patient for the first time, obviously you will ensure to understand what medication these patients are on and we do note that there's a number of medications that interfere with blood pressure control. Some of them raise blood pressure by themselves, some others make it more difficult for the blood pressure lowering drugs to actually work and here are just some of the most common oral contraceptives in obviously premenopausal women always worthwhile to understand what they are taking, sympathomimetic agents, decongestants for example can sometimes increase blood pressure, very commonly, particularly in the elderly, non-steroidal anti-inflammatory drugs. They work great for joint pain and other pain syndromes but are usually not good because they inhibit prostaglandins, they impact on kidney function and can raise blood pressure. We live in the era of transplantation medicine, so certain immunosuppressants such as cyclosporine or steroids are quite frequently used these days and each of those can raise blood pressure via various mechanisms, vasoconstriction, volume retention. So, it's important to understand that they can contribute it. Obviously, the ideal would be to remove those medications, but for example in a patient with kidney transplant you would not be able to stop immunosuppressants obviously, but knowing how they work may help you to target mechanisms that contribute to the rise of blood pressure and thereby make it a bit easier to achieve blood pressure control. In young people, we always have to think about the recreational drugs. Most common cause for emergency department presentation in young people is drug use and they often present with high heart rate, very high blood pressure, amphetamines in particular, so that’s something we will have to keep in mind, also some _____, so really just a general overview but important things to consider and taken into account when you're trying to deal with patients with resistant hypertension.
So, with that I would like to move a bit more into the physiology and I won't take too much of your time, but I think again it's important to understand which major mechanisms are in play because that will dictate which medication, we may be able to use, and which are most potent in lowering blood pressure. I talked already about the risk factors that are usually present such as older age, obesity, diabetes, smoking, high salt intake. What they often cause is alterations of kidney function. These patients tend to be more sensitive to salt, so reducing salt intake works usually very well with these patients. They often have endothelial dysfunction which then ultimately results in vascular remodelling, so structure alterations, vasoconstriction on the one side and volume expansion, volume overload essentially are two major features that often lead to resistant hypertension and obviously, you want to use medications that overcome the arteries and you want to use medications that help to alleviate volume expansion such as, for example diuretics and I remember that diuretic use is part of the definition of resistant hypertension. And let me just give you a quick idea why diuretics particularly in elderly are useful. You may think well my patient doesn't have any crackles on the lung, they don't have much peripheral oedema, why would I use a diuretic? Well, it is clinically often quite difficult to assess volume overload, but a lot of people, particularly those with impaired kidney function and elderly tend to have an element of that and this becomes particularly important _____ we become. What you see here is a very nice start as such where you see the blood pressure in millimetres of mercury graphed against the increase in intravascular volume. Now, if you are young and fresh and your arteries are very elastic, you can have a significant increase in your intravascular volume and the blood pressure will increase but not all that dramatically. So you've got a very steep curve here. With increasing age, with our arteries becoming stiffer, even little changes in intravascular volume will have a dramatic impact on your blood pressure and this is why diuretics tend to work quite well in the elderly because if you reduce fluid even by a bit, it may be quite powerful in bringing blood pressure down, so this is important to understand in order to prescribe the correct medications.
The next point I wanted to make was how to measure blood pressure accurately and this is very close to my heart and you know, imagine if you want to treat diabetes or elevated glucose levels. You rely on two things; this is the fasting glucose and HbA1c and you would expect from your laboratory that they are very accurate with the measurement of those because that will help you to decide whether put them let's say on oral antidiabetic medication. The same applies with blood pressure, but we all know how fluctuating blood pressure can be and that in the nature of it. There's not much we can do. However, we can try to measure blood pressure as accurately as possible, and I don't think we are there yet. This slide highlights all the important aspects that are required to assess blood pressure as accurately as possible and there are also highlights how much the individual aspects can change blood pressure. This is the ideal scenario. Patients sitting relaxed on a chair with armrests, the back supported, the legs on the ground, not crossed, the appropriately sized cuff around the upper arm, the arm supported, ideally nobody else around in the room, you wait five minutes before you take the first reading, you take three meetings and the average of that gives you the best way of measuring clinic blood pressure. You see, here if the feet are not supported or if the legs are crossed, that can make a difference between 2mmHg and 8mmHg and that is quite important. If the bladder hasn't been empty, that can make quite a bit of a difference, if the arm is not supported. So, all of this can add and I know in clinical practice, we are all pushed with time, but it is important to get it right because these numbers will be the ones we base usually our decisions on. I know we don't look at a single one, but if we have a good measure that is very informative.
Obviously, the gold standard in terms of assessing blood pressure is a 24-hour blood pressure monitor and I have very exciting news. You may have seen the recent federal budget and the High Blood Pressure Research Council has put in an application to MSEC to get ambulatory blood pressure monitoring listed and $40.5million have now put into the budget to allow a rebate for ambulatory blood pressure monitoring and that we will be available in November this year. So, usually patients have an out-of-pocket expense of around $8200, but now this will be covered and hopefully allow for more people to have 24-hour blood pressure monitoring and we are extremely pleased that the health minister has _____ to bring this through. Ambulatory blood pressure monitoring just an idea how it looks like, a cuff around the upper arm appropriately sized connected via this tube to a device that inflates the cuff usually every 15 to 30 minutes during daytime and 30 to 60 minutes during nighttime and it kind of automatically measures the blood pressure and what you end up with is a graph like this where you get between 50 and 70 readings, both day and nighttime and you can imagine this is much more accurate than even three measurements at any given time of the day and you can beautifully see the circadian blood pressure pattern with a nice dipping during sleep time as opposed to the day average, arise when people awaken, you can look at averages, you can look at the blood pressure load, so that's certainly enough material for an individual seminar, but I just really want to highlight how important ambulatory blood pressure monitoring can be in terms of finding and confirming elevated blood pressure or hypertension and also in terms of helping to treat these patients appropriately. How does it rank compared to the other modalities? Office blood pressure is what we are doing. Home blood pressure very important, particularly during the COVID pandemic. We have done a lot of patients who have bought their own devices and that seems to work quite well, particularly if you instruct them appropriately to measure the blood pressure and compared to both of those modalities you see 24-hour blood pressure certainly outperforms all of them. Now, obviously we cannot do a 24-hour blood pressure anytime or every time we see those patients. We do that perhaps once or twice but you see that in terms of accuracy, in terms of prognostic value, it is very important then. Please keep an eye open for this to become available.
Now, the other thing I want you to move on and this is a very important part, is the elephant in the room that is the fact, that unfortunately despite our best efforts, patients are not always adherent with prescribed medications. In fact, it is very common that they are not and this is kind of shocking data which demonstrates that usually around six months down the track, the adherence is down to around 50% or so. So, patients don't always tell us the truth and we have learned a lots with the advent of interventional approaches and this is data from a very interesting paper published in 2016 which looked at patients with resistant hypertension, so they were on three or more drugs, but blood pressure was uncontrolled and what they did in these studies, they either took a blood sample or a urine sample and they investigated whether or not they could identify the metabolites from the drugs that were prescribed and in black, you see the proportion of patients in whom no trace of any of those drugs were found in the urine or in plasma. This studied 35% of patients had zero traces in their blood or in their urine and another 30% or so had partial non-adherence indicating they took some of the drugs but not all and that varies a bit between the studies, but it's a big problem and it's really the elephant in the room and we have to verbalise that. We have to discuss it with our patients and ensure that they understand that they have to take the medication obviously. Otherwise, it doesn't work and we do have excellent data to show that poor adherence in indeed associated with worse outcomes. so in terms of all-cause mortality and particularly strokes, if you have good adherence as opposed to intermediate or poor adherence, you increase these patients rather increase their risk for cardiovascular events if they don't take the medication. That is something we will have to discuss with our patients and they need to know about it.
Now, this is of course a multidimensional problem. The therapy-related factors, obviously medication, can have side effects and we have to discuss that with the patient and let them know. There are often patient-related factors. They may not understand what risks they are exposed to with elevated blood pressure and that needs to be properly communicated. They may feel well, "I'm feeling fine. I have no symptoms. Why should I take a tablet?, but also we have to look at ourselves. There is often a bit of a problem with what we refer to as physician _____ that we see elevated blood pressure, but we don’t necessarily act upon it, so it is indeed a number of factors that play into this and again, we could have a separate seminar just on medication adherence but something to keep in mind and always remember patients may say they take the medications but often they don’t. If I have concerns, I usually put them either on a beta-blocker or a statin. Statins are very powerful to lower LDL. If that does not move, they probably have not taken the drugs. Beta-blockers are very powerful in reducing heart rate. If there is no change, it's quite likely they have not taken the medication.
So, that brings us to antihypertensive drug therapy and let me remind you of the few pathophysiological considerations we have taken on and that kind of dictates again the types of medication we usually use, very much in line with the Australian and other guidelines. You know this scheme, A - for inhibitors of the renin angiotensin aldosterone sustained, C -calcium channel blockers, D – diuretics. Three major drug classes, they should be used if needed in combination and why? Because they address three of the major factors that tend to result in increased blood pressure and help us to remove those. Now, if these drugs are not sufficient to lower blood pressure, then you obviously have a patient with resistant hypertension and then, it is worthwhile to look at thoroughly what may be the major driver of the resistance. Is it volume expansion? And you need a good physical examination you can look at whole range of markers. Is it perhaps increased sympathetic drive? Again, quite common in these patients, perhaps a high heart rate as the marker or is it mainly _____ this significant arterial stiffness and if in addition to these three major drug classes, lets say, you fear that there is quite a bit of volume expansion aside from the diuretic you used anyway, spironolactone, a mineralocorticoid receptor antagonist may be a very good choice or loop diuretics in patients with impaired kidney function. If you think that sympathetic activation is a key driver, obviously beta-blockers, alpha blockers or sometimes centrally acting sympathetic agent may be useful and if it is arterial stiffness, alpha blockers tend to be quite well. Obviously, you can combine all of these medications. Sometimes you have to be a bit cautious when we come to that, but this is the way you best approach the problem. So, you use your baseline three antihypertensive drugs. If that's not sufficient, you want to look at these factors, identify which one may be most prominent in these patients because that perhaps gives you the best chance with the fourth drug to target that mechanism and bring blood pressure down hopefully hard to target blood pressure levels.
Now, now why these specific three drugs? Whether there has been an excellent study a few years ago in the so-called PATHWAY-2 study and this study specifically addressed the question aside from the three major drug classes we use, again ACE inhibitors or ARB's plus calcium channel blockers plus diuretics which is perhaps the most potent for flying choice and this is critical in general practice where you see this problem quite frequently and they looked at spironolactone an additional diuretic if you wish, doxazosin and alpha blocker not available here in Australia and bisoprolol, beta-1 selective beta blocker. Very good choice, very good idea. All the patients who participated in that were on each of those drugs for a specific period of time 12 weeks and on placebo, and the major outcome of this study was that indeed spironolactone came out as the winner. So, it is widely accepted now that if you have resistant hypertension, remember that volume overload is very commonly one of the factors that contributes to it, particularly in the elderly and spironolactone outperformed both doxazosin and bisoprolol in terms of the blood pressure lowering efficacy. Certainly, significantly better than placebo, but all those drugs work, but as we said, you want to get the biggest bang for your buck and if you are already on the three antihypertensives, adding spironolactone tends to work best. Having said that, there are some precautions as you know spironolactone can raise potassium level, so we have to be cautious with that and measure potassium and check it once we initiated therapy with spironolactone and you also have to be cautious in patients with impaired kidney function because it can reduce estimated GFR and you want to check for those, but overall, it seems to work quite well.
Now, this is the scheme from the European Society of Hypertension and European Society of Cardiology combined guidelines, the latest guidelines aside from the International Society of Hypertension ones and they promote the use of combinations from the start. We're not quite there yet in Australia but we ought to have some new guidelines soon, but the concept is clear. RAS blocker, ACE inhibitor or angiotensin receptor blocker are not both of them CCB's calcium channel blocker and diuretics; three major drug classes. If that is not sufficient, you add spironolactone or if there are contraindications, an alpha blocker or a beta-blocker. If that doesn't get you where you want, that is perhaps time to think about referring the patient to a specialist to look perhaps again more specifically for secondary causes or quite rare conditions, but up to those four, I think this can very well be done in primary care and you see most of those patients anywhere. So, I think this is a nice reasonably simple and straightforward algorithm and scheme that hopefully helps you to run this in your practice.
Alright, so in the last five or six minutes before we come to questions, I would like to move into other alternative approaches and these are device-based approaches. This was predominantly develop because we know that not all patients want to take medication for the rest of their lives. Some have intolerance to some of the medications and I just highlight the role of the sympathetic nervous system in this slide and why do I do this? Because a lot of these novel interventions target the sympathetic nervous system and what you see here is that virtually every organ in the human body is innervated by these sympathetic nerves and it is specifically those organs that play a crucial role in blood pressure control such as the heart here, the kidneys and the peripheral vasculature that receives a very dense innervation with these sympathetic nerves. So, reducing sympathetic nerve activity by nature seems to be beneficial in terms of lowering blood pressure and reducing cardiovascular events and we do know that if there is for example increased sympathetic outflow to certain organs, so the sympathetic drive is generated in certain brainstem areas. If that is directed towards the kidneys, what do we get? We get sodium retention, vasoconstriction and activation of the renin-angiotensin aldosterone system. So, wouldn’t it make sense to try to inhibit this signalling to avoid these consequences and thereby keeping blood pressure low or not allowing blood pressure to rise. We also see if there is increased outflow to the heart, we usually get an increase in heart rate, stroke volume which raises blood pressure, and if this overactivity sustained over prolonged periods of time, the consequences are often arrhythmia and left ventricular hypertrophy. We are all too familiar with these end organ damage scenarios and obviously, the sympathetic nervous system plays an important role in the arterial tree. These arteries' arterioles are densely innervated and if there is increased sympathetic drive, there is vasoconstriction which again raises blood pressure, so how good would it be if we could inhibit sympathetic nerve activity and there is actually a number of interventional approaches, some more developed, some others not so much. For example, targeting the carotid body which is the chemosensor which sits in the neck between the internal and external carotid artery. We have got of course the baroreceptors and there are devices that you can implant to stimulate the baroreceptors and thereby reducing blood pressure and most advanced of all of these is however renal denervation, so the idea as I highlighted in the previous slide to inhibit that signalling between the brain and the kidneys, thereby targeting those three major mechanisms, vasoconstriction, sodium and water retention and release of renin to hopefully reduce blood pressure. And this concept has been developed actually 12-13 years ago now and had been tried in a number of studies. This is just another summary of the interventional approaches that are available at the moment, baroreflex activation therapy, some stents in certain areas that widen the arteries and reduce kind of the blood pressure by altering the baroreflex sensitivity and some others, but I would like to focus on the last five minutes or so on this so-called renal denervation approaches and the major ones that are available.
So, what does it do? Here is just a schematic of the renal artery, kidneys here on the side and this is the aorta. So, the idea is simply you go into the renal arteries and usually we have a lot of nerves running along the renal arteries, so with a catheter within the artery you can then admit certain type of energy, radiofrequency energy or ultrasound that targets these nerves that lie around the artery and the idea is to achieve a circumferential ablation pattern in order to target as many of these nerves as possible and this is an atomic depiction of what these nerves look like. Here again, the right kidney, here the adrenal gland sitting on top of the kidney, here you see the aorta, certain ganglia where lots of these nerve bodies come together and this is the renal artery here in red and along the renal artery, you see this beautiful network and mesh of sympathetic and sensory nerves and you see most of them travel along the renal artery but some just link and come to the vessels a bit later on, so the idea is to place a catheter in there, apply a certain type of energy to silence the nerves around these arteries and this can be achieved by a number of different approaches. Here you see, again a schematic. The nerves travel along the artery, either with this type of catheter, the so-called spiral catheter for electrodes that attach themselves to the vessel wall thereby achieving a circumferential ablation pattern. You can use ultrasound balloon based, catheter ablation using ultrasound or another way using alcohol injection into the periadventitial space to thereby target those nerves. So, elegant interventional approaches, do they work? Yes, they do. It has now been shown in a number of sham controlled clinical trials, so the best kind of evidence you can get, either placebo or in the device based sham controlled and what you see here is just the number of those studies, spyral hypertension on and off with these types of catheters, radiance hypertension, _____ with an ultrasound catheter does not really matter too much which type of energy source you use, but compared to the sham control, you see significant blood pressure lowering in all the studies that have been done so far and there is a few more to come. This is just how they were run, but I will skip this one. These interventions are safe, has been shown in more than 3000 patients that you usually have a very safe intervention which does not cause damage to the artery or any long-term consequences and this is of course important for an interventional approach.
This is data from a study that was done in patients who were off medication just to prove that it really reduces blood pressure and again, you see here the renal denervation as opposed to the sham control, highly significant blood pressure lowering efficacy in these studies. And an important aspect, if we think about blood pressure control, what we're trying to achieve is blood pressure control across the 24-hour period and this is what you see very nicely here. Once you had renal denervation, this curve separated very nicely, baseline in blue, three months follow-up in yellow and you see during daytime and during nighttime as well significant blood pressure lowering that coined the term renal denervation is always on effect. If you think about medication, if you stop taking your medication, obviously your blood pressure will go up, but when you have renal denervation, the effect is maintained and covers both day and night which is an important aspect of this procedure.
So, this is again just a summary of the more recent one. If you look at office blood pressure or ambulatory blood pressure, very clear-cut blood pressure reductions and you may remember we discussed before that a 5mmHg blood pressure reduction in office blood pressure reduces cardiovascular events by 10% and here you see 10mmHg, 12mmHg, so extremely likely that this will result in improved outcomes for these patients. These are just some meta-analysis looking at all the data that is available with renal denervation and you see, again quite clearly with all the major studies a very clear-cut reduction in blood pressure in these patients depending a bit on the baseline blood pressure, but both with or without concomitant medication both for systolic and diastolic and ambulatory and office blood pressure reading, so a very convincing data available now in this context. You may argue well, is this for everyone? No, it's not and you know, we can treat high blood pressure very effectively with good lifestyle modification. We have excellent drugs and medication, and we should use them as much as we can in the right combinations, but there are patients in whom this does not quite work. Some may not want to take medication, and this is a dataset that looked at preference of patients. So, people with hypertension either on medication or not were asked whether they would consider an interventional approach to bring their blood pressure down as opposed to medication or more medication and you see lot of people are comfortable with using medication, now around 60%, but 40% of those asked whatever blood pressure levels they had, were certainly interested in exploring an interventional approach, so these days we have got the opportunity to offer that to the patients and the key is that we maintain blood pressure reduction over prolonged periods of time and I think we are very fortunate to have renal denervation available as one of the additional tools, so patient preference should come into the equation. We should as physicians of course ensure that we have excluded secondary causes and then, we should sit together and find the best approach that suits our individual patient and provides us with the highest and biggest chance of making a difference reducing their blood pressure in the long term ideally getting to target blood pressure levels and thereby reducing the risk for our patients.
So, with that, I would like to summarise with patients who present with persistent hypertension, good medication history, and physical exam still very important, we have to make sure we measure blood pressure accurately, in the office but also at home and with 24-hour blood pressure monitoring. We have to look at concomitant medication and see whether or not we can reduce some of the medications that may interfere with blood pressure control. We have to exclude secondary causes we want to or engage our patients inadequate lifestyle and that often helps. We want to use the right medication based on pathophysiological principles. We want to be smart about it. We want to not just have a bit of guesswork. We want to have a good idea why we use those drugs and we combine them smartly. Quite easy, the three major drug classes and then some others, in particular, spironolactone, beta-blockers, and alpha blockers usually very useful. If they are not sufficient or if patients have certain preferences, remember we have now availability of interventional approaches and then, there are certain centres who can do that. Discuss with your hypertension specialist and that will hopefully result in improved blood pressure control in all patients, longer-term control and therefore reduction in cardiovascular risk.
With this, I thank you again for your time tonight for joining us and I will leave it to Trish to moderate some of the questions, so thank you very much. I will stop sharing my slides, so we can then move into the discussion.
Thanks very much professor. It was really interesting, informative talk and it is really reassuring that _____ is going to start having an MBS _____ for the ambulatory blood pressure _____. There is a few questions come through and I have a few of my own. With the renal denervation information that you provided. What are the longitudinal studies or is there a concern like, you know, I saw _____ three months, s there anything longer and is there a concern of re-innervation with time?
Excellent question indeed. Yes theoretically, and we have some animal data to show that nerves can regrow, so this is a given. However, these nerves do not tend to regain their functions, so while anatomically you may see the nerves, they are not able to transmit the neural signals and that usually results in prolonged and sustained long-term blood pressure control. We have published data up to 3 years follow-up, but personally we have data with more than 10 year follow-up and in those patients in whom blood pressure was reduced that is usually sustained for prolonged periods of time.
Excellent, and can I ask whereabouts in Australia is this currently being practised because I haven’t heard about it. I was just curious.
Look, there are specific centres. There is a number. In all major cities, there is usually a centre that can do renal denervation. The problem at the moment is it is not reimbursed, so you have to find a way. We usually do it as a part of clinical studies, clinical trials, but with the accumulating data, we hope that this will be available more widely, but it's not quite there yet. However, if our colleagues have patients where they believe that may be an option it's worthwhile to talk to the local hospital's cardiology departments and they usually will be able to guide them.
Fantastic. Now, just with some of the questions. So, lots of questions regarding certain medication and therapy, so _____ has asked any comment on clonidine use in resistant hypertension and it's evidence for the same?
Excellent. _____ that clonidine is a centrally sympatholytic agent and alpha-2 adrenergic receptor agonist that targets certain brain centres and thereby reduces sympathetic outflow, not very commonly used anymore because now you usually have to give it more than once and it has some side effects, dry mouth, tiredness and a rebound phenomenon if you withdraw it, but still powerful, infrequently used in emergency situation. There is probably some better centrally sympatholytic agents like moxonidine which act on a different receptor or rilmenidine only available in Europe, but these still have a very clear role to play. Personally, I use them quite frequently because I see a lot of these patients. So, they are certainly an alternative that are available and the last slide, the summary slide had this drug class called SIRAs, selective imidazoline receptor agonists, so absolutely central sympatholytic agents are still useful and they are available.
Excellent. Someone had a specific question about Conn syndrome, so if we suspect Conn syndrome, do you cease all antihypertensives and switch patient to verapamil and a need for further studies?
Ideally, what is probably worthwhile is to measure aldosterone-renin ratio before you start a medication because _____ is much more common than we thought, but usually the scenario is you have a patient with resistant hypertension. They are already on the right medications and these medications, ACE inhibitors in particular, ARBs, diuretics and beta-blockers. They either interfere with aldosterone or with renin, so if you want to look at the aldosterone-renin ratio, it can be false positive or false negative, so ideally you put them on medication that do not interfere with that and there are four drugs that can be used. One is verapamil as the colleague mentioned. The other one is prazosin, hydralazine and moxonidine. These four drugs do not interfere with the aldosterone-renin ratio, but it is sometimes tricky you need to change them, you have to allow for sufficient time, but if you want to do it properly, that's the way to go.
_____ has also asked, is there a triple pill combination available in Australia?
Absolutely, yes. Good point. Triple pill combinations were very fortunately in Australia. In fact, we have used two triple single pill combinations on the market here in Australia which usually contain all the three major drug classes; an angiotensin receptor blocker, a calcium channel blocker, usually amlodipine and a diuretic, usually hydrochlorothiazide. I use them very frequently because we know adherence is important and the more pills the patient has to take, the less likely they take them all, so single pill combinations are definitely recommended where possible. They are usually actually cost saving as well and it just makes it easier for the patient to take a single pill rather than three individual ones.
Excellent. And Masha asked if it's possible for you to explain about using calcium channel blocker and a beta blocker together?
That's perfectly _____. There is no problem with using a beta blocker and a calcium channel blocker. However, we have to differentiate between the dihydropyridine calcium channel blockers such as amlodipine, nifedipine and the non-dihydropyridine calcium channel blockers such as verapamil and diltiazem. For blood pressure lowering, we usually use amlodipine, nifedipine, etc., so the dihydropyridines and that is no problem, but if you would like to combine, let's say, verapamil with metoprolol, you have to be quite cautious because both drugs would have an impact on the heart rate. They both lower heart rate, so you would not want to use that in patients who have a heart block, for example. So, dihydropyridines, no problem, you can combine calcium channel blocker and a beta blocker, but be cautious with non-dihydropyridine ones, i.e., verapamil and diltiazem, and you will usually recommend not to combine them with beta-blockers.
Excellent. And, I know you talked about the effects of bringing the blood pressure down for these add-in groups. Is there any data on the mortality and morbidity effects based on the groups of certain medications, antihypertensives?
Absolutely, _____ endpoint data from studies to show that blood pressure lowering with those medications prevents cardiovascular events and improves mortality. We don't have that for every single drug class and that is not reflected in the guidelines. However, the Food and Drug Administration in the US accepts blood pressure lowering as a surrogate endpoint, the reason being the data is so overwhelming that if you lower blood pressure extremely likely you prevent strokes, heart attacks, heart failure, chronic kidney disease. So, whatever you can do and if that's lifestyle, that's terrific, when you lower blood pressure you reduce cardiovascular events, so you don't have to show it for every individual drug bringing the blood pressure down and you will get benefit regarding cardiovascular events.
Fantastic. Now, I just have a few more questions. I will combine them together. Some questions from Michael and _____, generally about when do you start looking for secondary causes for hypertension and yeah, so what's your practice?
_____ know, very common it's something hard to look for secondary causes in everyone. You should be suspicious on very young patients. I just saw in the last few weeks quite a number of adolescents, early 20s and in those ones, you always need to look for secondary causes. It is just not normal for them to have elevated blood pressure even if they are overweight or obese. We see that more frequently, but that's certainly the young ones, no doubt. If you have a very rapid onset of high blood pressure, if the blood pressure is very high, if patients have smoking history, for example or have other atherosclerotic vascular disease, not unlikely they may have renal artery stenosis, so look for those ones. If they present with specific symptoms, flushes, sweating, etc., you think about pheochromocytoma. Very simple, just do plasma metanephrines and that gives you a good indication whether that's a possibility. So, those are the ones and of course, as we mentioned in the presentation, if you need more than three drugs and blood pressure is still not controlled, there may well be an underlying secondary cause and that's again worthwhile to screen for secondary forms of hypertension.
Excellent. And then, there are a few questions about ambulatory blood pressure monitoring. So, someone has asked is it better to do it on a weekday or a weekend day, or should we do both?
Again, excellent. We usually recommend to do it on a working day. Patients may of course, they are all that interferes with my whatever they do. Obviously, most people would have probably a desktop and that's not a problem, but if somebody is in the building industry, has to climb a crane, for example, you know that can be a bit dangerous, but what are we trying to do? We want to get a good idea about the circadian blood pressure pattern for most of the patients' week. Obviously, the weekend is only two days. Most people work for five days a week from, let's say 9 to 5 whatever. And you know, the pressure during those times is what our body is most exposed to. So, we would prefer to do it on a working day if feasible and that gives us a good indication of where they are at, but if there is no other way, you can do it on weekends as well, but working days are preferred.
And, can I ask, you mentioned that there is clinician hesitancy to start patients on blood pressure medications. For the young patients that we often see, often they might say they want to try lifestyle, do you think we are doing the patient _____ whilst you practised about when, because you said that longer untreated does result in more risk of resistant hypertension later on, history of the chronic untreated hypertension, so what's is your practice?
So, all _____ find the reasons why a patient's blood pressure may be elevated and that is correct. You know, you should look for those, but if somebody went up the stairs, was late for the appointment and then just sits down and had a bit of a rush or stress, and the blood pressure is elevated, we tend to say, Oh yeah, that's because of that and that may well be the case, so we are not denying that this could be possible, but we should follow up with out-of-office blood pressure monitoring home blood pressure or others and we should not waste much time. If a blood pressure is uncontrolled, we now know very clearly even in high normal range, mild hypertension, if we bring the blood pressure down, 5mmHg, 10% risk reduction. It is worthwhile to do and I do not see a point in waiting too long. Obviously, if you have a low-risk patient with mild hypertension and he is obese or eats a lot of salt, you tell him, well go away, you know, reduce your salt intake, exercise, lose a bit of weight. There is not too much urgency, but then again if six months down the track nothing has changed, I would start an antihypertensive medication.
Just a few more, sorry, Prof. _____ asked what is the best time to take antihypertensive medication, morning or night?
Well, that was an interesting study, a bit of a controversial study that suggested that if you take your pills at nighttime, you have further significant benefit in terms of outcomes. That study is a bit controversial, but I indeed do use night blood pressure dosing, not infrequently, particularly if patients have a non-dipping pattern, so if their blood pressure, usually blood pressure reduces during nighttime, but somebody with sleep apnoea, for example, the blood pressure during nighttime may not be reduced and then, I often try to counteract by giving one of the tablets as a nightly dose, but the general principle is we want these drugs ideally to work. We want long-acting drugs that work for 24 hours and thereby cover the patient and if they take the medication regularly, it should not make much of a difference and you also have to take adherence into account. If a patient takes all the medication in the morning, that's their routine, they are done for the rest of the day. If you have to take it two or three times, at different times, it's more likely they forget or they are busy, so you know, it's a balance between those factors, but single pill combinations are useful, ideally give the drugs at one time of the day but if needed by all means, give as a nightly dose, it tends to work quite well.
And just following from that, _____ has asked do you use prazosin often in an older patient with resistant high blood pressure and if so, what's the starting dose because they're worried about causing too much hypotensive.
I unfortunately had an elderly patient _____ and I started him on prazosin and got a significant blood pressure drop. Had a fall, was not injured but you have to be cautious with prazosin. There is perhaps better alpha blocker, but unfortunately prazosin is the only one available in Australia and usually I start very cautiously 1mg twice daily or even 0.5mg. The 1mg tablets is the lowest dose you can get, but it tends to work well. I have got a number of patients who have tolerated very well but you have to warn the patients that orthostatic symptoms are not uncommon. I warn them to be cautious when they stand up from supine or sitting position, make sure that they sit down again if they felt lightheaded or dizzy, but you can uptitrate it quite nicely in 1mg steps, but it is usually advisable to start with 1mg bd or even 0.5mg twice daily and then slightly go up while maintaining the other medication.
Sorry, Prof. Do you have the time, some questions have been upvoted. Is that okay if I ask them?
Go ahead. That's why we are here.
Excellent. So, with taking the blood pressure, _____ ask which arm is best to use? And with the blood pressure taking as well, _____ has asked, should we always measure blood pressure with palpatory method before, before performing the auscultatory method? what is exactly the cause for auscultatory gap and do the digital blood pressure machines take into consideration this auscultatory gap?
Excellent question. To answer the first, _____ understood that correctly which arm. Usually, we use non-dominant arm, but what you should do, as we religiously do here in our clinic. First time, we see a patient we measure it on both arms. Ideally, we have a device that can measure it simultaneously and we use the arm with the higher reading for future measurements. If you identify a difference more than 15 to 20mmHg, there may be anatomical abnormalities that caused that difference in blood pressure. That may need an ultrasound of the subclavian artery or other imaging for example, so that is relevant. From a practical perspective, the non-dominant arm is usually easier, particularly if they do a home blood pressure because they have to fit the cuff around their arm, and that works better with the dominant hand to actually put the cuff around, but the general guidance is to use it on the arm that gives the higher readings after you have done both. The oscillometric devices are excellent devices in general. Most of them work very well. They are actually quite accurate and the High Blood pressure Research Council had an initiative more than 10 years ago and most general practitioners out there should have one of those machines which you can program and they are very good. They sometimes give you an error if a patient presents with atrial fibrillation and that's exactly, I guess what the question was referring to. These oscillometric devices depend upon a regular sinus rhythm and that allows them to actually measure the mean arterial pressure and then, the systolic and diastolic is calculated. However, if you have atrial fibrillation, you know the cardiac output varies with every beat. You know, it is very irregular. That makes it difficult for those devices and sometimes they are not the most accurate in that context. So, that's a bit of a setback, but in general the validated and there is websites that give you an idea which devices are validated, whether oscillometric, semi-automatic, or automatic devices tend to be very good, very useful. We use them almost exclusively. I do auscultatory method occasionally, but we very much rely on those devices.
Excellent. I am just going to do last two questions. So, Troy has asked what is the role of the CVD risk calculators to guide decision-making for hypertension treatment?
Very important. I am sorry I haven't covered that, but as you know cardiovascular risk assessment is often an important basis for treatment decisions and I completely agree with that approach. The problem often is these cardiovascular risk assessment tools, as you know from the New Zealand Australian cardiovascular risk calculators, they are not supposed to be used in adults below the age of 45 because their young age usually indicates they are at lower risk. If you have already high risk, let's say you had a previously event, you have diabetes, you are above the age of 60 or 65, you are already at high risk, so you do not need the risk calculator, but in general, it's the right thing to do. Assess the cardiovascular risk in your patient, then it gives you an idea where your patients sit and then you may want to reduce the blood glucose, the cholesterol and the blood pressure and the more of those crucial factors you can target and bring to target levels, the more likely you have even further benefit for cardiovascular outcome. So, yes please, take-home message, cardiovascular risk assessment is important and should be done in those relevant patients.
Excellent and _____ has noticed that some nephrologist and cardiologist combine an ACE inhibitor and ARB or exceed the daily recommended dose of either and why is this done? And is seen quite often.
My advice is don’t trust the nephrologist and the cardiologist. I am just kidding. But, I am a nephrologist myself and look in general combining ACE inhibitors and ARBs is essentially a no-no these days. However, particularly in nephrology we know they will start to indicate if this patient has severe proteinuria, for example, ultra-high doses of ACE inhibitors or ARBs can sometimes reduce the proteinuria and this is because, there is a renal and circulatory renin-angiotensin system, but this is really in specialist hands, and it is not advised in general practice. This is in perhaps, you know, rare individual cases or where a patient doesn't tolerate anything but an ACE and ARBs, but essentially the message should be you should not combine ACE inhibitors and ARBs, and leave it to specialists. They would make a case why it may be useful in an individual patient, but in general it should not be used.
Excellent. So, one last question. _____ is wondering in terms of an usual tests for secondary causes of hypertension, what would expect a BP _____ prior to the patient coming to you?
Usually, aldosterone-renin ratio is very useful and what I would advise, if for example a young person comes for the first time and you identify that young person and young is now anywhere between 18 if you talk about adults and let's say 40-45, it is not exceedingly high. You know, 200 and you have to start something by the way. It's worthwhile to do an aldosterone-renin ratio because they're not on any medication and it really shows you the physiological circumstances and you may just see high aldosterone suppressed renin and high aldosterone-renin ratio and then you could more from there. You obviously still treat them, but you've got a baseline. Looking at the renal arteries is an important one as well. So, I would hope to do an ultrasound of the kidneys and a renal artery doppler in lean patients and in obese and experienced _____ you may need a CT or an MRI, but you have to be cautious you need contrast etc., and there are some risks with CTs and MRIs, so you have to be a bit cautious and if there is any history of flushing and palpitations, plasma free metanephrines, simple test. You do not necessarily have to do urine. Free plasma metanephrines are the best choice. You just order it and they have a blood test and that gives you, rules out the major secondary causes or give you an idea that that may be present.
Excellent. Well, I am afraid that's all we have time for this evening and thank you very much everyone for attending, and we hope enjoyed the webinar, and again a fantastic presentation, a big thank you to our presenter, Prof Markus Schlaich for sharing your knowledge and time this evening and _____ for our webinar partners, Medtronic. Thanks all for joining.